pre-formulation, and use of a pre-formulation.

专利摘要:
pre-formulation, and, use of a pre-formulation the present invention relates to compositions forming a low viscosity mixture of: a. at least one glycerol diacil and / or at least one tocopherol; B. at least one phospholipid component comprising phospholipids having i. polar head groups comprising more than 50% phosphatidyl ethanolamine, and ii. two acyl chains each independently having 16 to 20 carbons, where at least one acyl chain has at least one unsaturation in the carbon chain and there are no more than four unsaturations across two carbon chains; ç. at least one biocompatible organic solvent, containing oxygen, of low viscosity; wherein optionally at least one bioactive agent is dissolved or dispersed in the low viscosity mixture; and wherein the preformulation forms, or is capable of forming at least one non-lamellar liquid crystalline phase structure upon contact with an aqueous fluid. the invention further relates to methods of treatment comprising the administration of such compositions and to pre-filled delivery devices and kits containing the formulations.
公开号:BR112014013693A2
申请号:R112014013693-9
申请日:2012-11-28
公开日:2020-06-30
发明作者:Fredrik Tiberg；Markus Johnsson
申请人:Camurus Ab；
IPC主号:

专利说明:

[0001] [0001] The present invention relates to precursors of formulations (pre-formulations) that comprise lipids that upon exposure to water or aqueous media, such as body fluids, undergo spontaneously at least one phase transition, thus forming a matrix of controlled release which, optionally, is bioadhesive. Foundations
[0002] [0002] Many bioactive agents, including pharmaceuticals, nutrients, vitamins, and so on, have a "functional window". This means that there is a range of concentrations through which these agents can be seen to provide some biological effect. Whenever the concentration in the appropriate part of the body (for example, locally or as shown by the serum concentration) falls below a certain level, no beneficial effect can be attributed to the agent. Likewise, there is generally a higher level of concentration, above which no further benefit is derived from increased concentration. In some cases, increasing the concentration above a certain level results in undesirable or even dangerous effects.
[0003] [0003] Some bioactive agents have a long biological half-life and / or a wide functional window and thus can be administered occasionally, maintaining a functional biological concentration over a substantial period of time (for example, 6 hours to several days ). In other cases, the clearance rate is high and / or the functional window is narrow and, therefore, to maintain a biological concentration within this window, regular (or even continuous) doses of a small amount are necessary. This can be particularly difficult when non-oral routes of administration (for example, parenteral administration) are desirable. In addition, in some circumstances, such as when installing implants (for example,
[0004] [0004] Prolonged activity is, moreover, important in situations in which a smoothing property or physical barrier is provided by a formulation. In such circumstances, the biological effect can be provided, for example, by separating a biological tissue from some undesirable agent or environment or by providing a soothing interface between the tissue and its surroundings. When compositions provide such a barrier or interfacial property, whether including a "drug" -like active agent or not, this is an advantage if the composition is sufficiently permanent to allow a reasonable period between administrations.
[0005] [0005] Different methods have been used and proposed for the prolonged release of biologically active agents. Such methods include compositions administered orally slow-release, such as coated tablets, formulations designed for gradual absorption, such as transdermal patches and slow-release implants, such as "sticks" implanted under the skin.
[0006] [0006] A method by which the gradual release of a bioactive agent has been proposed is called "deposit injection". In this method, a bioactive agent is formulated with carriers that provide a gradual release of an active agent over a period of several hours, days, weeks or even months. These are often based on a degradation matrix that gradually degrades and / or disperses in the body to release the active agent.
[0007] [0007] The most common of the established deposit injection methods depends on a polymeric deposit system. This is typically a biodegradable polymer such as poly (lactic acid) (PLA) and / or poly (lactic-co-glycolic acid) (PLGA) and can be in the form of a solution in an organic solvent, a prepolymer mixed with a initiator, encapsulated polymer particles or polymer microspheres. The polymer or polymer particles trap the active agent and are gradually degraded releasing the agent by slow diffusion and / or as the matrix is absorbed. Examples of such systems include those described in US 4938763, US 5480656 and US 611943 and may result in the supply of active agents over a period of up to several months. These systems, however, have a number of limitations, including manufacturing complexity and sterilization difficulties (especially microspheres). Local irritation caused by lactic acid and / or glycolic acid released at the injection site is also an obvious disadvantage. There is also often a very complex procedure for preparing the injection dose of the precursor powder which requires reconstitution of the system prior to administration to a subject, for example, by injection.
[0008] [0008] From a drug distribution point of view, polymer depot compositions also have the disadvantage of accepting only relatively low drug charges and which have a "delay / explosion" release profile. The nature of the polymeric matrix, especially when applied as a solution or prepolymer, causes an initial burst of drug release when the composition is administered for the first time. This is followed by a slow release period, while matrix degradation begins, followed finally by an increase in the release rate for the desired sustained profile. This explosion / delay release profile can cause the in vivo concentration of the active agent to explode above the functional window immediately after administration, then fall back to the bottom of the functional window during the delay period before reaching a sustained functional concentration. Evidently, from a functional and toxicological point of view, this explosion / delay release profile is undesirable and can be dangerous. This can also limit the equilibrium concentration that can be provided, due to the danger of adverse effects at the “peak” point.
[0009] [0009] The state-of-the-art deposit systems were sought for addressing the explosion release problem. In particular, the use of hydrolyzed polylactic acid and the inclusion of block copolymers of polylactic acid - polyethylene glycol have been proposed to obtain the "low explosion" polymeric system described in US 6113943 and US
[00010] [00010] An alternative to the more established polymer based deposit systems is the use of a slow release matrix based on lipids comprising a liquid crystalline phase. Such systems have been proposed, for example, in US 5151272, and WO2005 / 117830. Such compositions have many advantages and are potentially highly effective, but in some situations it may be advantageous to have lipid-based compositions that are even longer lasting, more resistant to chemical agents and / or enzymatic degradation and / or physically more robust than those proposed in the known literature.
[00011] [00011] The formation of non-lamellar phases in certain regions of the amphiphilic (eg lipid) / water, amphiphilic / oil and amphiphilic / oil / water phase diagrams is a well-known phenomenon. Such phases include non-lamellar crystalline phases, such as the cubic P, cubic D, cubic G, cubic micellar and hexagonal phases, which are fluid at the molecular level, but show significant long-range order, and the L3 phase which comprises a multiplicity of bi-continuous networks interconnected from the bilayer sheets that are non-lamellar, but do not have the long-range order of the liquid crystalline phases. Depending on the average curvature of the leaves or amphiphilic layers, these phases can be described as normal (average curvature for the nonpolar region) or inverted (average curvature for the polar region).
[00012] [00012] The knowledge of the spontaneous or preferential curvature of a particular component allows some degree of prediction about which structures will be formed or capable of being formed by that amphiphile in aqueous mixtures. However, particularly when mixtures of amphiphiles are concerned, the exact nature of the phase structure and the physical properties of the composition will largely depend on the specific interaction between the components with each other and / or with the solvent and other components of the mixtures. .
[00013] [00013] The crystalline liquid does not laminar and the L3 phases formed by certain amphiphiles and mixtures thereof are thermodynamically stable systems. That is, they are not simply a metastable state that will separate and / or reform into layers, lamellar phases or the like, but they are the stable thermodynamic form of the lipid / solvent mixture.
[00014] [00014] Previous attempts to develop lipid deposit formulations, such as in US 5151272 and Us 5807573, which use liquid crystal phases can, in some cases, be effective in terms of distribution, but their performance was less than ideal for other critical properties. In particular, the liquid cubic crystalline phases are relatively viscous in nature. This makes application with a standard syringe difficult, and possibly painful for the patient, and makes filtration sterilization impossible because the composition cannot be passed through the necessary thin pored membrane.
[00015] [00015] WO2005 / 117830, for example, provides an improved system that has a low viscosity, in order to improve the ease of manufacture, handling and administration with a standard syringe, allow sterile filtration and reduce injection pain for the patient. However, for long-term deposit formulations and / or for formulations having protective or softening properties (such as surface coating formulations for use, for example, in oral applications), a fundamental property is related to the robustness of the gel formed by the preformulation, in the presence of, for example, aqueous body fluids in relation to chemical and / or mechanical degradation, for example, erosion, dissolution / fragmentation / dissolution by endogenous active surface agents (surfactants), enzymes of lipid degradation and / or physical breakdown.
[00016] [00016] The present inventors have now established that the provision of a preformulation comprising particular amphiphilic components, in a biologically tolerable solvent and, optionally, at least one bioactive agent, especially in a low viscosity phase, as a molecular solution, provides a preformulation with much improved mechanical and / or chemical / enzymatic robustness. In addition, preformulation maintains | many or all of the advantages of previous lipid deposit systems, that is, it is easy to manufacture, it can be filtered with sterilized, it has a low viscosity (allowing easy and less painful administration), it allows a high level of bioactive agent to be incorporated (thus allowing a small amount of the composition to be used) and / 00o forms a desired non-lamellar deposit composition in vivo having an "explosion" or "non-explosion" release profile. The advantages in terms of the protective nature and / or smoothness of the compositions can also be maintained. The compositions are also formed from materials that are non-toxic, biotolerable and biodegradable.
[00017] [00017] Due to its improved resistance to degradation by erosion and / or fragmentation by physical and / or chemical means, the preformulation is especially suitable for the formation of deposit compositions after parenteral administration for long-term drug distribution , for example, several days to several months after parenteral administration. The compositions are also advantageous for non-parenteral (e.g., local or topical) administration to the body cavities and / or body surfaces or elsewhere.
[00018] [00018] In particular, the compositions of the present invention are more resistant to chemical / biological degradation and their mechanical resistance is improved compared to existing lipid deposit systems, while maintaining the ability to spontaneously self-organize in situ When tested in fragmentation / degradation systems that cause turbidity after the deposit break, the turbidity factor of the present formulations has been shown to be a factor ten lower than for previous lipids based on liquid crystal formation systems. This makes the compositions of the invention particularly effective in terms of release longevity. They are also suitable for application in areas with high erosion / degradation problems, for example, for oral application, or applications in the lower GI tract.
[00019] [00019] A slow-release, lipid-based composition is described in WO2006 / 131730 for GLP-1 and analogues thereof using mixtures of lipids comprising phosphatidylcholine. This is a highly effective formulation, but the concentration of active agent that can be included in the formulation is limited by its solubility. Evidently, a higher concentration of the active agent, together with the improvement of the mechanical and / or chemical / enzymatic robustness allows the possibility of an even longer duration of the deposit products, products that maintain a higher systemic concentration, and products that present a volume injection, which are factors of considerable advantage in appropriate circumstances. It would therefore be of considerable value to establish a path by which the highest concentrations of active agents can be included in a lipid-based deposit formulation.
[00020] [00020] The present inventors have now established that by incorporating at least one polar solvent, a preformulation can be generated by correcting many of the deficiencies of known deposit formulations, and which can be applied to provide an improved controlled release of active agent. of peptide. With the use of specific components for carefully selected reasons and, in particular, with a mixture of an alcohol and a polar solvent, the robust deposit formulation can be generated having a combination of properties that exceed the performance of even known controlled release compositions . Summary of the Invention
[00021] [00021] Seen from a first aspect, the invention thus provides a preformulation comprising a low viscosity, non-liquid crystalline mixture of: a. at least one glycerol diacil and / or at least one tocopherol; B. at least one phospholipid component comprising phospholipids having i. polar head groups comprising more than 50% phosphatidyl ethanolamine, and ii. two acyl chains each having, independently, 16 to 20 carbon atoms, where at least one acyl chain has at least one carbon chain unsaturation, and there are no more than four unsaturations across two carbon chains; ç. at least one biocompatible organic solvent, containing oxygen, of low viscosity; wherein optionally at least one bioactive agent is dissolved or dispersed in the low viscosity mixture; and wherein the preformulation forms, or is capable of forming at least one non-lamellar phase structure (e.g., non-lamellar liquid crystalline) upon contact with an aqueous fluid.
[00022] [00022] Generally, aqueous fluid is a body fluid, such as fluid from a mucosal surface, tears, sweat, saliva, gastrointestinal fluid, extravascular fluid, extracellular fluid, interstitial fluid or plasma, and the preformulation will form a structure liquid crystalline phase when placed in contact with a surface, area or cavity of the body, (for example, in vivo) through contact with the aqueous body fluid. The preformulation of the invention can optionally contain a certain amount of water before administration, but this is not sufficient to lead to the formation of the necessary liquid crystalline phase.
[00023] [00023] Thus, in a modality applicable to all aspects of the invention, the preformulation further comprises: d. up to 20% by weight of at least one polar solvent, by weight of the components a) + b) + c) + d), preferably, wherein said polar solvent, has a dielectric constant of at least 28 measured at 25ºC, from more preferably at least 30 measured at 25ºC.
[00024] [00024] In a second aspect, the invention provides a method of delivering a bioactive agent to a human or non-human (preferably mammalian) animal body, this method comprising administering a preformulation comprising a non-liquid crystalline mixture , low viscosity of: a. at least one glycerol diacil and / or at least one tocopherol; B. at least one phospholipid component comprising phospholipids having i. polar head groups that comprise more than 50% phosphatidyl ethanolamine, and
[00025] [00025] The method of administration suitable for the method of the above invention will be an appropriate method for the condition to be treated and the bioactive agent used. A parenteral deposit will thus be formed by parenteral administration (for example, subcutaneous or intramuscular), while a bioadhesive non-parenteral deposit (for example, topical) composition can be formed by administering to the surface of the skin, mucous membranes and / or nails, for ophthalmic, nasal, oral or internal surfaces or for cavities, such as oral, nasal, rectal, vaginal or buccal cavities, the periodontal pocket or cavities formed after the extraction of an implanted or natural structure, or before the insertion of an implant (for example, a joint, stent, cosmetic implant, tooth, tooth filler or other implant).
[00026] [00026] Seen from another aspect, the invention provides a method for the preparation of the liquid crystalline composition which comprises exposing a preformulation comprising a non-liquid, non-liquid, low viscosity mixture of: a. at least one glycerol diacil and / or at least one tocopherol; B. at least one phospholipid component comprising phospholipids having
[00027] [00027] The liquid crystalline composition formed in this method can be bioadhesive, as described herein. Another aspect of the invention, therefore, resides in the generation of a bioadhesive formulation by administering any of the formulation precursors (pre-formulations) indicated here for a body surface, like any of those body surfaces indicated here. The increased strength of the composition of the invention makes it particularly suitable for the administration of active agents over an extended period. In addition, the composition demonstrates better resistance to erosion, which further increases the duration of administration, for example, injections once a month or once every three months (once every three months). In particular, because the formulations of the present invention have more unusual and surprising resistance to degradation by the digestive system, such as bile acids, a more highly advantageous application of the present pre-formulations is in oral administration, in which other deposit-type systems are inadequate. Parenteral and oral administration methods are thus more preferred for this composition.
[00028] [00028] Seen from yet another aspect, the invention provides a process for the formation of a preformulation suitable for the administration of a bioactive agent to a subject (preferably mammal), said process comprising the formation of a non-liquid crystalline mixture low viscosity of: a. at least one glycerol diacil and / or at least one tocopherol; B. at least one phospholipid component comprising phospholipids having i. polar head groups comprising more than 50% phosphatidyl ethanolamine, and ii. two acyl chains each independently having 16 carbon atoms, where at least one acyl chain has at least one unsaturation in the carbon chain, and there are no more than four unsaturations across two carbon chains; ç. at least one biocompatible organic solvent, containing oxygen, of low viscosity; and dissolving or dispersing at least one bioactive agent in the low viscosity mixture, or in at least one of the components a, b or c, before the formation of the low viscosity mixture.
[00029] [00029] The methods for forming preformulations of the present invention (with or without bioactive agents) will preferably comprise the mixture of components a), b) and c), as these components are described herein. Such a mixing method may, one way, comprise mixing components a) and b) prior to the addition of component c). Alternatively or additionally, the mixture of components a), b) and c) may comprise heating a mixture of these components to a temperature above 24ºC (for example, 25 to 50ºC) for a suitable period (for example, by 1 to 24 hours). This method will preferably occur under conditions such that a clear, homogeneous mixture of a single phase is generated.
[00030] [00030] Seen from another aspect, the invention also provides the use of a non-liquid, low viscosity crystalline mixture of: a. at least one glycerol diacil and / or at least one tocopherol;
[00031] [00031] This use can be for the manufacture of a medicine for use in the treatment, prevention and / or palliation of any condition indicated here.
[00032] [00032] In yet another aspect, the invention provides a method of treatment or prophylaxis for a human or non-human (preferably mammal) animal subject which comprises administering a preformulation according to the first aspect of the invention.
[00033] [00033] In a corresponding aspect, the present invention provides a preformulation as described in any embodiment here for use in therapy, as for use in any of the therapies described herein. Thus, preforms can be used in the treatment, prevention and / or palliation of any condition indicated here.
[00034] [00034] The pre-formulations of the present invention are highly advantageous in that they are stable to prolonged storage in their final "ready to use" form. As a result, they can easily be provided for administration or by healthcare professionals or by patients or their caregivers, who do not need to be fully trained healthcare professionals and may not have the experience or skills to make preparations following the instructions / schedules. complex reconstitution.
[00035] [00035] In yet another aspect, the present invention provides a disposable delivery device (which must also include a component of the device) preloaded with one or more than a metered dose of a preformulation of the present invention. Such a device will, in one embodiment, typically contain a single dose ready for administration and will generally be packaged sterile so that the composition is stored within the device until administration. Such an embodiment is particularly suitable for the deposit aspects of the invention and is very suitable for parenteral deposit aspects. Suitable devices include cartridges, ampoules and, in particular, syringes and syringe barrels, either with integral needles or with standard accessories (eg, luer) adapted to fit a suitable disposable needle. In an alternative embodiment, the device can contain a plurality of doses or administrations (for example, 2 to 100 doses or administrations) of the preformulation. Such an embodiment is particularly suitable for aspects of the present invention, in which no bioactive agent is present and / or for aspects of the present invention, in which non-parenteral (e.g., topical) formulations (especially bioadhesive formulations) are generated.
[00036] [00036] In a further aspect, the present invention thus provides a disposable delivery device pre-loaded with at least a metered dose of a preformulation comprising a low viscosity mixture:
[00037] [00037] The pre-filled devices of the invention can also be suitably included in an administration kit, the kit of which also constitutes an additional aspect of the invention. In yet another aspect, the invention thus provides a kit for the administration of at least one bioactive agent, said kit containing a measured dose of a preformulation of the invention and optionally an administration device or component thereof. Preferably, the dose will be kept within the device or component, which will be suitable for im administration or, preferably, s.c. Kits can include additional administration components, such as needles, cotton swabs, etc. and, optionally and preferably, they will contain instructions for administration. Such instructions will typically refer to route administration, as described herein and / or for the treatment of a disease indicated here above.
[00038] [00038] In yet another aspect, the invention thus provides
[00039] [00039] In one embodiment, applicable to all aspects of the invention, the active agent, when present, excludes somatostatin receptor agonists, in other words, the active agent does not comprise any somatostatin receptor agonist.
[00040] [00040] In an additional modality, the active agent, when present, can exclude certain agonists of specific somatostatin receptors, namely pasireotide, octreotide and / or salts and mixtures thereof. In this embodiment, the agent can comprise agonists of somatostatin receptors, with the exception of pasireotide, octreotide and / or salts and mixtures thereof. Detailed Description
[00041] [00041] As used here, the term "low viscosity mixture" is used to indicate a mixture that can be easily administered to a subject and, in particular, easily administered through a standard syringe and needle arrangement. This can be indicated, for example, by the ability to be dispensed from a 1 ml disposable syringe through a 22 awg needle (or a 23 gauge) by manual pressure. In a particularly preferred embodiment, the low viscosity mixture should be a mixture capable of passing through a standard sterile filtration membrane, such as a 0.22 µm syringe filter. In other preferred embodiments, a similar functional definition of a suitable viscosity can be defined as the viscosity of a preformulation that can be sprayed using a compression pump or pressurized spray device using conventional spray equipment. A typical range of suitable viscosities would be, for example, 0.1 to 5000 mPas. The viscosity is preferably 1 to 1000 mPas, more preferably 1 to 800 mPas, such as 50 to 750 mPas, and more preferably, 50 to 500 mPas at 20 ° C.
[00042] [00042] It has been observed that with the addition of small amounts of low viscosity solvent, as indicated here, a very significant change in viscosity can be provided. For example, adding just 5% solvent can reduce viscosity 100 times and adding 10% can reduce viscosity up to 10,000 times. In order to achieve this synergistic, non-linear effect in reducing viscosity it is important that a solvent of appropriately low viscosity and adequate polarity is employed. Such solvents include those described below.
[00043] [00043] The solvents used in the preformulation of the invention must be biocompatible. In particular, it is preferred that the solvents used are non-halogenated, in particular, non-chlorinated solvents. Preferably, halogenated solvents, especially chlorinated solvents, are excluded from the preformulation of the invention. Thus, in one embodiment, the pre-formulations of all aspects of the invention do not contain any significant amount of halogenated solvent. Thus, for example, the amount of halogenated solvent can be less than 1% by weight (for example, 0 to 1% by weight) of the total weight of the preformulation. This will preferably be less than 0.5%, more preferably less than 0.1% and more preferably less than 0.01% by weight.
[00044] [00044] When percentages or ratios are specified here, these will be by weight, unless otherwise specified or the context requires otherwise. Generally, percentages will be relative to a specified set of components, as% of the total weight of components a), b) and c). However, when no other basis is specified, the percentages will be by weight of the total precursor formulation (pre-formulation).
[00045] [00045] Particularly preferred examples of low viscosity mixtures are molecular solutions and / or isotropic phases such as L, and / or L3 phases. As described above, L; it is a non-lamellar phase of interconnected sheets that has some phase structure, but does not have the long-range order of a liquid crystalline phase. Unlike liquid crystalline phases, which are generally very viscous, L phases; are low viscosity. Obviously, phase L mixtures; and the molecular solution and / or L3 phase particles; suspended in a molecular solution of volume of one or more components are also suitable. The L phase is the so-called “inverted micellar” or microemulsion phase. The most preferred low viscosity mixtures are molecular solutions, L; 3 phases and mixtures thereof. L-phases are less preferred, except in the case of swollen L-phases, as described below.
[00046] [00046] The present invention provides a preformulation comprising components a, b, c and, optionally, at least one bioactive agent, as indicated herein. One of the important advantages of the pre-formulations of the invention is that components a and b can be formulated in a wide range of proportions. In particular, it is possible to prepare and use the pre-formulations of the present invention which have a much higher proportion of component b) from phospholipid to diacyl glycerol and / or tocopherol, without risking phase separation and / or unacceptably high viscosities in the pre-formulation. The weight ratios of components a: b can thus be 80:20 to 5:95. Preferred ratios will generally be 80:20 to 20:80, for example, 70:30 to 30:70. Preferably, the ratios are in the range of 40:60 to 60:40. More preferably, the ratios are in the range of 45:55 to 55:45, for example, 48:52 to 52:48, especially around 50:50.
[00047] [00047] In a preferred embodiment of the invention, there is a greater proportion of component b than component a. That is, the weight ratio of a: b is less than 50:50, for example, 50:50 to 5:95, preferably 48:52 to 20:80 and more preferably 45:55 to 30:70 .
[00048] [00048] The amount of component c in the pre-formulations of the invention will be at least sufficient to provide a low viscosity mixture (e.g., a molecular solution, see above) of components a, b and b will be easily determined for any particular combination of components by conventional methods. The phase behavior itself can be analyzed using techniques such as visual observation in combination with polarized light microscopy, nuclear magnetic resonance, X-ray diffraction and cryotransmission electron microscopy (cryo-TEM) to look for solutions, L phases, or L3, or liquid crystalline phases. Viscosity can be measured directly by standard means. As described above, an appropriate practical viscosity is one that can be effectively injected and particularly filtered sterile. This will be easily appreciated as indicated here. The maximum amount of component ca to be included will depend on the exact application of the preformulation, but in general, the desired properties will be provided by any amount that forms a low viscosity mixture (for example, a molecular solution, see above) and / or a solution with a sufficiently low viscosity. Since administration of unnecessarily large amounts of solvent to a subject is generally undesirable, the amount of component c will typically be limited to no more than ten times (for example, three times) the minimum amount required to form a mixture of low viscosity, preferably not more than five times and more preferably not more than twice this value. The composition of the present invention can, however, contain a greater amount of solvent than would be acceptable in an immediate dosage composition. This is because the process by which the active agents are released slowly (for example, formation of liquid crystalline phase shells as described herein) also serves to delay the passage of the solvent from the composition. As a result, the solvent is released over a period of time (for example, minutes or hours), rather than instantly, so it can be better tolerated by the body.
[00049] [00049] As a general guide, the weight of component c will typically be about 2 to 40% of the total weight of components a), b) and c), or the total weight of components a), b), c) and d) when component d) is present. This proportion is preferably (especially for injectable deposits) 4 to 30%, for example, 5 to 25% by weight. Most preferably, component c) is in the range of 7 to 20%, for example, 9 to 18% by weight. For non-parenteral deposits (for example, orally) component c) is preferably in the range of 2 to 30%, for example, 2 to 20%. Most preferably, component c) is in the range of 2 to 10% by weight.
[00050] [00050] In a modality applicable to all aspects of the invention, the preformulation additionally comprises component d)
[00051] [00051] When present, it is preferred that said polar solvent has a dielectric constant of at least 28 measured at 25 ° C, more preferably, at least 30 measured at 25 ° C. Preferred polar solvents include water, propylene glycol (PG) and N-methyl-2-pyrrolidone.
[00052] [00052] In an alternative embodiment, the compositions can exclude a polar solvent (that is, they can exclude all solvents with a dielectric constant above 30 to 20ºC) with the optional exception of NMP. Component a) - Diacil Glicerol / Tocopherol
[00053] [00053] Component "a", as indicated herein, is a neutral lipid component comprising a polar "head" group and also non-polar "tail" groups. Generally, the head and tail portions of the lipid will be joined by a fraction of ester, but this fixation can be done by means of an ether, an amide, a carbon-carbon bond or other fixation. Specifically in the preformulation of the invention, a component is a glycerol diacyl and has two non-polar "tail" groups.
[00054] [00054] Mono-acyl ("smooth") lipids are generally less well tolerated in vivo and, when present, will form a smaller part of component a) (for example, less than 10%). Preferably, for parenteral compositions, it will be less than 10% of mono-acyl lipids present as a proportion of component a). For non-parenteral compositions (for example, orally) it will preferably be less than 20% of mono-acyl lipids present as a proportion of component a). Examples of mono-acyl lipids include glycerol mono-oleate (GMO).
[00055] [00055] The two non-polar groups can have the same number or a different number of carbon atoms and can each independently be saturated or unsaturated. Examples of non-polar groups include the C1-6 alkyl and alkenyl groups, which are typically present as esters of long-chain carboxylic acids. These are often described by reference to the number of carbon atoms and the number of unsaturations in the carbon chain. Thus, CX: Z indicates a hydrocarbon chain having X carbon atoms and Z unsaturations. Examples include particularly palmitoyl (C16: 0), phtanoyl (C16: 0) palmitoleoil (Cl6: 1), stearoyl (C18: 0) groups oleoyl (CI8: 1), elaidoyl (C1I8: 1), linoleoyl (C18: 2), linolenoyl (C18: 3) and araquidonoil (C20: 4). Thus, typical non-polar chains are based on fatty acids from the lipids of natural esters, including palmitic, phyanic, palmitic, stearic, oleic, elaidic, linoleic, linolenic or arachidonic acids, or corresponding alcohols. Preferred non-polar chains are C16-Cx groups (for example, C16 to Ci8), especially Cr groups. This is more preferable if the non-polar tail groups of component a) essentially consist of unsaturated CI18 groups. Especially preferred are groups C18: 1 and C18: 2 (and mixtures thereof), for example, oleyl (C1I8: 1) and / or linoleyl (C18: 2) groups. Thus, dioleyl, dilinoleyl and / or oleyl / linoleyl diacyl glycerols and all mixtures thereof are highly suitable.
[00056] [00056] The glycerol diacil, when used as all or part of the “a” component, can be synthetic or can be derived from chemically modified and / or purified natural sources, such as vegetable oils. Mixtures of any number of diacyl glycerols can be used as a component. Most preferably, this component will include at least a portion of glycerol dioleate (GDO). A highly preferred example is the DAG which comprises at least 50%, preferably,
[00057] [00057] A highly preferred alternative or additional class of compounds for use as all or part of component a), are tocopherols. As used here, the term "a tocopherol" is used to indicate non-ionic lipid tocopherol, often known as vitamin E, and / or any suitable salts and / or analogs thereof. Suitable analogs will be those that provide the phase behavior, without toxicity, and phase change upon exposure to aqueous fluids, which characterize the compositions of the present invention. Such analogs will generally not form liquid crystalline phase structures as a pure compound in water. The most preferred of the tocopherols is the tocopherol itself, having the structure below. Of course, in particular, when it is purified from a natural source, there may be a small proportion of non-tocopherol “contaminant”, but this is not sufficient to alter the beneficial phase behavior or lack of toxicity. Typically, a tocopherol will not contain more than 10% non-tocopherol analog compounds, preferably not more than 5% and most preferably not more than 2% by weight. |
[00058] [00058] In another advantageous embodiment of the invention, component a) comprises at least 50%, preferably at least 70% and more preferably, consists essentially of tocopherols, in particular tocopherol as shown above.
[00059] [00059] A preferred combination of constituents for component a) is a mixture of at least one DAG with at least one tocopherol. Preferably, the DAG will have non-polar C1-6 alkyl or alkenyl tail groups, for example, oleyl, dioleyl and / or linoleyl groups. Such mixtures include 2:98 to 98: 2 by weight of tocopherol: GDO, for example, 10:90 to 90:10 of tocopherol: GDO and especially 20:80 to 80:20 of these compounds. Similar mixtures of tocopherol with other DAGs are also suitable.
[00060] [00060] Component a) can be present in the range of 20 to 80% by weight of the total weight of components a), b) and c), or the total weight of components a), b), c) and d) when the component d) is present. Preferably, component a) will independently be present in the range of 25 to 65% by weight, for example, 30 to 55% by weight. Most preferably, component a) will be present in the range of 35 to 45% by weight. Component b) - Phospholipid component
[00061] [00061] Component "b" in the present invention is at least one phospholipid component comprising phospholipids having i. polar head groups comprising more than 50% phosphatidyl ethanolamine, and ii. two acyl chains each having independently 16 to 20 carbon atoms, where at least one acyl chain has at least one carbon chain unsaturation, and there are no more than four unsaturations across two carbon chains.
[00062] [00062] As with component a), this component comprises a polar head group and at least one non-polar tail group. The difference between components a) and b) is found mainly in the polar group. The non-polar portions can thus be properly derived from the corresponding fatty acids or alcohols considered above for component a). The phospholipid component b) comprises phospholipids containing two acyl groups which may be the same or different.
[00063] [00063] Preferred polar "head" groups of phospholipids include phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SM), phosphatidylinositol (PI) and comprise at least 50% PE. The most preferred polar group is therefore phosphatidylethanolamine (PE). The phospholipid component b) comprises at least one phospholipid having polar head groups comprising more than 50% PE, preferably at least 75% PE, for example, at least 80% PE or at least 90% PE. Preferably, phospholipid component b) comprises at least one phospholipid with polar head groups consisting essentially of 100% phosphatidyl ethanolamine (for example, more than 90% PE or more than 95% PE).
[00064] [00064] In an embodiment applicable to all aspects of the invention, component b) further comprises at least one phospholipid having i. polar head groups comprising more than 90% phosphatidyl choline, and ii. two acyl chains each independently having 16 carbon atoms, where at least one acyl chain has at least one carbon chain unsaturation, and there are no more than four unsaturations across two carbon chains.
[00065] [00065] Preferably, phospholipid component b) will comprise phospholipids selected from phosphatidyl ethanolamines and mixtures of phosphatidyl ethanolamines with at least one phospholipid selected from, phosphatidyl choline, phosphatidyl inositols, and sphingomyelins. It is preferred that the phospholipid component b) comprises at least 50% PE, for example, more than 50% PE, preferably at least 70% PE and more preferably at least 80% PE. Component b) can consist essentially of 100% PE (for example,> 95% PE).
[00066] [00066] A typical phospholipid component b) can comprise PE and PC in a ratio ranging from 51:49 to 90:10, for example from 70:30 to 80:20.
[00067] [00067] Preferably, component b) comprises a maximum of 25% phosphatidylcholine (PC), for example, 20% PC, or in the range of 0 to 10% PC. Preferably, component b) comprises a maximum of 25% phosphatidylinositol (PI), for example O to 10% PI. Preferably, component b) comprises a maximum of 25% sphingomyelin, for example, 0 to 10% sphingomyelin. Most preferably, component b) comprises a maximum of 25% of the combined contributions of PC, PI and / or sphingomyelin, for example 0 to 10%.
[00068] [00068] More preferably, phospholipid component b) comprises dioleoyl phosphatidyl ethanolamine (DOPE), Soy PE and / or Egg PE, or mixtures of at least one of DOPE / soy PE / PE with at least one dioleyl phosphatidyl choline (DOPC), Soy PC (SPC), and / or Egg PC (EPC).
[00069] [00069] The phospholipid portion can be derived from a natural source. Suitable sources of phospholipids include egg, heart (eg, beef), brain, liver (eg, beef), milk, and plant sources, including soy. Particularly preferred are the soy and egg phospholipids, especially Soy PE and Egg PE. Such sources may provide one or more compounds of component b), which may include any phospholipid mixture. Preferably, component b) comprises Soy PE and / or Egg PE.
[00070] [00070] Phospholipid component b) (as a whole) forms, preferably, an inverted hexagonal liquid crystalline phase at 37 ° C, in the presence of excess aqueous phase, for example, excess water.
[00071] [00071] In a preferred modality, component Db) comprises DOPE and DOPC and / or Soy PC and / or Egg PC,
[00072] [00072] Since the pre-formulations of the invention must be administered to a subject for the controlled release of an active agent, it is preferred that components a and b are biocompatible. In this regard, it is preferable to use, for example, diacyl glycerol compounds and phospholipids instead of mono-acyl (smooth) compounds. A notable exception to this is tocopherol, as described above. Although it has only one alkyl chain, it is not a "smooth" lipid, in the sense of the convention. The nature of tocopherol as a well-tolerated essential vitamin makes it highly biocompatible.
[00073] [00073] Furthermore, it is more preferred that the lipids and phospholipids of components a and b are naturally occurring (whether they are derived from a natural source or are of synthetic origin). Naturally occurring lipids tend to be tolerable both systemically and locally with lesser amounts of inflammation and reaction in the subject's body. This is not only more comfortable for the subject, but can increase the residence time of the resulting deposit composition, especially for parenteral deposits, since less immune system activity is recruited to the site of administration. In certain cases, however, it may be desirable to include a portion of a non-naturally occurring lipid in components a and / or b. This can be, for example, a "lipid ether", in which the head and tail groups are joined by an ether bond, instead of an ester. Such non-naturally occurring lipids can be used, for example, to change the rate of degradation of the resulting deposit composition by having a greater or lesser solubility or vulnerability to degradation mechanisms present at the active agent release site. Although all proportions are within the scope of the present invention, in general, at least 50% of each of components a and b will be naturally occurring lipids. This will preferably be at least 75% and can be up to substantially 100%. Particularly preferred are lipids derived from soy and / or egg.
[00074] [00074] Two - particularly preferred combinations of components a and b are GDO with DOPE, and tocopherol with DOPE, especially in the region of 20-80% by weight of GDO / tocopherol, 20-80% by weight of DOPE and 2-40% by weight. solvent weight (especially ethanol and NMP or mixtures thereof). Most preferred is the combination of 35-65% by weight of component a), 35-65% by weight of component b), and 2-30% by weight of component c), of the total weight of components a), b) and c), (ed), when present). In one embodiment, solvent component c) does not comprise PG or other polar solvents present in optional component d). This is especially true when the optional polar solvent component d) is present.
[00075] [00075] In addition to amphiphilic components a and b, pre-formulations of the invention may also contain additional amphiphilic components at relatively low levels. In one embodiment of the invention, the preformulation contains up to 10%, preferably up to 7% (by weight of components a) and b)) of a charged amphiphile, in particular, an anionic amphiphile, such as a fatty acid. Preferred fatty acids for this purpose include capronic, caprylic, capric, lauric, myristic, palmitic, phyanic, paimitolic, stearic, oleic, elaidic, linoleic, linolenic, arachidonic, behenic or lignoceric acids, or the corresponding alcohols. The preferred fatty acids are palmitic, stearic, oleic and linoleic acids, in particular oleic acid.
[00076] [00076] Component b) can be present in the range of 20 to 80% by weight of the total weight of components a), b) and c). Preferably, component b) will be present in the range of 25 to 65% by weight, for example, from to 55% by weight. More preferably, component b) will be present in the range of 35 to 45% by weight of the total weight of components a), b) and c), or the total weight of components a), b), c) and d) when the component d) is present.
[00077] [00077] Components a) and b) can independently be present in the range of 20 to 80% by weight of the total weight of components a), b) and c), or of the total weight of components a), b), c ) and d) when component d) is present. Preferably, components a) and b) will be independently present in the range of 25 to 65% by weight, for example, from 30 to 55% by weight. More preferably, components a) and b) will independently be present in the range of 35 to 45% by weight.
[00078] [00078] Preferably, the total of components a) and b) will be at least 30% by weight of components a), b) and c), more preferably at least 60% by weight of components a), b) and c), or the total weight of components a), b), c) and d) when component d) is present.
[00079] [00079] The total of the lipid components, i.e. component a) and component b), will preferably be at least 30% by weight of the complete preformulation, more preferably at least 50% by weight of the preformulation - complete formulation. In one embodiment, the total of components a), b), o), component d) optional, when present, and any optional active agent when present, will be at least 70% by weight of the total composition. This can preferably be at least 80, more preferably at least 90% by weight and in a form of the preformulation it will consist essentially of these components. By "consists essentially of" as used herein it is indicated in an amount of at least 90%, preferably at least 95% by weight.
[00080] [00080] In a preferred embodiment, the preformulation can have at least 15% component a) and / or at least 15% component b) by weight of components a) + b) + c), or of the total weight of components a), b), c) and d) when component d) is present.
[00081] [00081] Component "c" of the preformulations of the invention is an organic solvent containing oxygen. Since the preformulation must generate a deposit composition after administration (for example, in vivo), upon contact with an aqueous fluid, it is desirable that this solvent is tolerable for the subject and is able to mix with the aqueous fluid, and / or diffusion or dissolution out of the preformulation in the aqueous fluid. Solvents having at least moderate water solubility are therefore preferred.
[00082] [00082] In a preferred version, the solvent is such that a relatively small addition to the composition comprising a and b, that is, below 20% (by weight), or more preferably, below 10%, gives a great reduction of viscosity of an order of magnitude or more. As described herein, the addition of 10% solvent can produce a reduction of two, three or even four orders of magnitude of the viscosity on the solvent-free composition, even if the composition is a solution or L phase, containing no solvent, or an unsuitable solvent, such as water (subject to the special case considered below), or glycerol.
[00083] [00083] Typical solvents suitable for use as component c include at least one solvent selected from alcohols, ketones, esters (including lactones), ethers, amides and sulfoxides. Examples of suitable alcohols include ethanol and isopropanol. Monools are preferable to diols and polyols. When diols or polyols are used, this is preferably in combination with an at least equal amount of mono-ol or other preferred solvent. Examples of ketones include propylene carbonate and acetone. Suitable ethers include diethyl ether, glycofurol, diethylene glycol monoethyl ether, dimethyl isobarbide, and polyethylene glycols. Suitable esters include ethyl acetate and isopropyl acetate, and dimethyl sulfide is as suitable as a sulfite solvent. Suitable amides and sulfoxides include N-methyl pyrrolidone (NMP), 2-pyrrolidone, dimethylacetamide (DMA) and dimethyl sulfoxide (DMSO), respectively. Less preferred solvents include dimethyl isosorbide, tetrahydrofurfuryl alcohol, diglyme and ethyl lactate.
[00084] [00084] Since the pre-formulations are to be administered to a living subject, it is necessary that the solvent component c be sufficiently biocompatible. The degree of biocompatibility will depend on the method of application and since component c can be any mixture of solvents, a certain amount of a solvent that would not be acceptable in large quantities can, of course, be present. In general, however, the solvent or mixture that forms component c must not cause unacceptable reactions from the subject upon administration. Generally, such solvents will be hydrocarbons or, preferably, oxygen-containing hydrocarbons, both optionally with other substituents, such as nitrogen-containing groups. It is preferred that little or no component c contains hydrocarbons substituted by halogens since they tend to have a low biocompatibility. When a portion of halogenated solvent such as dichloromethane or chloroform is needed, this proportion will generally be minimized. When the deposit composition is to be formed non-parenterally a larger range of solvents can, of course, be used than when the deposit must be parenteral.
[00085] [00085] Component c as used herein can be a single solvent or a mixture of suitable solvents, but will generally be of low viscosity. This is important because one of the fundamental aspects of the present invention is that it provides pre-formulations that are of low viscosity and a primary role of a suitable solvent is to reduce this viscosity. This reduction will be a combination of the effect of decreasing the viscosity of the solvent and the effect of molecular interactions between the solvent and the lipid composition. An observation of the present inventors is that the low viscosity oxygen-containing solvents described herein have highly advantageous and unexpected molecular interactions with the lipid parts of the composition, thus providing a non-linear reduction in viscosity with the addition of a small volume solvent.
[00086] [00086] The viscosity of component and "low viscosity" solvent (single solvent or mixture) should typically be no more than 18 mPas at 20 ° C. That is, preferably, not more than 15 mPas, more preferably, not more than 10 mPas and most preferably, not more than 7 mPas at 20 ° C.
[00087] [00087] The solvent component c will generally be at least partially lost in the in vivo formation of the deposit composition, or diluted by absorbing water from the air and / or the surrounding tissue. It is preferred, therefore, that component c is at least to some extent miscible and / or dispersible in water and at least must not repel water, as water absorption is prevented. In this regard too, oxygen-containing solvents with a relatively small number of carbon atoms (for example, up to 10 carbon atoms, preferably up to 8 carbon atoms) are preferred. Obviously, when more oxygen is present, a solvent tends to remain soluble in water with a greater number of carbon atoms. The ratio of carbon to heteroatom (for example, N, O, preferably oxygen) will thus often be about 1: 1 to 6: 1, preferably from 2: 1 to 4: 1. When a solvent with a ratio outside these preferred ranges is used, then it will preferably be no more than 75%, preferably no more than 50%, in combination with a preferred solvent (such as ethanol). This can be used, for example, to decrease the rate of solvent evaporation from the preformulation, in order to control the rate of formation of liquid crystalline deposit.
[00088] [00088] Preferably, component c) is selected from alcohols, ketones, esters, ethers, amides, sulfoxides and mixtures thereof. Most preferably, component c) is selected from monoalcohols, diols, triis, ethers, ketones and amides. The most preferred solvents for component c) are selected from the group consisting of low molecular weight PEGs (200-500 Dalton), ethanol, NMP, or mixtures thereof. Especially preferred are ethanol and NMP or mixtures thereof.
[00089] [00089] As mentioned above, as a general guide, the weight of component c will typically be about 2 to 40% of the total weight of components a), b) and c), or the total weight of components a), b ),) and d) when component d) is present. This proportion is preferably (especially for injectable deposits) 4 to 30%, for example, 5 to 25% by weight. Most preferably component c) is in the range of 7 to 20%, for example, 9 to 18% by weight. Component d) Optional - Polar Solvent
[00090] [00090] While it has previously been suggested that controlled release lipid compositions should be formulated substantially in the absence of water, in order to avoid conversion to high viscosity liquid crystalline phases, it has now been established that a small, carefully controlled amount of a polar solvent like water can provide considerable benefits. In particular, the inclusion of this polar solvent (preferably comprising water) allows for further improvements in controlling the initial release of the active agent, allows for the higher stable loading of some active peptide agents, provides for faster deposit formation and / or provides more reduced discomfort by injection. Any of these factors potentially provides a significant improvement in the context of therapeutic drug distribution, patient health and / or patient compliance.
[00091] [00091] The pre-formulations of the present invention can thus also contain a polar solvent, component d), in addition to component c). A suitable amount of combined solvents, i.e., c) + d), will typically be greater than 1% by weight of the preformulation, for example 2-30% by weight, particularly 2-25% by weight, especially 5-20% by weight. Most preferably, component d) is present in the range of 5-15%, especially 6-12%, by weight of the total composition. Component d) is preferably water, propylene glycol or mixtures thereof. In a preferred aspect, the pre-formulations of the invention contain ethanol as component c) with water and / or propylene glycol as component d).
[00092] [00092] In one embodiment, the preformulation comprises at least 1.5% (for example, at least 4.5%) of water, as part of component d) (by weight of the total composition) with the remainder being propylene glycol . At least 5% water, with the balance of component d) being preferred PG. Component d) can comprise or consist of water.
[00093] [00093] In an alternative embodiment, component d) may comprise or consist of propylene glycol.
[00094] [00094] Suitable polar solvents, as an optional component d) can typically have a dielectric constant of at least 28 when measured at 25 ° C, for example, at least 30 when measured at 25 ° C. The highly suitable polar solvents include water, PG and NMP, as well as their binary and ternary mixtures.
[00095] [00095] Preferably, suitable polar solvents, as optional component d) are not included as part of the main solvent component c). For example, component c) can exclude water, propylene glycol and / or mixtures thereof.
[00096] [00096] Preferably, the total level of components c) and d) is not more than 35% by weight, preferably not more than 30% by weight, preferably 10-30% by weight, more preferably 12-25 % by weight of the components a) + b) + c) + d).
[00097] [00097] The ratio of components c) and d) will also have potential advantages in the compositions of the invention. In particular, by including some polar solvent, which is miscible with the mono-alcohol component (especially water), the slight sensation that can be caused at the injection site from the alcohol content can be substantially eliminated. Thus, in one embodiment, the weight ratio of components c): d) can be in the range of 30:70 to 70:30, more preferably, from 40:60 to 60:40. In one embodiment, the amount of alcohol component c), by weight, is not greater than the amount of the polar solvent, d). The ratios of c): d) ranging from 30:70 to 50:50 are, therefore, appropriate in such modality. Approximately equal amounts of components c) and d) are highly appropriate.
[00098] [00098] In a preferred combination, component a) is GDO or tocopherol, component b) is DOPE or a mixture of DOPE and PC, component c) is ethanol, NMP or mixtures thereof, and component d) is water, PG or mixtures thereof, in the ranges of 35-65% by weight of component a), 35-65% by weight of component b), 2-20% by weight of component c), and 5-15 % by weight of component d).
[00099] [00099] A highly preferred combination for the preformulation is GDO, DOPE, ethanol, and water / propylene glycol or mixtures thereof. As indicated above, the appropriate amounts of each component suitable for the combination are the amounts given here for the individual components, in any combination.
[000100] [000100] Preferably, components a), b) and c) constitute 80 to 95% by weight of the total composition and component d) constitutes 10 to 20% by weight of the total composition. Bioactive Agent
[000101] [000101] The pre-formulations of the present invention preferably contain one or more bioactive agents (described equivalently as
[000102] [000102] Drug agents that can be delivered according to the present invention include drugs that act on cells and receptors, peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscles, cardiovascular system, smooth muscles, system of blood circulation, hormonal and endocrine system, blood circulatory system, synoptic sites, neuroeffective junction sites, immune system, reproductive system, skeletal system, autacoid system, Food and excretory systems, histamine system, and central nervous system .
[000103] [000103] Examples of drugs that can be delivered by the composition of the present invention include, but are not limited to, antibacterial agents, modulating agents - immunological, - including immunostimulants and immunosuppressants, anticancer and / or antiviral drugs, such as nucleoside analogs, o paclitaxel and its derivatives, anti-inflammatory agents / drugs, such as non-steroidal anti-inflammatory drugs and corticosteroids, cardiovascular drugs, including cholesterol and blood pressure lowering agents, analgesics, antiemetics, including histamine H1 receptor antagonists, NKI, and 5-HT ;, corticosteroids and cannabinoids, antipsychotics and antidepressants, including serotonin reuptake inhibitors, prostaglandins and derivatives, vaccines, and bone modulators. Diagnostic means include labeled radionuclide compounds and contrast agents, including X-rays, and MRI and ultrasound contrast enhancing agents. Nutrients include vitamins, coenzymes, dietary supplements, etc.
[000104] [000104] Particularly suitable active agents include those that normally have a short residence time in the body due to rapid degradation or excretion and those with poor oral bioavailability. These include active agents based on peptides, proteins and nucleic acids, hormones and other agents that occur naturally in their native or modified forms. Through the administration of such agents in the form of a depot composition formed from the preformulation of the present invention, the agents are delivered at a sustained level for a period of time that can last for days, weeks or even several months, despite having fast clearance rates. This offers obvious advantages in terms of stability and patient compliance over the dosage several times a day for the same period. In a preferred embodiment, the active agent thus has a biological half-life (from entry into the bloodstream) of less than 1 day, preferably less than 12 hours, and more preferably less than 6 hours. In some cases, this can be as low as 1-3 hours or less. Suitable agents are also those with poor oral bioavailability compared to that obtained by injection, where the active agent also or, alternatively, has a bioavailability below 20%, or preferably below 2%, especially below 0.2%, and more preferably, below 0.1% in oral formulations.
[000105] [000105] The active agents based on peptide and protein include human and veterinary drugs selected from the group consisting of adrenocorticotropic hormone (ACTH) and its fragments, angiotensin and its related peptides, antibodies and their fragments, antigens and their fragments, atrial natriuretic peptides, bioadhesive peptides, bradykinins and their related peptides, calcitonin peptides including calcitonin and amylin and their related peptides, vasoactive intestinal peptides (VIP) including growth hormone releasing hormone (GHRH), glucagon and secretin, peptides opioids including pro-opiomelanocortin (POMC) peptides, enkephalin pentapeptides, pro-dynorphin peptides and related peptides, peptides related to pancreatic polypeptides such as neuropeptide (NPY), YY peptide (PYY), pancreatic polypeptide (PPY), protein fragments cell surface receptor, chemotactic peptides, cyclosporine s, cytokines, dynorphins and their related peptides, fragments of P-lidotropin and endorphins, enkephalin and their - related proteins, enzyme inhibitors, immunostimulating peptides and polyamino acids, fibronectin fragments and their related peptides, gastrointestinal peptides, antagonists and agonists of the gonadotropin-releasing hormone (GnRH), glucagon-like peptides | and 2, growth hormone releasing peptides, immunostimulating peptides, insulins and insulin-like growth factors, interleukins, lutenizing hormone releasing hormones (LHRH) and their related peptides (which are equivalent to GnRH agonists, as described below) , melanocortin receptor agonists and antagonists, melanocyte stimulating hormones and their related peptides, peptides related to nuclear localization signal, neurotensins and their related peptides, neurotransmitter peptides, opioid peptides, oxytocins, vasopressins and their related peptides, the hormone of parathyroid and its fragments, protein kinases and their related peptides, somatostatins and their related peptides, substance P and its related peptides, transforming growth factors (TGF), and their related peptides, tumor necrosis factor fragments,
[000106] [000106] Another and considerable advantage of the depot compositions of the present invention is that the active agents are released gradually over long periods without the need for repeated doses. The compositions are therefore highly suitable for situations in which patient compliance is difficult, unsafe or where a dosage level is very important, such as mood-altering assets, those active with a narrow therapeutic window, and those that are administered at children or people whose lifestyle is incompatible with a safe dosing regimen and for “lifestyle” assets where the inconvenience of repeated dosing can outweigh the benefit of the asset. Particular classes of assets for this aspect offer a special advantage and include contraceptives, hormones, including contraceptive hormones, and particularly hormones used in children, such as growth hormone, anti-additive agents, and drugs used to treat low-adhesion populations, such as patients suffering from schizophrenia, Alzheimer's, or Parkinson's disease, antidepressants and anticonvulsants.
[000107] [000107] Cationic peptides are particularly suitable for use when a part of the preformulation comprises an anionic amphiphile compound, such as an anionic fatty acid or lipid, including phosphatidic acid, phosphatidylglycerol, phosphatidylserine. In this embodiment, preferred peptides include octreotide, lanreotide calcitonin, oxytocin, interferon-beta and gamma, interleukins 4, 5, 7 and 8 and other peptides that have an isoelectric point above pH 7, especially above pH 8.
[000108] [000108] In a preferred aspect of the present invention, the composition of the invention is such that an inverted micellar cubic phase (12), or a mixed phase, including phase 1, is formed after exposure to aqueous fluids, and a polar active agent be included in the composition. Particularly suitable polar active agents include peptide and protein actives, oligonucleotides, and small water-soluble actives, including those listed above. Of particular interest in this regard are the octreotide peptide and other somatostatin-related peptides, alpha and beta interferons, glucagon-like peptide 1 receptor agonists and glucagon-like peptide 2, leuprorelin and other GnRH, abarelix and other GnRH, zolendronate antagonists and ibandronate and other bisphosphonates.
[000109] [000109] Since all u-opioid receptor agonists of choice for the treatment of moderate to severe chronic pain (morphine, hydromorphone, fentanyl, methadone, oxycodone, and buprenorphine) have the same mechanism of action, their physical characteristics -chemicals and pharmacokinetics are more critical in determining the appropriate route of administration and formulation of the product to be used. For example, the short elimination half-life of opioids such as morphine, hydromorphone, and oxycodone requires that these agents be administered frequently to achieve analgesia at all times, which makes them excellent candidates for long-acting release formulations. Fentanyl and buprenorphine undergo significant first-pass metabolism and lack sufficient bioavailability after oral administration. Along with their high potency, fentanyl and buprenorphine are excellent candidates for the long-acting injectable depot formulation of the invention. Sufentanil, remifentanil, oxymorphone, dimorphone, dihydroetorfin, diacetylmorphine are other potent opioid receptor agonists suitable for the invention.
[000110] [000110] Buprenorphine is also used for maintenance treatment of opioid addiction, as well as potentially addiction to cocaine and amphetamine and methamphetamine, where current sublingual buprenorphine formulations suffer from low bioavailability, high variability and limited effect duration, resulting in problems with unpredictable dose response and withdrawal symptoms, particularly in the mornings. These issues are effectively addressed by the use of the injection depot formulation of the present invention, as are the problems with misuse and disorientation, where the need for high sublingual doses is explored by injection, where the effect is significantly greater for the same dose thus facilitating the misuse of drugs. Likewise, opioid antagonists can be used for the treatment of addiction using a convenient injection depot system, as provided by the invention. Opioid antagonists suitable for use with the invention are naloxone, nalmefene and naltrexone.
[000111] [000111] Antipsychotics, including risperidone, iloperidone, paliperidone, olanzapine, ziprazidone and aripiprazole are also highly suitable for the invention, in view of the potential for improving patient adherence to treatment, as well as providing stable plasma levels throughout the time. Likewise, the invention is useful in the treatment of dementia, Alzheimer's disease and Parkinson's disease, which negatively affect cognition. Suitable active ingredients include donepezil, rivastigmine, galantamine, and emantine, and pramipexole.
[000112] [000112] A particular advantage of the present invention, when used in combination with active protein / peptide agents is that the aggregation of the active agent is suppressed. In a preferred embodiment, the present invention thus provides a deposition precursor and, in particular, a deposition composition as described herein comprising at least one active peptide or protein agent, wherein no more than 5% of the active agent is in aggregate form. Preferably, not more than 3% are aggregated and, more preferably, not more than 2% (especially less than 2%) are in aggregate form. This stabilization of non-aggregated proteins is highly advantageous from the point of view of high efficiency, low side effects and predictable absorption profile. In addition, it is highly expected that protein / peptide therapies will have low levels of protein aggregation in order to ensure regulatory approval.
[000113] [000113] Gonadotropin releasing hormone agonists (GnRH agonists) are synthetic peptides modeled after the hypothalamic neurohormone GnRH that interacts with the gonadotropin releasing hormone receptor to obtain its biological response, releasing follicle stimulating hormones of pituitary hormone (FSH) and lutenizing hormone (LH). GnRH agonists are useful in the treatment of cancers that are hormonally sensitive and where a state of hypogonadism decreases the chances of a recurrence. Thus, they are commonly used in the medical control of prostate cancer and have been used in patients with breast cancer. Other areas of indication include the treatment of delayed puberty in individuals with precocious puberty, treatment of female disorders that are dependent on estrogen production. In addition, women with menorrhagia, endometriosis, adenomyosis or uterine fibroids may receive GnRH agonists to suppress ovarian activity and induce a hypoestrogenic state.
[000115] [000115] The GnRH itself is post-translationally modified decapeptide with a pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-GIy-NH structure (GnRH-D). Two natural variants are also known, GRH-II with 5-His, 7-Trp, 8-Tyr and GARH II with 7-Trp substitutions. 8-Read. Several peptide analogs with agonist properties are known, most of which have 10-GIy-NH, replaced by N-Et-NH ,. Fertirelin has a 10-Gly substitution for N-Et-NH only, while analogs with additional substitutions on GnRH-I include Leuprorelin (Leuprolide), (6-D-Leu). Buserelin (6-Ser (Bu ')), Histrelin (6-d-His (Imbzl)), Deslorelin (6-D-Trp). Another common ninth-peptide agonist is Goserelin, which is replaced with 6-Ser (Bu ') and has 10-GIy-NH, replaced by AzaGly-NH ,. Narafelin (6-d-Nal) and Triptorelin (6-d-Trp) both retain the group 10-Gly-NH,>. The structures of the two most common GRNRH agonists (Leuprolide and Goserelin) are shown below as acetate salts.
[000116] [000116] Leuprolide: piro-Glu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-N-Et-NH, (acetate).
[000117] [000117] Goserelin: - piro-Glu-His-Trp-Ser-Tyr-D-Ser (Bu ') - Leu-Arg- Pro-Azgly-NH, (acetate).
[000118] [000118] A small number of GnRH antagonists are also known, again based on the structure of GnRH-I. These include Abareiix (D-Aia-D-Phe-D-Ala-Ser-Tyr-D-Asp-Leu-Lys ('Pr) -Pro-D-Ala). Antarelix (D-Nal-D-Phe-D-Pal-Ser-Phe-D-Hcit-Leu-Lys - ('Pr) -Pro-D-Ala); Cetrorelix (D-Nal-D-Phe-D-Pal-Ser-Tyr-D-Cit-Leu-Arg-Pro-D-Ala), Ganirelix (D-Nal-D-Phe-D-Pal-Ser-Tyr -D-hArg-Leu-HArg-Pro-D-Ala), Itrelix (D-Nal-D-Phe-D-Pal-Ser-NicLys-D-NicLys-Leu-Lys ('Pr) -Pro-D- Ala) and Nal-Glu (D-Nal-D-Phe-D-Pal-Ser-D-Glu-D-Glu-Leu-Arg-Pro-D-Ala).
[000119] [000119] The administration of single doses of a GnRH agonist, such as leuprolide, stimulates the release of gonadotropins from the pituitary (ie, LH and FSH), resulting in an increase in serum LH and FSH and stimulation of ovarian and testicular steroidogenesis . Transient increases in serum testosterone and dihydrotestosterone (DHT) in men and in serum concentrations of estrone and estradiol in premenopausal women are seen during initial therapy with single daily doses of the drug.
[000120] [000120] Although the effect of a potent GnRH agonist during short-term and / or intermittent therapy is stimulating steroidogenesis, the main effect of the drug in animals and humans during long-term administration is inhibition of gonadotropin secretion and suppression of ovarian and testicular steroidogenesis. The exact mechanism of action has not yet been fully elucidated, but continuous therapy with a GnRH agonist apparently produces a decrease in the number of pituitary GnRH and / or testicular LH receptors, resulting in pituitary and / or desensitization. testicular, respectively. The drug does not appear to affect the receptor's affinity for gonadotropins. Leuprolide's mechanism of action may also involve the inhibition and / or induction of enzymes that control steroidogenesis. Other mechanisms of action may include the secretion of an LH molecule with altered biological activity or a decrease in the normal pulsatile patterns of LH and FSH secretion.
[000121] [000121] A number of serious medical indications are related and / or affected by the concentration of gonadal steroid hormones. These include certain neoplastic diseases, including cancers, especially of the breast and prostate, and benign prostatic hypertrophy; precocious or delayed puberty in adolescents; hirsuitism; Alzheimer's disease; and certain conditions related to the reproductive system, such as hypogonadism, anovulation, amenorrhea, oligospermia, endometriosis, leiomyomas (uterine fibroma), premenstrual syndrome, and polycystic ovary diseases. The control of this system is also important in IVF methods.
[000122] [000122] Although treatment with a GnRH agonist can be expected to aggravate conditions affected by the concentration of gonadal steroid hormone, the infrared effect discussed above results in the decrease of these hormones to castrate the level, if therapy is continued for about 2 weeks or more. As a result, hormone-receptive tumors, such as certain prostate and breast cancers, as well as precocious puberty and many of the other conditions mentioned above can be improved or alleviated by long-lasting GnRH agonist therapy.
[000123] [000123] The pre-formulations of the present invention contain one or more analogs of GnRH or another active (see above) (which are intended by any reference to "active agents" here). Since GnRH is a peptide hormone, typical GnRH analogs will be peptides, especially 12 or less amino acids. Preferably, these peptides will be structurally related to GnRH 1, II and / or III, and / or one or more of the known analogs, including those mentioned herein. The peptides may contain only the amino acids selected from the 20 α-amino acids indicated in the genetic code, or more preferably, they may contain the respective isomers and other natural and unnatural amino acids (usually a, B or y amino acids) and their analogs and derivatives. Preferred amino acids include those listed above, as constituents of the known GnRH analogs.
[000124] [000124] Amino acid derivatives are especially useful at the peptide terminal, where the amino terminal group, or carboxylate group can be replaced by, or with any other functional group, such as hydroxy, alkoxy, carboxy, ester, amide, uncle , amide, amine, alkylamine, di- or tri-alkyl amine, alkyl (by which is meant everywhere here C, -Ci, 7 alkyl, preferably C1-Cs alkyl, for example, methyl, ethyl, n -propyl, isopropyl, n-butyl, iso-, sec- or t-butyl, etc.), aryl (e.g. phenyl, benzyl, naphthyl, etc.) or other functional groups, preferably with at least one heteroatom and, preferably, with no more than 10 atoms in total, more preferably, no more than 6.
[000125] [000125] The particularly preferred GnRH analogs are the 6 to 12 alpha-amino acid peptides, the specific examples of which include those indicated above and, in particular, leuprolide and goserelin, from the sequences indicated above.
[000126] [000126] By "GnRH analogs", as used herein, any GnRH agonist or antagonist is indicated, preferably peptides, peptide derivatives and peptide analogs. Peptide-derived GnRH agonists are more preferred, as indicated above, and especially leuprolide or goserelin.
[000127] [000127] The GnRH analog will generally be formulated as 0.02 to 12% by weight of the total formulation. Typical values will be 0.1 to 10%, preferably 0.2 to 8% and more preferably 0.5 to 6%. A GnRH analog content of about 1-5% is more preferred.
[000128] [000128] The doses of the GnRH analog suitable for inclusion in the formulation and thus the volume of the formulation used, will depend on the rate of release (as controlled, for example, by the type of solvent and amount of use) and duration of release, as well as the desired therapeutic level, the activity of the specific agent, and the clearance rate of the chosen particular asset. Typically, an amount of 0.1 to 500 mg per dose would be adequate to provide a therapeutic level between 7 and 180 days. This will preferably be 1 to 200 mg. For leuprolide or goserelin, the level will typically be around 1 to 120 mg (for example, for a duration of 30 to 180 days). Preferably, the amount of leuprolide will be about 0.02 to 1 mg per day, between injections for deposits intended for release over 30 days to 1 year, preferably 3 to 6 months. Of course, the stability of the asset and the linearity of the release rate will mean that the load for the duration may not be in a linear relationship. A deposit administered every 30 days can have, for example, 2 to 30 mg or a 90 day deposit can have 6 to 90 mg of active, as one of the GnRH analogs is indicated here.
[000129] [000129] When the active agent comprises an SHT antagonist; or SHT antagonist; second generation, it is preferably selected from odansetron, tropisetron, granisetron, dolasetron, palonosetron, alosetron, cilansetron and / or ramosetron or mixtures thereof. The doses of the SHT3 antagonist suitable for inclusion in the formulation and, thus, the volume of the formulation used, will depend on the release rate (as controlled, for example, by the type of solvent and amount of use) and duration of release, as well as the desired therapeutic level, the activity of the specific agent, and the clearance rate of the particular asset chosen. Typically, an amount of 1 to 500 mg per dose, may be adequate to provide a therapeutic level between 5 and 90 days. This will preferably be
[000130] [000130] Somatostatins (Growth Hormone Release Inhibition Factors, SSTs) are natural peptide hormones, widely distributed in animals, acting as neurotransmitters in the central nervous system, and have several regulatory effects of paracrine / autocrine in various tissues . Two biologically active products are known in higher species, SST-14 and SST-28, a SST-14 congener extended at the N-terminal.
[000131] [000131] SST-14 is a 14-residue cyclic peptide hormone having the sequence Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys, in which the two cysteine residues are linked by a disulfide bridge to generate a type II B-loop in the Phe-Trp-Lys-Thr key binding sequence. The biological half-life of natural SST-14 is very short (1-3 minutes) and therefore is not, in itself, a viable therapy in current formulations, but an increasing number of somatostatin receptor agonists are becoming available with greater longer activities and / or purification in vivo.
[000132] [000132] Somatostatin receptor agonists (SARS), such as SST-14, SST-28, octreotide, lanreotide, vapreotide, pasireotide (SOM 230) and related peptides, are used or indicated in the treatment of a variety of conditions under which are typically administered over an extended period. SRAs form a preferred group of active agents for use in the present invention.
[000133] [000133] Octreotide, for example, is the synthetic octapeptide with the sequence of D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol (2-7 disulfide bridges) and is normally administered in in the form of an acetate salt. This SST-14 derivative maintains the key Phe- (D) Trp-Lys-Thr B-loop necessary for SST-1-like activity in vivo but, in contrast to the natural hormone, has a terminal half-life of about 1 , 7 hour. Octreotide is used to treat diseases, including carcinoid tumors and acromegaly, and is typically administered over a prolonged period of weeks, or more commonly over many months or years. Somatostatin receptor agonists are of particular interest for the treatment of many different types of cancers, since a wide variety of tumors express somatostatin receptors (SSTRs). There are five types of known SSTRs (SSTRI-SSTR5), also exhibiting a high affinity for SST-14. The most investigated somatostatin receptor agonists, including octreotide, show high selectivity for SSTR2 and SSTR5; thus, octreotide is of particular interest for the treatment of tumors that express these types of receptors.
[000134] [000134] The most common “simple” formulation of octreotide is Novartis “Sandostatin” (RTM). This is an aqueous solution for subcutaneous injection (s.c.), and a dose of 100 µg reaches a peak concentration of 5.2 ng / ml in 0.4 hour after injection. The duration of action can be up to 12 hours, but s.c. dosing is usually performed every 8 hours. Evidently, s.c. injection 3 times a day, for periods of months or years, is not an ideal dosing regimen.
[000135] [000135] Pasireotide is a multi-receptor target somatostatin analogue with high affinity for the somatostatin receptor subtypes sstr1,2,3 and sstr5 that were developed for the treatment of diseases - “neuroendocrine. Two pasireotide formulations have been developed today: an immediate-release formulation for subcutaneous injection (sc) and a long-acting release formulation (LAR). The structure of pasireotide is as follows:
[000136] [000136] Pasireotide was initially developed by Novartis Pharma as a treatment for Cushing's disease / syndrome and acromegaly, but has potential applicability in the treatment of various conditions for which somatostatin analogs such as octreotide are indicated, including carcinoid tumors.
[000137] [000137] After a single subcutaneous dose of pasireotide, human plasma levels typically peak rapidly, about 15 minutes to 1 hour after dosing, with an initial half-life of 2-3 hours after the peak. Although the clearance half life is longer for the later stages of the decline, it is clear that the Cmax / Cmedia for such distribution will be quite high.
[000138] [000138] The pasireotide LAR is a long-acting formulation of pasireotide that addresses some of the issues above. However, this is a system based on polymer microparticles with the inherent limitations of such a system, as are known in the art and described hereinbefore.
[000139] [000139] Carcinoid tumors are intestinal tumors resulting from specialized cells with paracrine functions (APUD cells). The primary tumor is commonly found in the appendix, where it is clinically benign. Secondary, metastatic, intestinal carcinoid tumors secrete excessive amounts of vasoactive substances, including serotonin, bradykinin, histamine, prostaglandins, and polypeptide hormones. The clinical result is carcinoid syndrome (an episodic skin flushing syndrome, cyanosis, abdominal cramps and diarrhea in a patient with valvular heart disease and, less commonly, asthma and arthropathy). These tumors can grow anywhere in the gastrointestinal tract (and in the lungs) with approximately 90% in the appendix. The rest occurs in the skin, stomach, colon or rectum. Currently, treatment of carcinoid syndrome begins with i.v. bolus injection, followed by infusion. When a sufficient effect on symptoms is established, treatment with an octreotide deposit formulation formulated in polylactic-co-glycolic acid (PLGA) microspheres is initiated. However, during the first two weeks or more after the injection of the deposit, s.c. injections of octreotide daily are recommended to compensate for the slow release of the PLGA beads.
[000140] [000140] Some of the preformulations of the present invention contain salts of one or more somatostatin receptor agonists (which are preferred examples of active peptide agents which, in turn, are intended by any reference to "active agents" used here ). Since SST-14 is a peptide hormone, typical somatostatin receptor agonists will be - peptides, especially 14 or less amino acids. Preferably, these peptides will be structurally restricted as such because they are cyclic and / or have at least one intramolecular crossover dye. Amide, ester or particularly disulfide crosslinks are highly suitable. Preferred restricted peptides will exhibit a type-2 B-loop. This turn is present in the key region of somatostatin. The peptides can contain only the amino acids selected from those 20 a-amino acids indicated in the genetic code, or more preferably, they can contain the respective isomers and other natural and unnatural amino acids, (usually a, f; or y, L- or D amino acids) and their analogs and derivatives. The term "somatostatin receptor agonist", as used here, can optionally also cover SST-14 and / or SST-28, since there are viable peptide assets when formulated as salts in the high performance slow release formulations described on here.
[000141] [000141] Derivatives of amino acids and amino acids not normally used for protein synthesis are especially useful at the terminal of peptides, where the amino terminal group or carboxylate group can be replaced by, or with any other functional group, such as hydroxy, alkoxy, ester, amide, thio, amine, alkyl amine, di- or tri-alkyl amine, alkyl (by which we mean everywhere C; -Cig alkyl, preferably C; -C; g alkyl, for example methyl , ethyl, n-propyl, isopropyl, n-butyl, iso-, sec- or t-butyl etc.), aryl (e.g. phenyl, benzyl, naphthyl, etc.) or other functional groups, preferably with at least one heteroatom and, preferably, with no more than 10 atoms in total, more preferably, no more than 6.
[000142] [000142] The particularly preferred somatostatin receptor agonists are the 6 to 10 α-amino acid peptides, of which specific examples include octreotide, lanreotide (of NH sequence,; - (D) Naph-Cys-Tyr- (p) Trp-Lys-Val-Cys-Thr-CONH, and its cyclic derivative of the NH> sequence - (p) Naph-Cys-Tyr- (p) Phe-Lys-Val-Cys-Thr-CONH; both having a crosslink of intramolecular disulfide Cys-Cys), SOM 230 (see structure above) and vapreotide. The most preferred are octreotide and pasireotide.
[000143] [000143] The somatostatin receptor agonist will generally be formulated as 0.1 to 10% by weight of the total formulation. Typical values will be 0.5 to 9%, preferably 1 to 8% and more preferably 1 to 7%. A 2-5% somatostatin receptor agonist content is most preferred.
[000144] [000144] The doses of the somatostatin receptor agonist suitable for inclusion in the formulation and, thus, the volume of the formulation used will depend on the release rate (as controlled, for example, by the type of solvent and amount of use) and duration of release , as well as the desired therapeutic level, activity and clearance rate of the particular asset chosen. Typically, an amount of 1 to 500 mg per dose may be adequate to provide a therapeutic level between 7 and 90 days. This will preferably be 5 to 300 mg. For octreotide, the level will typically be around 10 to 180 mg (for example, for a duration of 30 to 90 days). Preferably, the amount of octreotide will be about 0.2 to 3 mg per day between injections. Thus, a deposit administered every 30 days can have 6 to 90 mg or a 90 day deposit can have 18 and 270 mg of octreotide.
[000145] [000145] For Pasireotide, the dosage can typically be an amount of about 0.05 to 40 mg per week of deposit duration, preferably 0.1 to 20 mg per week of duration (for example, 1 to 5 mg per week) for a duration of 1 to 24 weeks, preferably 2 to 16 (for example, 3, 4, 8, 10 or 12) weeks. In an alternative embodiment, the pre-formulation can be formulated for weekly dosing (for example, every 7 + 1 day). A total dose of 0.05 to 250 mg of Pasireotide per dose would be adequate to provide a therapeutic level between 7 and 168 days. This will preferably be 0.1 to 200 mg, for example, 0.2 to 150 mg to 0.1 to 100 mg, 20 to 160 mg, etc. Of course, the stability of the asset and the effects on the release rate will mean that the load for duration may not be in a linear relationship. A deposit administered every 30 days can have, for example, 0.2 to 20 mg of Pasireotide, or a 90 day deposit can have 30 to 60 mg of Pasireotide.
[000146] [000146] When the salt of an active peptide agent, such as an SRA, is used in the formulations of the present invention, it will be a biologically acceptable salt. Suitable salts include the acetate, pamoate, chloride or bromide salts. The chloride salt is the most preferred.
[000147] [000147] The amount of bioactive agent to be formulated with the pre-formulations of the present invention will depend on the functional dose and the period during which the deposit composition formed upon administration takes to provide a sustained release. Typically, the dose formulated for a particular agent will be around the equivalent of the normal daily dose multiplied by the number of days the formulation takes to release. Of course, this amount must be adapted to take into account any adverse effects of a large dose at the start of treatment and, therefore, this will generally be the maximum dose used. The exact amount adequate in any case will be easily determined by proper experimentation.
[000148] [000148] Preferably, the preformulation of the invention will comprise 0.1-10% by weight of said active agent, by weight of components a) + b) + c) (and d) if present).
[000149] [000149] Preferably, the active agent when present is selected from: interferons; GnRH agonists buserelin, deslorelin, goserelin, leuprorelin / leuprolide, naferelin and triptorelin; GnRH antagonists, for example, cetrorelix, ganirelix, abarelix, degarelix; glucagon-like peptide-1 (GLP-1) and analogs thereof, for example, GLP-1 (7-37), GLP-1 (7-36) amide, liraglutide, exenatide, and lixisenatide (AVEOO010); glucagon-like peptide 2 agonists (GLP-2) and analogs thereof, for example, GLP-2 and Elsiglutide (ZP1846); DPPIV inhibitors; somatostatins SST-14 and SST-28 and somatostatin receptor agonists (SSTR), for example, octreotide, lanreotide, vapreotide, pasireotide.
[000150] [000150] Other peptides suitable for the invention include: angiopcptin, angiotensin 1, II, III, anti-inflammatory, anti-inflammatory peptide 2, aprotinin, bradykinin, bombesin, calcitonin, calcitriol, cholecystokinin factor (CCK), colony stimulating factor, colony factor corticotropin release, C-Peptide, VD DDA, dermofin-derived tetrapeptide (TAPS), dynorphin, endorphins, endostatin, endothelin, l-endothelin, enkephalins, epidermal growth factor, erythropoietin, fibroblast growth factor, follicle stimulating hormone , follistatin, follitropin, galanin, galanin-like peptide, galectin-1, gastrin, gastrin-releasing peptide, G-CSF, ghrelin, glial-derived neurotrophic factor, GM-CSF, granulocyte colony stimulating factor, growth hormone, factor of growth hormone release, hepatocyte growth factor, insulin, insulin-like growth factors I and I, interferons, interleukins, leptin, inhibitory factor leukemia, melanocortin 1, 2, 3, 4, melanocyte-stimulating metastin hormone, monocyte chemotactic protein-1 (MCP-1), morphiceptin, NEP1-40, neuropeptide Y, neuropeptide W, orexin-A & orexin-B , oxytocin p21-Cipl / WAF-I1, fusion protein TAT, parathyroid hormone, growth factor derived from epithelium pigment (PEDF), peptide, peptide, prorenin loop region, YY peptide (3-36), factor of platelet activation, platelet-derived growth factor, pro-renin decapeptide, protegrin-1, PR39, prolactin, relaxin, secretin, substance P, tumor necrosis factor, urocortin, vascular endothelial growth factor, vasoactive intestinal polypeptide, vasopressin .
[000151] [000151] Most preferably, the active agent is at least one selected from buprenorphine, octreotide, pasireotide, leuprolide and goserelin. For example, at least one selected from buprenorphine, leuprolide and goserelin.
[000152] [000152] In one embodiment, applicable to all aspects of the invention, the active agent excludes agonists from somatostatin receptors,
[000153] [000153] In an additional modality, the active agent, when present, can exclude certain agonists of specific somatostatin receptors, namely pasireotide, octreotide and / or salts and mixtures thereof. In this embodiment, the active agent can comprise somatostatin receptor agonists, with the exception of pasireotide, octreotide and / or salts and mixtures thereof.
[000154] [000154] In one embodiment, applicable to all aspects of the invention, the following preformulation, together with the devices and kits containing said preformulation, processes for its formation and / or distribution, and the use of said preformulation -formulation can be excluded: a pre-formulation comprising a low-viscosity non-liquid crystalline mixture of: a. 25-55% by weight of at least one glycerol diacyl and / or at least one tocopherol; B. 25-55% by weight of at least one phospholipid component comprising phospholipids having i. polar head groups comprising more than 50% phosphatidyl ethanolamine, and ii. two acyl chains each having independently 16 carbons where at least one acyl chain has at least one unsaturation in the carbon chain, and there are no more than four unsaturations across two carbon chains; ç. 5-25% by weight of at least one low viscosity, biocompatible organic solvent containing oxygen; wherein 0.1-10% by weight of at least one active peptide agent, comprising at least one somatostatin receptor agonist is dissolved or dispersed in the low viscosity mixture;
[000155] [000155] The nature of the components of the preformulations of the present invention is that they are normally naturally occurring and highly biocompatible. They therefore cause little or no irritation when in contact with a body surface and can serve to form a soothing layer and / or barrier on that surface. In such circumstances, an additional effect may be provided by an "active" bioactive agent, such as any of those described here. However, a beneficial property may exist as a result of the physical and / or biological effects of the preformulation and / or the long-acting composition that is formed upon administration.
[000156] [000156] Thus, in one embodiment, the optional bioactive agent may be without any of the formulations described here, where the context allows. Administration
[000157] [000157] As mentioned above, the preformulation of the invention can be administered and the methods of the invention applied using an appropriate route for the condition to be treated and the bioactive agent used. The term "parenteral" as used here is given its established meaning of "through the skin" instead of all "non-oral" routes. Thus, parenteral mainly indicates administration by injection, infusion and similar techniques (such as needle-free injection). The term “non-parenteral”, therefore, covers different routes of application through the skin. A parenteral deposit will thus be formed parenterally (for example, injectables, such as administration by subcutaneous or intramuscular injection) whereas a non-parenteral deposit composition (eg, oral, topical) can be formed by administration on the surface of the skin, mucous membranes and / or nails, for ophthalmic, nasal, oral or internal surfaces or for cavities such as nasal, rectal, vaginal or oral cavities, cavities or periodontal pockets formed after the extraction of a natural structure or implanted or before an implant is inserted (for example, a joint, stent, cosmetic implant, tooth, tooth filler, or other implant).
[000158] [000158] In one embodiment, the pre-formulations of the present invention will generally be administered parenterally. This administration will generally not be an intravascular method, but it will preferably be subcutaneous or intramuscular intracavitary. Typically, administration will be by injection, the term of which is used here to indicate any method in which the formulation is passed through the skin, such as through a needle, catheter or needle-less injector.
[000159] [000159] In parenteral deposition precursors (especially subcutaneous (sc)), the preferred active agents are those suitable for systemic administration, including antibacterial agents (including amikacin, monocycline and doxycycline), local and systemic analgesics (including tramadol, fentanyl, morphine , hydromorphone, Dbuprenorphine, methadone, oxycodone, codeine, asperine, acetaminophen), immunosuppressants (such as thalidomide, lenalidomide, sirolimus, deforolimus, everolimus, temsirolimus, Umirolimus, zotarolimus), anti-inflammatory drugs, as anti-inflammatory drugs , indometansine, sulindac, tolmetins, salicylic acids such as salicylamide, diflunisal), Cox1 or Cox2 inhibitors (such as celecoxib, rofecoxib, valdecoxib), oncology and endocrinology agents (including octreotide, lanreotide, buserelin, luprorin, avelin, ghrelin, ghrelin delusions, abarelix, degarelix, fulvestrant, alpha interferon, beta interferon, darbepo alpha ethine, epoetin alfa, beta, delta, cytarabine, docetaxel, and paclitaxel), antiemetics (such as granisetron, odansetron, palonsetron, aprepitant, fosaprepitant, netupitant,
[000160] [000160] In an alternative embodiment, the formulations of the present invention can form non-parenteral deposits, where the active agent is released slowly on a body surface. It is especially important in this embodiment that the pre-formulations of the invention and / or the liquid crystalline deposit compositions thus formed should preferably be bioadhesive. This means that the compositions must coat the surface to which they are applied and / or on which they form, as appropriate and must remain even when this surface is subjected to an air or liquid flow and / or friction. It is particularly preferred that the liquid crystalline deposit compositions that are formed are stable to washing with water. For example, a small volume of deposit precursor can be applied to a body surface and exposed to a flow of five hundred times its own volume of water per minute for 5 minutes. After this treatment, the composition can be considered bioadhesive if less than 50% of the bioactive agent has been lost. Preferably, this level of loss will be compensated when the water equals 1000 times and, more preferably, 10,000 times the volume of the composition which is poured per minute for five or, preferably 10 minutes.
[000161] [000161] Although the non-parenteral deposit compositions of the present invention can absorb all or part of the water necessary to form a liquid crystalline phase structure from the biological surfaces with which they are contacted, some additional water can also be used. absorbed from the surrounding air. In particular, when a thin layer of high surface area is formed, then the affinity of the composition for water may be sufficient to form a liquid crystalline phase structure in contact with water in the air. The "aqueous fluids" are referred to here, so it is at least partially the air that contains some moisture in this modality.
[000162] [000162] Non-parenteral deposit compositions will typically be generated by applying the preformulation topically to the body surface or to a naturally or artificially generated body cavity and / or to the surface of an implant. This application can be carried out by direct application of liquid, such as by spraying, dipping, rinsing, applying a plaster or ball roller, intracavity injection (for example, to an open cavity with or without the use of a needle), painting, drip (especially in the eyes) and similar methods. A highly effective method is spraying by pump or aerosol and, of course, this requires that the viscosity of the preformulation is as low as possible and is therefore highly suitable for the compositions of the invention. Non-parenteral deposits can, however, be used to deliver systemic agents, for example, transmucosally or transdermally.
[000163] [000163] Non-parenteral deposits can also be used for application to surfaces, particularly implants and materials that will be in contact with the body or part of the body or fluids. Devices, such as implants, catheters, etc., can thus be treated, for example, by immersion or spraying with the pre-formulations of the invention, which will form a solid layer to reduce the introduction of infection. Anti-infectious actives are particularly suitable in this regard.
[000164] [000164] Conditions particularly suitable for symptomatic or causative treatment by topical bioadhesive depot compositions of the present invention include skin conditions (such as pain resulting from any cause, including cracks, scratches and skin conditions including eczema and herpes), conditions eye, pain (including pain due to genital infection, such as genital herpes), infections and conditions for fingernails and / or toenails (such as bacterial or fungal nail infections, such as onychomycosis or poronichia). Topical-type bioadhesive formulations can also be used to deliver systemic active agents (for example, medications), particularly by oral, transdermal or rectal absorption through the skin. Antiemetics and travel sickness medication are a preferred example, as is nicotine (for example, in anti-smoking aids). Whenever the context allows, "topical application", as referred to here, includes systemic agents applied non-parenterally to a specific region of the body.
[000165] [000165] Periodontal infections are particularly suitable for treatment by the compositions of the present invention. In particular, compositions known to treat periodontal infection are difficult to apply or are generally ineffective. The most widely used periodontal deposit composition comprises the insertion of a collagen chip within the periodontal space, from which an anti-infective agent is released. This chip is difficult to insert and is not shaped to match the shape and volume of the periodontal space, so that the infection pockets can remain untreated. In contrast to this, the compositions of the present invention, applied as a low viscosity preformulation,
[000166] [000166] Non-parenteral deposit compositions are also of significant benefit in combination with active non-pharmaceutical agents, such as cosmetic actives, fragrances, essential oils, etc. Such non-pharmaceutical deposits will maintain the important aspects of bioadhesion and release sustained to provide prolonged cosmetic effects, but can be easily applied by spraying or smearing.
[000167] [000167] Active agents particularly suitable for administration of non-parenteral deposit (eg, oral or topical), which comprises intraoral, buccal, nasal, ophthalmic, dermal, vaginal administration routes, include antibacterial agents, such as chlorhexidine (for example , chlorhexidine digluconate or chlorhexidine dihydrochloride), chloramphenicol, triclosan, tetracycline, terbinafine, tobramycin, sodium fusidate, butenafine, metronidazole (the latter especially for the treatment (for example, symptomatic) of acne rosacea - adult acne or acne some vaginal infections), antivirals, including acyclovir, anti-infectives, such as bibrocathol, ciprofloxacin, levofloxacin, local painkillers, such as benzidamine, lidocaine, prilocaine, xylocaine, bupivacaine, painkillers, such as tramadol, fentanyl, morphine, morphine, oxycodone, codeine, asperine, acetaminophen, antiemetics (such as granisetron, odansetron, palonsetron, aprepitant, fosaprepitant, netupitant, dexamethasone, in particular, 5SHT antagonists; or SHT antagonists; second generation; preferably, selected from odansetron, tropisetron, granisetron, dolasetron, palonosetron, alosetron, cilansetron and / or ramosetron or mixtures thereof). NSAIDS, such as ibuprofen, flurbiprofen, naproxen, ketoprofen, ketorolac, fenoprofen, diclofenac, etodalac, diflunisal, oxaproxin, piroxicam, piroxicam, indometansine, sulindac, tolmetin, salicylic acids such as salisilamide and diflunisib, or Coxlunisal2 valdecoxib, corticosteroids, immunostimulating agents and anticancer (for example, methylaminolevulinate hydrochloride, interferon alfa and beta), anticonvulsants (for example, tiagabine or gabapentin topiramate), hormones (such as testosterone, and testosterone undecanoate, medroxyprogesterone, estrroxyprogesterone, estradiol). growth hormones (such as human growth hormone), and growth factors (such as granulocyte and macrophage colony stimulating factor), = immunosuppressants - (cyclosporine, sirolimus, tacrolimus, everolimus), nicotine and antivirals (eg, acyclovir) . Phase Structures
[000168] [000168] The pre-formulations of the present invention provide non-lamellar liquid crystalline deposition compositions after exposure to aqueous fluids, especially in vivo, and in contact with body surfaces. In a preferred embodiment, the liquid crystalline phases of the invention are formed in situ.
[000169] [000169] As used here, the term "non-lamellar" is used to indicate a normal or reverse liquid crystalline phase (such as a hexagonal or cubic phase), or the L3 phase or any combination thereof. The term
[000170] [000170] Preferably, in the preformulation of the invention, the structure of the liquid crystalline phase formed after contact with an aqueous fluid is a reverse hexagonal phase (H>) structure and / or a reverse cubic phase structure (1) or a mixture, or intermediates thereof. With the intermediaries we refer to the phases with average curvatures between the average curvature of phases H, and L, respectively, and what the position in a phase diagram is between these two phases, in which case both are present. Preferably, the liquid crystalline phase structure is selected from H, LI or mixtures thereof.
[000171] [000171] For many combinations of lipids, there are only a few non-lamellar phases, or they exist in any stable state. It is a surprising feature of the present invention that the compositions as described herein, often have non-lamellar phases that are not present with various other combinations of components. In a particularly advantageous embodiment, therefore, the present invention relates to compositions having a combination of components for which a region of the L1, and / or L phase, exists when diluted with aqueous solvent. The presence or absence of such regions can be easily tested for any particular combination by simply diluting the composition with an aqueous solvent, and studying the resulting phase structures, by the methods described herein.
[000172] [000172] In a highly advantageous embodiment, the compositions of the invention can form an L phase, or a mixed phase, including the IL phase in contact with water. The LI phase, is a reverse cubic liquid crystalline phase having discontinuous aqueous regions. This phase is of particular advantage in the controlled release of active agents and especially in combination with polar active agents, such as water-soluble active agents because the discontinuous polar domains prevent the rapid diffusion of the active principles. L-deposit precursors are highly effective in combination with L-phase deposit formation. This is because L-phase is a so-called “inverted micellar” phase that has a continuous hydrophobic region surrounding the discrete polar nuclei. L, therefore, has similar advantages with hydrophilic assets. In transient stages upon contact with the body fluid, the composition can comprise multiple phases, since the formation of an initial surface phase will delay the passage of the solvent to the core of the deposit, in particular, with substantial sized administrations of the internal deposits . Without adhering to theory, it is believed that this transient formation of a surface phase, especially a liquid crystalline surface phase, serves to drastically reduce the “explosion / delay” profile of the present compositions by immediately restricting the exchange rate between the composition and the environment. The transient phases can include (usually in order from the outside towards the center of the deposit): H> or La, L., Lo and liquid (solution). It is highly preferred that the composition of the invention is capable of forming at least two and, more preferably, at least three of these phases simultaneously in transient stages after contact with water at physiological temperatures. In particular, it is highly preferable that one of the phases formed, at least transiently, is the L phase.
[000173] [000173] It is important to take into account that the pre-formulations of the present invention are of low viscosity. As a result, these pre-formulations should not be in any volume liquid crystalline phase, since all liquid crystalline phases have a significantly higher viscosity than could be administered by a syringe or spray dispenser. The pre-formulations of the present invention will thus be in a non-liquid crystalline state, such as a solution, phase L, or L3, particularly solution or Lx. The L phase, as used here throughout the document, is preferably an L, "swollen" phase containing more than about 10% by weight of the solvent (component c) having a reduced viscosity effect. This is in contrast to an L, "concentrated" or "swollen" phase containing no solvent, or a lesser amount of solvent, or containing a solvent (or mixture) that does not provide the decrease in viscosity associated with low viscosity solvents containing oxygen, specified here.
[000174] [000174] After administration, the pre-formulations of the present invention undergo a phase structure transition from a low viscosity mixture to a high viscosity deposit composition (generally adherent to the fabric). This will generally be a transition from a swollen molecular mixture, phase L, and / or L3 to one or more liquid crystalline phases (of high viscosity), such as normal or inverted hexagonal or cubic liquid crystalline phases or mixtures thereof. As indicated above, further phase transitions can also occur after administration. Obviously, the complete phase transition is not necessary for the operation of the invention, but at least one surface layer of the administered mixture will form a liquid crystalline structure. Generally, this transition will be rapid at least for the surface region of the administered formulation (the part in direct contact with air, body surfaces and / or body fluids). This will be even more preferably over a few seconds or minutes (for example, up to 30 minutes, preferably up to 10 minutes, more preferably, 5 minutes or less). The remainder of the composition may change from phase to liquid crystalline phase more slowly by diffusion and / or as the surface region is dispersed.
[000175] [000175] In a preferred embodiment, the present invention thus provides a pre-formulation as described herein, of which at least a portion of a hexagonal liquid crystalline phase forms upon contact with an aqueous fluid. The hexagonal phase thus formed can gradually disperse, releasing the active agent, or it can later convert to a cubic liquid crystalline phase, which in turn then gradually disperses. It is believed that the hexagonal phase will provide a faster release of the active agent, in particular, the hydrophilic active agent, than the structure of the cubic phase, in particular, phases 1, and L ,. Thus, when the hexagonal phase forms before the cubic phase, this will result in the initial release of an active agent to bring the concentration to an effective level quickly, followed by a gradual release of a “maintenance dose” as the cubic phase degrades. In this way, the release profile can be controlled.
[000176] [000176] Without adhering to theory, it is believed that after exposure (for example, to body fluids), the pre-formulations of the invention lose some or all of the organic solvents included in them (for example, by diffusion and / or evaporation) and remove aqueous fluids from the body environment (for example, moist air close to the body or the in vivo environment), so that at least part of the formulation generates a particularly non-lamellar liquid crystalline phase structure. In most cases, these non-lamellar structures are highly viscous and are not easily dissolved or dispersed in the in vivo environment and are bioadhesive and therefore are not easily rinsed or washed. In addition, due to the non-lamellar structure having large polar, non-polar and border regions, it is highly effective in solubilizing and stabilizing many types of active agents and protects them from degradation mechanisms. As the deposit composition formed from the preformulation gradually degrades over a period of days, weeks or months, the active agent is released gradually and / or diffuses out of the composition. Since the environment within the deposit composition is relatively protected, the pre-formulations of the invention are highly suitable for active agents with a relatively low biological half-life (see above). Robustness
[000177] [000177] The pre-formulations of the invention have improved strength compared to liquid deposit formulations known in the art. This is demonstrated by its better performance in terms of robustness to erosion / fragmentation, and robustness to degradation / mechanics.
[000178] [000178] One way to study robustness in vitro is to simulate in vivo conditions, subject lipid gels to an aqueous environment rich in surfactant and subsequently measure the increase in turbidity (or apparent absorbance) of the resulting aqueous phase from of fragments of lipids eroded by the surfactant. These lipid fragments are released into the solution as suspended particles and give rise to a substantial increase in the turbidity of the solution due to light scattering. Bile salts are often used as the surfactant of choice for the study of the dissolution of the formulation given its biological importance and endogenous nature. They are also among the most challenging components of the in vivo environment for a deposit system to tolerate, and thus a system that is resistant to bile salts is potentially of considerable value in drug distribution.
[000179] [000179] The turbidity factor of the preformulations of the present invention was measured using the process described in example 3. The turbidity factor can be considered a measure of the robustness of the preformulation with respect to erosion / fragmentation, ie , chemical degradation. The turbidity factor (TF) is thus defined here as the absorbance (or turbidity) at 600 nm of the aqueous phase resulting from placing a 200 mg aliquot of the preformulation in 5 ml of a 0.1% solution in weight of sodium taurocholate in phosphate buffered saline (pH 7.4), at 37ºC for 6 hours under a rotation of 150 rpm.
[000180] [000180] The pre-formulations of the present invention have a reduced turbidity factor, compared to existing formulations. Preferably, the turbidity factor is reduced by at least 50% compared to the existing pre-formulations. More preferably, the turbidity factor of the pre-formulations of the invention is reduced by at least 60% compared to that of existing pre-formulations. For example, the turbidity factor of the invention may be less than or equal to half, preferably less than 40% of the turbidity factor of the pre-existing formulation.
[000181] [000181] It is a considerable and surprising benefit of the present precursor formulations that they show markedly superior resistance to degradation compared to the corresponding formulations, in which the phospholipid component (component b)) is phosphatidyl choline. Thus, for example, the turbidity factor over an equivalent composition in which component b) is PC is reduced by at least 50%. More preferably, the turbidity factor of the pre-formulations of the invention is reduced by at least 60% compared to that of equivalent pre-formulations in which component b) is PC (e.g., soybean PC). For example, the turbidity factor of the invention may be less than or equal to half, preferably less than 40% of the turbidity factor of the corresponding PC-containing preformulation.
[000182] [000182] Preferably, the turbidity factor of the pre-formulations according to the invention can be about 0.6 or less, for example, 0.4. Most preferably, the turbidity factor may be 0.3 or less, for example, 0.25 or less. Most preferably, the turbidity factor may be 0.2 or less.
[000183] [000183] Compared to existing liquid deposit preformulations (such as those in which component b) is PC, such as soybean PC), preferably, the turbidity factor of the preformulations of the invention is reduced by at least minus a factor of three, for example, a factor of five, more preferably, a factor of eight or more and preferably a factor of ten.
[000184] [000184] In a preferred embodiment, the absorbance value of a pre-formulation based on PE according to example 3 will be in the range of one third to one eighth of the corresponding formulation based on PC. For example, a preformulation based on GDO / PE can have an absorbance value of one third to one eighth of the corresponding GDC / PC composition.
[000185] [000185] It is a particular and unexpected advantage of the present pre-formulations that they show a remarkable resistance to degradation by bile acids. This has considerable advantages in providing compositions that can be administered orally and persist through the digestive tract for some time without being broken / digested. In particular, the precursor formulations of the present invention are useful for delivering active agents to the GI tract. Since the composition still protects the trapped active agent from the conditions of the GI tract, this modality can be applied in combination with assets that are susceptible to degradation in the GI tract, such as peptides. Many peptides are described herein and can be used appropriately in the present embodiment. The distribution of an active agent to a portion of the lower GI tract of the duct is a highly preferred modality that can be applied to all relevant aspects of the invention. The pre-formulations can therefore be for the delivery of an active agent to the lower GI tract of the bile duct, etc. The treatment methods and similar applications can correspondingly be for the treatment of a condition in a region of the lower GI tract. of the bile duct.
[000186] [000186] In combination with the characteristics and preferred characteristics indicated herein, the pre-formulations of the present invention can have one or more of the following preferred characteristics independently or in combination: The optional active agent is present in the pre-formulation; The preformulation forms a liquid crystalline phase structure that is bioadhesive; Preferably, said liquid crystalline phase structure is an inverted hexagonal phase structure or an inverted cubic phase structure, or mixtures thereof, such as H, and / or L, or mixtures thereof; The non-polar tail groups of component a) each independently consist essentially of unsaturated C18 groups; or component a) consists essentially of at least one tocopherol: or component a) consists essentially of a mixture of glycerol dioleate (GDO) and tocopherol; Component b) is selected from phosphatidyl ethanolamine, or mixtures of phosphatidyl ethanolamines with at least one selected from phosphatidyl choline, phosphatidyl inositois and sphingomyelin; Phospholipid component b) comprises at least 50%
[000187] [000187] The active agent is selected from drugs, antigens, nutrients, cosmetics, fragrances, flavorings, diagnostic agents, vitamins, dietary supplements and mixtures thereof.
[000188] [000188] When said active agent is a drug, said drug is selected from drugs of small hydrophilic molecules, drugs of small lipophilic molecules, drugs of small amphiphilic molecules, peptides, proteins, oligonucleotides and mixtures thereof.
[000189] [000189] Said drug is selected from buprenorphine, fentanyl, granisetron, odansetron, palonsetron, aprepitant, fosaprepitant, somatostatin, somatostatin-related peptides dexamethasone, somatostatin 14, somatostatin 28, octreotide, lanreotide, the same pastreotide, vapreotide, and vapreotide , interferons, buserelin as GnRH agonists, goserelin, leuprorelin (leuprolide), triptorelin, GnRH antagonists, bisphosphonates, glucagon-like peptides 1 and 2 and analogs, such as GLP-I receptor agonists and GLP-2 receptor agonists GLP-1 (7-37), GLP-1 (7-36) amide, liragiutide, lixisenatide (AVEO010), and exenatide.
[000190] [000190] The pre-formulation is administrable by injection.
[000191] [000191] The pre-formulation is manageable by spraying, dipping, rinsing, application from a plaster or ball roller, painting, dripping, pump spraying or aerosol spraying.
[000192] [000192] The preformulation has a turbidity factor below 1, where the turbidity factor (TF) is defined as the absorbance (or turbidity) at 600 nm of the aqueous phase resulting from the placement of a 200 mg aliquot of the pre-formulation in 5 ml of a 0.1% solution by weight of sodium taurocholate in phosphate buffered saline (pH 7.4), at 37ºC for 6 hours under a rotation of 150 rpm.
[000193] [000193] The pre-formulation is injectable and forms a deposit that provides continuous release of the active agent for at least two weeks, preferably at least one month, in which said active agent comprises at least one selected from: a . leoprolide b. octreotide; ç. GLP-1; d. buprenorphine e. fentanyl; f. pasireotide; g. goserelin.
[000194] [000194] In combination with the characteristics and preferred characteristics indicated herein, the method (s) of release of the present invention can have one or more of the following preferred characteristics independently or in combination.
[000195] [000195] The method comprises administering at least one formulation with one or more preferred characteristics, as indicated above.
[000196] [000196] The method comprises the administration of at least one preformulation, as described herein, by subcutaneous injection, intramuscular injection, intracavity injection through tissue, intracavity injection into an open cavity without tissue penetration, spraying, lamination, smear , brushing, painting, rinsing, or dripping.
[000197] [000197] The method comprises administration by means of a pre-filled delivery device as indicated herein.
[000198] [000198] The method comprises administration through a needle no larger than a 20 gauge, preferably less than a gauge
[000199] [000199] The method comprises a single administration every 7 to 360 days, preferably from 7 to 120 days, for example, 14 to 90 days.
[000200] [000200] The method comprises a single administration every 4 to 180 days, preferably about 90 days.
[000201] [000201] In combination with the characteristics and preferential characteristics indicated here, the use (s) of the pre-formulations indicated here in the manufacture of medicines may have one or more of the following preferential characteristics, independently, or in combination: The use comprises the use at least one formulation with one or more preferred characteristics, as indicated above; The use comprises the manufacture of a medicament for the administration of at least one formulation as indicated herein; The use comprises the manufacture of a drug for administration by means of a pre-filled administration device, as indicated herein; The use comprises making a medicament for administration through a needle no larger than a 20 gauge, preferably less than a 20 gauge, and more preferably, a 23 gauge or less; The use includes the manufacture of a drug for administration once every 7 to 360 days, preferably from 7 to 120 days, for example, 14 to 90 days.
[000202] [000202] In combination with the characteristics and preferred characteristics indicated herein, the pre-filled devices of the invention can have one or more of the following preferred characteristics independently or in combination: They contain a preferred formulation, as indicated herein;
[000203] [000203] The method is for prophylaxis against at least one state selected from infection during surgery, infection during implantation, burns, infection at the burn site, cuts or abrasions, oral infections, genital infections and infections resulting from activities resulting from exposure to infectious agents.
[000204] [000204] The invention will now be further illustrated by reference to the following non-limiting Examples and attached Figures. Figures
[000205] [000205] Figure 1: apparent absorbance (turbidity) of the aqueous phase measured at 600 nm for gels with the indicated lipid compositions (% by weight) incubated in 0.1% by weight sodium taurocholate (NaTC). The gels were incubated at 37ºC for 6 hours with moderate agitation (150 rpm). See also Table 1 for composition details.
[000206] [000206] Figure 2: X-ray diffraction patterns of DOPE / GDO mixtures fully hydrated in saline solution at 25, 37 and 42ºC between DOPE / GDO weight ratios of 75/25 and 35/65, as indicated in the figure. The positions of the relative diffraction peak indicate that the liquid crystal structure changes from inverted hexagonal to inverted micellar cubic (spatial group Fd3m) when the GDO content is increased.
[000207] [000207] Figure 3: X-ray diffraction patterns of mixtures of DOPE / GDO (60/40 by weight) and DOPE / TOC (60/40 by weight) completely hydrated in saline solution at 25, 37 and 42ºC. The positions of the relative diffraction peak indicate the same inverted micellar liquid crystalline structure (Fd3m) within the investigated temperature range.
[000208] [000208] Figure 4: X-ray diffraction patterns of DOPE / GDO mixtures (50/50 by weight) fully hydrated (in saline (0.9% NaCl w / v)), including octreotide at 25, 37 and 42ºC. The concentration of octreotide in the respective lipid formulation is shown in the figure. The positions of the relative diffraction peak indicate the same inverted micellar liquid crystal structure (Fd3m) within the investigated octreotide concentration and temperature range.
[000209] [000209] Figure 5: In vivo pharmacokinetic profile of buprenorphine after subcutaneous administration of three formulations of the invention in rats. The error bars indicate the standard deviation (n = 6). Formulation compositions are shown in Example 12.
[000210] [000210] Figure 6: In vivo pharmacokinetic profile of leuprolide (LEU) after subcutaneous administration in rats. The error bars indicate the standard deviation (n = 8). The formulation compositions are indicated in the Example
[000211] [000211] Figure 7: In vivo pharmacokinetic profile of octreotide (OCT) after subcutaneous administration in rats. The error bars indicate the standard deviation (n = 6). The formulation compositions are indicated in the Example
[000212] [000212] Figure 8: In vivo pharmacokinetic profile of octreotide (OCT), after subcutaneous administration in rats. The error bars indicate the standard deviation (n = 6). The formulation compositions are indicated in the Example
[000213] [000213] Figure 9: In vivo pharmacokinetic profile of octreotide (OCT) after subcutaneous administration in rats. The error bars indicate the standard deviation (n = 6). The formulation compositions are indicated in the Example
[000214] [000214] Figure 10: A comparison of the mechanical strength of liquid crystalline gels formed by mixtures of DOPE / GDO and SPC / GDO in aqueous solution (PBS, pH 7.4). The following phospholipid / GDO weight ratios were investigated and compared: 70:30 (a), 65:35 (b), 60:40 (c), 55:45 (d) and 50:50 (e). Material Examples
[000215] [000215] Phosphatidyl choline (SPC) - Lipoid S100 from Lipoid,
[000216] [000216] Liquid pre-formulations (2 g) of phospholipid and diacylglycerol were prepared by weighing the respective lipid and solvent components according to Table 1, in 3 mL (2R) flasks followed by mixing at 40 ° C until that homogeneous liquid solutions were obtained (<20 h). After cooling to room temperature, all formulations were observed to be homogeneous liquids of low viscosity. Table 1. Composition of liquid pre-formulations comprising phospholipid and diacylglycerol (% by weight) B bs bs kh ho -—-—-— KSPCDOPEGDO = 25 / 25.00 | E is is ia DONATED SAO EB b8 | 62 = & E Efrceno = zsmo
[000217] [000217] All liquid preformulations in Table 1 were subjected to a gelation test in which 0.20 g of the respective formulation was injected in 5 ml of PBS (pH 7.4) in 6 ml injection glass vials (6R) using disposable 1 mL Luer-Lock syringes and 23 G needles. All formulations were easily injected using a 23 G needle size. The resulting gels were visually inspected after 1 h at room temperature and found to be they formed coherent gels that cannot be broken by gently shaking the vials. Example 3: Robustness of lipid gels in the presence of bile salts
[000218] [000218] For deposit formulations of prolonged duration and / or for oral formulations, an important property is related to the robustness of the gel for erosion / fragmentation by endogenous surfactants and / or lipid degrading enzymes. One way to study robustness in vitro is to subject lipid gels to an aqueous environment rich in surfactant and subsequently measure the increase in turbidity (or apparent absorbance) of the resulting aqueous phase from lipid fragments eroded by surfactants. Such lipid fragments give rise to a substantial increase in the turbidity of the solution due to the dispersion of light. Bile salts are often used as the surfactant of choice for the study of dissolution of the formulation given its biological importance and endogenous nature. Therefore, the gels (0.20 g) formed in PBS by the formulations shown in Table 1 were placed in 5 ml of a 0.1% by weight solution of sodium taurocholate (NaTC) in PBS. The resulting samples were then transferred to an incubator maintained at 37ºC with a rotation speed of 150 rpm. After 6 hours, the samples were removed from the incubator, turned upside down twice, and the respective aqueous solution was transferred to a 1.5 ml disposable semi-micro cuvette for measuring absorption. Turbidity or absobance (apparent) was measured using a PerkinElmer Lambda 40 UV / Vis spectrometer and air was only used for background correction. The results of the robustness study are shown in Figure 1.
[000219] [000219] As is evident from Figure 1, the more the PE component (DOPE) is included in the formulation, the more robust the gel is for surfactant-induced erosion. For example, by including 50% DOPE with respect to SPC (SPC / DOPE = 50/50 weight / weight) (Formulationott 3 and 7 in Table 1), a significant drop in turbidity is observed as a result of increased robustness for erosion induced by surfactant. This effect is more pronounced for formulations containing an SPC / DOPE weight ratio of 25/75 (Formulation ! 4), and more pronounced for formulations comprising only the DOPE component in combination with GDO (Formulations 5, 8, 9 and 10 in Table 1). In fact, the aqueous solutions of the gels that comprise only DOPE / GDO (Formulations 5, 8, 9 and 10 in Table 1) were completely transparent to the naked eye. Example 4: Liquid pre-formulations comprising phospholipids, diacylglycerol and buprenorphine
[000220] [000220] For 0.475 g of Formulation * t 1-10 in Table 1 (Example 1) 25 mg of buprenorphine base (BUP) was added to give BUP 5% by weight in total, and the resulting samples (in vials) 2R injection glass) were placed in a roller mixer at 40ºC for about 20 hours. All formulations were verified to be homogeneous and transparent liquids of low viscosity after cooling to room temperature. Example 5: Liquid preformulation comprising phospholipid, diacylglycerol and leuprolide acetate
[000221] [000221] For 0.485 g of Formulationott 5 in Table 1 (Example 1) 15 mg of leuprolide acetate (LEU) were added to give the LEU 3% in total and the resulting sample (2R injection glass vial) ) was placed in a roller mixer at room temperature for about 48 hours. Example 6: Liquid preformulations comprising phospholipid, diacylglycerol, polar solvent and low viscosity organic solvent
[000222] [000222] Liquid pre-formulations (1 g) of phospholipid and diacylglycerol were prepared as described in Example 1. After mixing, all formulations were observed to be homogeneous, low-viscosity liquids at room temperature. The formulations compositions are given in Table 2. Table 2. Composition of liquid pre-formulations containing phospholipid, diacylglycerol, polar solvent and low viscosity organic solvent (% by weight) mM Bbs3 bo bg ho p | PB Bb bo bs Bo pp | Bo Bb 1 bi bs b3 pp | MM bs ho br bp2 EF bs bs h8 PF ho | he boo bo he Ff Be | mr ho kb 3 ha | ba | BB ke2 6 2 mo | kg | Example 7: Liquid pre-formulations comprising a phospholipid and α-tocopherol
[000223] [000223] Liquid pre-formulations (2 g) of phospholipid and a-tocopherol (TOC) are prepared by weighing the respective lipid and solvent components according to Table 3 in 3 ml bottles (2R) followed by mixing with rolls at 40ºC until homogeneous liquid solutions are obtained (<20 h). After cooling to room temperature, all formulations are observed to be homogeneous liquids of low viscosity. Table 3. Composition of liquid pre-formulations comprising phospholipid and α-tocopherol (TOC) (% by weight)
[000224] [000224] The liquid preformulations (2 g) of DOPE and GDO were prepared by weighing the required amount of the respective lipid components in 3 ml (2R) bottles followed by the addition of EtOH, to a total concentration of 10-15% in Weight. The weight ratio of the lipids in the different samples was in the range of DOPE: GDO = 75: 25-35: 65. The samples were mixed in a roller mixer at 40ºC until homogeneous liquid solutions were obtained (<20 h). After cooling to room temperature, all formulations were observed to be homogeneous, low viscosity liquids. The respective formulation (0.5 g) was then injected in 5 ml of saline (NaCl 0.9% w / v) in 6 ml (6R) injection glass vials using 1 ml disposable Luer-Lock syringes and injection needles. 23 G. All formulations were easily injected using the needle size 23G. The resulting gels were allowed to equilibrate in a roller mixer at room temperature for 10 days before small angle X-ray scattering measurements (SAXS).
[000225] [000225] SAXS Synchrotron measurements were made on the I911 beam line at MAX-lab (Lund University, Sweden), using a 165 mm Marresearch CCD detector mounted on a Marresearch Desktop Beamline beam base plate. The liquid crystalline samples of DOPE / GDO / saline were mounted between the Kapton windows on a steel sample holder at a sample-detector distance of 1916.8 mm. The diffractograms were recorded at the indicated temperatures (Figure 2) under high vacuum with a wavelength of 0.91 Å and the beam size of 0.25 x 0.25 mm (full width at half height) for the sample. The exposure time for each sample was 3 min. The resulting CCD images were integrated and analyzed using the calibrated wavelengths and the positions of the detector. The positions of the relative diffraction peaks shown in Figure 2 indicate that the liquid crystal structures change from inverted hexagonal (H2) with high DOPE content to inverted micellar cubic (12, space group Fd3m) when the GDO content is increased. Example 9: Liquid crystalline phase structures of Mixtures of DOPE / TOC and DOPE / GDO in the presence of the aqueous phase
[000226] [000226] Liquid preformulations (2 g) of DOPE / GDO and DOPE / TOC were prepared by weighing the required amount of the respective lipid components in 3 ml (2R) flasks followed by the addition of EtOH, to a total concentration of 10% by weight. The weight ratio of the lipids in the different samples was DOPE: GDO and DOPE: TOC = 60:40. The samples were mixed in a roller mixer at 40ºC until liquid homogeneous solutions were obtained (<20 h). After cooling to room temperature, the formulations were observed to be homogeneous liquids of low viscosity. The respective formulation (0.5 g) was then injected in 5 ml of saline (NaCl 0.9% w / v) in 6 ml (6R) injection glass vials using 1 ml disposable Luer-Lock syringes, and 23G needles. The formulations were easily injected using the needle size of 23G. The resulting gels were allowed to equilibrate in a roller mixer at room temperature for 10 days before small angle X-ray dispersion measurements (SAXS).
[000227] [000227] Synchrotron SAXS measurements were performed as described in Example 8 and the results are shown in Figure 3. The positions of the relative diffraction peaks (figure 3) indicate the same inverted micellar liquid crystalline (Fd3m) structure for both mixtures of DOPE / GDO and DOPE / TOC (60/40 w / w) within the investigated temperature range.
[000228] [000228] Synchrotron SAXS measurements were performed as described in Example 8 and the results are shown in Figure 4, where the diffractogram of the DOPE / GDO mixture without octreotide was also included. The positions of the relative diffraction peaks indicate that the inverted micellar liquid crystalline (Fd3m) structure observed for the DOPE / GDO mixture without the octreotide active agent is retained within the investigated octreotide concentration ranges and temperatures. Example 11. Formulation comprising DOPE, GDO, EtOH, PG and pasireotide (pamoate salt)
[000229] [000229] A liquid preformulation (2 g) comprising DOPE and GDO was prepared by weighing the required amount of the respective lipid component in 2 ml (2R) flasks followed by adding the required amount of EtOH and PG. The sample was mixed in a roller mixer at 40ºC until a homogeneous liquid solution was obtained (<20 h). After cooling to room temperature, pasireotide pamoate (or SOM230) was added to the formulation to obtain a final concentration of about 30 mg / ml pasireotide (calculated as a free base). The final sample composition is given in Table 5. Table 5. Composition of liquid preformulation comprising DOPE, GDO, EtOH, PG and Pasireotide (% by weight). The pasireotide concentration corresponds to approximately 30 mg of pasireotide free base / mL. Example 12: In vivo pharmacokinetic study of formulations comprising buprenorphine
[000230] [000230] Liquid pre-formulations (6 g) comprising BUP, DOPE and GDO were prepared by weighing the required amount of the respective component in 10 ml (10R) bottles followed by the addition of EtOH. The samples were mixed in a roller mixer at 40ºC until liquid homogeneous solutions were obtained (about 6 hours). The respective formulation was then sterilized by filtration under pressure of 2.5 bar of nitrogen using a sterilized 0.2 micron PVDF membrane filter from Miilipore. Formulation compositions are provided in Table 6. Table 6. Composition of liquid pre-formulations comprising DOPE, GDO, EtOH and BUP (% by weight). The concentration of BUP corresponds to 50 mg of BUP base / mL. Formulation = ——BUP ——— boE ko Eom | BUP-1
[000231] [000231] The formulations in Table 6 were injected subcutaneously to male Sprague-Dawley rats at a dose volume of 0.2 ml / kg (10 mg BUP / kg). Bloods for pharmacokinetics were collected before the dose, and at 1 hour, 6 hours, 1 day, 2 days, 5 days, 8 days, 14 days, 21 days and 28 days after dosing. 0.2 ml blood samples were collected by sublingual bleeding in EDTA-treated test tubes (Capiject 3T-MQK, Terumo Medical Corporation). The blood was placed on ice immediately after collection and centrifuged (approximately 1500xg, at 5ºC for 10 min) within 30 to 60 minutes. The plasma was transferred to translucent test tubes properly labeled with 1.5 ml propylene (Microcentrifuge tubes, Plastibrand, Buch & Holm) and stored below - 70ºC until transport on dry ice for analysis. The concentration of buprenorphine in the rat plasma samples was analyzed using an ELISA assay for BUP determination in EDTA rat plasma samples.
[000232] [000232] The pharmacokinetic profiles (PK) obtained are shown in Figure 5 and demonstrate sustained BUP release for at least 28 days. Example 13: In vivo pharmacokinetic study of formulations containing leuprolide acetate
[000233] [000233] Liquid preformulations comprising phospholipid and GDO were prepared by weighing the required amount of the respective lipid component in 15 ml (15R) flasks followed by the addition of EtOH. The samples were mixed in a roller mixer at 40ºC until homogeneous liquid solutions were obtained. The required amount of LEU was dissolved in the required amount of WFI containing 0.1 mg EDTA / ml. The respective lipid / EtOH solution was then added to the LEU / WFI solution. The resulting formulations were finally mixed in a roller mixer at room temperature and subjected to sterile filtration under 2.5 bar nitrogen pressure using a 0.2 micron sterile PVDF membrane filter from Millipore. The total lot size was 7 g, and the compositions of final formulations are shown in the Table
[000234] [000234] The formulations in Table 7 were injected subcutaneously to male Sprague-Dawlcy rats at a dose volume of 0.2 ml / kg (5 mg LEU acetate / kg). Blood for pharmacokinetics was collected before the dose and 1 hour, 6 hours, 1 day, 2 days, 5 days, 8 days, 14 days, 21 days and 28 days after dosing. Blood samples of 0.25 mL were collected by sublingual bleeding in test tubes treated with EDTA (Capiject 3T-MQK, Terumo Medical Corporation). The blood was placed on ice immediately after collection and centrifuged (approximately 1500xg, at 5ºC for 10 min) for 30 to 60 minutes. The plasma was transferred to 1.5 ml green propylene test tubes properly labeled (Microcentrifuge tubes, Plastibrand, Buch & Holm) and stored below - 70ºC until transport on dry ice for analysis. Leuprolide analysis was performed using the high sensitivity EIA kit (Des-Gly 10, D-LEU6, Pro-NHEt9) -LHRH (leuprolide) (S-1174, Bachem / Peninsula Laboratories), adapted for LEU analysis in plasma with rat EDTA.
[000235] [000235] The PK profiles obtained are shown in Figure 6 demonstrating sustained LEU release for at least 28 days for both formulations. Notably, the LEU-2 formulation comprising DOPE showed more stable plasma levels over time and, in particular, plasma levels from day 14 to day 28. Example 14: Study 1 of the in vivo pharmacokinetics of a formulation comprising octreotide
[000236] [000236] Liquid preformulations comprising DOPE / GDO and SPC / GDO were prepared by weighing the required amount of the respective lipid component in 15 ml (15R) flasks followed by the addition of EtOH. The samples were mixed in a roller mixer at 40ºC until homogeneous liquid solutions were obtained. The required amount of octreotide hydrochloride was weighed in a 10 ml (10R) glass vial followed by the addition of the respective lipid / FtOH solution. The resulting formulations were mixed in a roller mixer at RT (room temperature) until homogeneous liquid solutions were obtained. The respective formulation was then sterilized by filtration under pressure of 2.5 bar of nitrogen using a sterile 0.2 micron PVDF membrane filter from Millipore. The batch size was 7 g, and the compositions of the final formulations are provided in Table 8. Table 8. Composition of liquid pre-formulations containing phospholipid, GDO, cosolvent and OTC (% by weight). The concentration of OTC corresponds to 45 mg of octreotide-free base / mL. ber2 RB O pp ko ko ho)
[000237] [000237] The formulations in Table 8 were injected subcutaneously to male Sprague-Dawley rats at a dose volume of 0.6 mL / Kkg (27 mg of octreotide-free base / kg). Bloods for pharmacokinetics were collected before the dose, and 1 hour, 6 hours, 1 day, 2 days, 5 days, 8 days, 14 days, 21 days, 28 days and 35 days after dosing. Blood samples from
[000238] [000238] The pharmacokinetic profiles obtained are shown in Figure 7, which demonstrates the sustained release of OCT for at least 35 days for both formulations. Notably, the OCT-1 formulation, which comprises DOPE, showed more stable plasma levels over time and, in particular, plasma levels from day 14 to day 35. Example 15: Study 2 of in vivo pharmacokinetics of formulations comprising octreotide
[000239] [000239] Liquid preformulations (5 & comprising phospholipid, GDO, cosolvents and octreotide were prepared as described in Example 14. The final formulation compositions are shown in Table 9. Table 9. Composition of liquid preformulations comprising phospholipid, GDO, cosolvent and OCT (% by weight) O SE SE Eee Es es Fes e cê
[000240] [000240] The formulations in Table 9 were injected subcutaneously to male Sprague-Dawley rats in a dose volume of 0.2 mL / Kkg (9 mg of OCT-free base / kg of OCT-1 and OCT-2 and 4 mg of free base of OCT / kg of OCT-3 and OCT-4). Bloods for pharmacokinetics were collected before the dose, and 1 hour, 6 hours, 1 day, 4 days, 6 days, 8 days, 11 days, 14 days, 18 days, 21 days, 25 days and 28 days after dosing. The sampling and bioassay procedure was as described in Example 14.
[000241] [000241] The PK profiles obtained are shown in Figure 8, which demonstrates the sustained release of OCT for at least 28 days for all formulations. Notably, the formulations OCT-1 and OCT + 3, comprising DOPE showed more stable plasma levels over time and, in particular, the highest plasma levels from day 14 to day 28. The variability in plasma concentrations measured over longer times after injection (> 21 days) it was also lower for DOPE-based formulations, especially pronounced for the OCT-3 formulation with 20 mg of OCT free base / mL.
[000242] [000242] An interesting and noteworthy result in the study was that deposits of DOPE-based formulations were present at the injection site in all animals at the termination whereas half or more of the animals that received SPC-based formulations showed complete clearance of the deposit matrix. This indicates differences in the in vivo degradation kinetics of the lipid matrix and supports PK data in longer times after injection where DOPE-based formulations showed higher and less variable plasma levels. Example 16: Study 3 of in vivo pharmacokinetics of formulations comprising octreotide
[000243] [000243] Pre-formulations (5 g) comprising phospholipid, GDO, cosolvents and octreotide were prepared as described in Example 14. The compositions of the final formulation are shown in Table 10. Table 10. Composition of liquid pre-formulations containing phospholipid, GDO, cosolvent and OCT (% by weight). The concentration of OCT corresponds to 20 mg of free base of OCT / mL. Formulation = “Bctr —bore Ekc Goo Eom | pers =. b3a bs Ff Bbso4 fhooo |
[000244] [000244] The formulations in Table 10 were injected subcutaneously to male Sprague-Dawley rats in a dose volume of 0.2 ml / kg (4 mg of OCT free base / kg). Bloods for pharmacokinetics were collected before the dose, and 1 hour, 6 hours, 1 day, 4 days, 6 days, 8 days, 12 days, 14 days, 19 days, 21 days and 28 days after dosing. The sampling and bioassay procedure was as described in Example 14.
[000245] [000245] The pharmacokinetic profiles obtained are shown in Figure 9, which demonstrates the sustained release of OCT for at least 28 days for all formulations. Higher initial release and lower plasma OCT levels were observed for the OCT-5 formulation while the plasma profiles were similar for the other formulations. Example 17: Formulations comprising DOPE, GDO, EtOH, PG and GLP-1 receptor agonists
[000246] [000246] Liquid pre-formulations (2 g) comprising DOPE and GDO are prepared by weighing the required amount of the respective lipid component in 2 ml (2R) bottles followed by the addition of the required amount of EtOH and PG. The samples are mixed in a roller mixer at 40ºC until homogeneous liquid solutions are obtained. After cooling to room temperature, exenatide (EXT) and liraglutide (LIR), respectively, are added to the formulations to give a final concentration of about 10 mg of GLP-1 receptor agonist / mL. The final compositions of the samples are shown in Table 11. Table 11. Composition of liquid pre-formulations comprising DOPE, GDO, EtOH, PG and EXT or LIR (% by weight). The concentration of
[000247] [000247] Liquid pre-formulations (1 g) of the mixtures of DOPE / GDO and SPC / GDO were prepared by weighing the required amount of the respective lipid components in 3 ml (2R) flasks followed by the addition of EtOH to a total concentration of 10% by weight. The weight ratio of the lipids in the different samples was in the range of DOPE: GDO = 70: 30-50:50 and SPC: GDO = 70: 30-50: 50. The samples were mixed in a roller mixer at 40ºC until liquid homogeneous solutions were obtained (<20 h). After cooling to room temperature, the formulations were observed to be homogeneous, low viscosity liquids. The respective formulation (0.5 g) was then injected in 5 ml of phosphate buffered saline (pH 7.4) in 10 ml (10R) glass injection vials using 1 ml disposable Luer-Lock syringes and needles of 23G. The formulations were easily injected using the needle size of 23G. The resulting gels were allowed to equilibrate on a mechanical mixing table at 37ºC and 150 rpm for 20 days before the robustness measurement.
[000248] [000248] Measurements of liquid crystalline strength were performed using a TA.XT plus Texture Analyzer (Stable Micro Systems Ltd., UK) equipped with a 2 mm thick stainless steel needle. Force vs. distance dependencies were recorded by needle penetration at about 4 mm into liquid crystalline gels at a speed of 0.5 mm / s. The greater the force required to penetrate the needle, the greater the mechanical strength of the gel.
[000249] [000249] The results are shown in Figure 10, which show in all cases that DOPE-based liquid crystalline gels (LC) are significantly more mechanically robust compared to SPC-based LC gels. This result is in line with the increased resistance to surfactant-induced erosion, as exemplified in Example 1. The higher mechanical strength of DOPE-based formulations compared to SPC-based formulations can also be a reason for the difference in performance in vivo between the types of formulation, as described in Examples 13-15. Example 19: Liquid pre-formulations comprising phospholipid, diacylglycerol and goserelin acetate
[000250] [000250] Liquid pre-formulations (2 g) comprising DOPE, SPC and GDO are prepared by weighing the required amount of the respective lipid component in 2 ml (2R) bottles followed by the addition of the required amount of co-solvent. The samples are mixed in a roller mixer at 40ºC until homogeneous liquid solutions are obtained. After cooling to room temperature, goserelin acetate (GOS) is added to the formulations in the final concentration indicated in Table 12.
Table 12. Composition of liquid pre-formulations comprising DOPE, SPC, GDO, cosolvent and GOS (% by weight). [= son] Too Tm and Ts)
CEIETE TO Tre TIE —— Cr TE E TT —— TT TWT 1 - Co FF TI E —— CF EEE —— a Rs as is 5 GR EST a 5 5 1 - CcooTEITITE IA CR Te Ts Cr ET TT ET 6 CAE o EE and

权利要求:
Claims (29)
[1]
1. Preformulation, characterized by the fact that it comprises a low viscosity, non-liquid crystalline mixture of: a. at least one glycerol diacil and / or at least one tocopherol; B. at least one phospholipid component comprising phospholipids having L polar head groups comprising more than 50% phosphatidyl ethanolamine, and a. two acyl chains each independently having 16 to 20 carbons, where at least one acyl chain has at least one unsaturation in the carbon chain and there are no more than four unsaturations across two carbon chains; wherein said phospholipid component b) comprises more than 50% phosphatidyl ethanolamine (PE); ç. at least a low viscosity, biocompatible organic solvent containing oxygen; having a ratio of a) to b) between 80:20 and 20:80 by weight; wherein optionally at least one bioactive agent is dissolved or dispersed in the low viscosity mixture; wherein the preformulation has a viscosity of 0.1 to 5000 mPa.s at 20 ° C; and wherein the preformulation forms, or is capable of forming at least one non-lamellar liquid crystalline phase structure upon contact with an aqueous fluid.
[2]
2. Preformulation according to claim |, characterized in that said liquid crystalline phase structure is a reverse hexagonal phase structure or a reverse cubic phase structure or mixtures thereof, such as an H> structure, L7 or mixtures thereof.
[3]
3. Preformulation according to any of the claims | or 2, characterized by the fact that the non-polar tail groups of component a) each consist independently of unsaturated C18 groups.
[4]
4. Preformulation according to any one of claims 1 to 3, characterized in that component a) essentially consists of at least one tocopherol; or where component a) consists essentially of a mixture of glycerol dioleate (GDO) and tocopherol.
[5]
Preformulation according to any one of claims 1 to 4, characterized in that component b) is selected from phosphatidyl ethanolamines or mixtures of phosphatidyl ethanolamines with at least one selected from phosphatidyl choline, phosphatidyl inositols and sphingomyelin, preferably, phosphatidyl choline, such as Soybean PC (SPC) and / or dioleyl phosphatidyl choline (DOPC).
[6]
6. Preformulation according to any one of claims 1 to 5, characterized in that said phospholipid component b) comprises at least 75% PE, for example, at least 80% PE or at least 90% PE and, more preferably, essentially 100% PE.
[7]
7. Preformulation according to any of the claims | to 6, characterized by the fact that the phospholipid component b) comprises a phospholipid having polar head groups consisting essentially of 100% phosphatidyl ethanolamine.
[8]
Preformulation according to any one of claims 1 to 7, characterized in that the phospholipid component b) further comprises at least one phospholipid having i. polar head groups comprising at least 90%
phosphatidyl choline, and ii. two acyl chains each having 16 to 20 carbons independently, where at least one acyl chain has at least one unsaturation in the carbon chain, and there are no more than four unsaturations across two carbon chains.
[9]
9. Preformulation according to any of the claims | to 8, characterized by the fact that the phospholipid component b) comprises at least 10% PC, for example, at least 20% PC or at least 30% PC, preferably SPC, DOPC or mixtures thereof.
[10]
10. Preformulation according to any one of claims 1 to 9, characterized in that component b) comprises about 70% PE and about 30% PC, more preferably about 80% PE and about 20% PC and more preferably about 90% PE and about 10% PC.
[11]
11. Preformulation according to any of the claims | to 10, characterized by the fact that component b) of phospholipid forms a hexagonal phase in contact with excess water at temperatures in the range of 36 to 40ºC.
[12]
12. Preformulation according to any one of claims 1 to 11, characterized in that it has an L, and / or L; 3 phase structure of molecular solution.
[13]
13. Preformulation according to any of the claims | to 12, characterized by the fact that it has a ratio of a) to b) between 40:60 to 60:40 in weight.
[14]
14. Preformulation according to any one of claims 1 to 13, characterized by the fact that it has at least 15% of component a) and / or at least 15% of component b) by weight of components a) + b) + c).
[15]
15. Preformulation according to any one of claims 1 to 14, characterized by the fact that it has 2 to 40% of component c) by weight of components a) + b) + c).
[16]
16. Preformulation according to any one of claims 1 to 15, characterized in that component c) is selected from alcohols, ketones, esters, ethers, amides, sulfoxides and mixtures thereof, including dimethyl sulfoxide (DMSO), ethanol , n-methyl pyrrolidone (NMP), or mixture of NMP and ethanol.
[17]
17. Preformulation according to any one of claims 1 to 16, characterized in that it additionally comprises up to 10% by weight of a) + b) of a charged amphiphile.
[18]
18. Preformulation according to any one of claims 1 to 17, characterized in that it has 0.1 to 10% by weight of said active agent by weight of the components a) + b) + c).
[19]
19. Preformulation according to any one of claims 1 to 18, characterized in that it further comprises: up to 20% by weight of at least one polar solvent d) by weight of components a) + b) + c) + d), preferably 1.2 to 20% by weight, preferably 2 to 20% by weight, more preferably 5 to 18% by weight, more preferably 8 to 15% by weight; preferably wherein said polar solvent has a dielectric constant of at least 28 measured at 25 ° C, more preferably at least measured at 25 ° C.
[20]
20. Preformulation according to claim 19, characterized in that component d) comprises or consists of water or propylene glycol or mixtures thereof.
[21]
21. Preformulation according to claim 19 or claim 20, characterized by the fact that component d) comprises at least 2% water.
[22]
22. Preformulation according to any one of claims 19 to 21, characterized in that component c) comprises at least one Dbiocompatible, organic, monoalcoholic solvent, preferably at least one selected from the group consisting of ethanol, propanol , isopropanol or mixtures thereof, more preferably ethanol; or wherein component c) comprises NMP or mixtures of NMP and ethanol.
[23]
23. Preformulation according to any one of claims 19 to 22, characterized in that the combined components c) and d) are present in a total level less than or equal to 40% by weight, preferably 30% by weight, more preferably 25% by weight, for example, in the range of 15 to 20% by weight.
[24]
24. Preformulation according to any one of claims 1 to 30, characterized in that said active agent is selected from drugs such as hydrophilic small molecule drugs, lipophilic small molecule drugs, amphiphilic small molecule drugs, peptides , proteins, oligonucleotides and their mixtures, antigens, nutrients, cosmetics, fragrances, flavorings, diagnostic agents, vitamins, dietary supplements and their mixtures.
[25]
25. Preformulation according to claim 24, characterized in that said drug is selected from opioid agonists such as buprenorphine and fentanyl, GnRH agonists such as buterelin, deslorelin, goserelin, leuprorelin / leuprolide, naferelin and triptorelin, antagonists GnRH such as cetrorelix, ganirelix, abarelix, degarelix, somatostatins such as SST-14 and SST-28; somatostatin receptor (SSTR) agonists such as octreotide, lanreotide, vapreotide and pasireotide; glucagon-like peptide receptor agonists (GLP-1) such as GLP-1 (7-37), GLP-1 (7-36) amide, liraglutide, exenatide and lixisenatide (-AVEO010); and glucagon-like peptide agonists such as ZP1846; and their mixtures.
[26]
26. Preformulation according to any one of claims 1 to 25, characterized by the fact that it is administrable by injection, spraying, dipping, rinsing, applying a ball pad or roller, painting, dripping, aerosol spraying or spraying pump.
[27]
27. Injectable preformulation as defined in any of the claims | to 26, characterized by the fact that it forms a deposit providing continuous release of active agent for at least two weeks, in which said active agent comprises at least one selected from leuprolide, octreotide, GLP-1, buprenorphine, fentanyl, pasireotide and goserelin .
[28]
28. Use of a preformulation as defined in any one of claims 1 to 27, characterized in that it is for preparing a drug for sustained administration of an active agent.
[29]
29. Use of a preformulation as defined in any of the claims | to 27, characterized by the fact that it is to prepare a medication for the treatment of a selected condition of bacterial infection, fungal infection, sore skin, eye conditions, sore genitals, infections and conditions for fingernails and / or toes, nausea travel, addiction including depending on nicotine, periodontal infection, conjunctivitis, glaucoma and hormonal deficiency or imbalance; or for prophylaxis against at least one selected condition of infection during surgery, infection during implantation, sunburn, infection at the burn site, cuts or grazes, oral infections, genital infections and infections resulting from activities resulting from exposure to infectious agents.

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法律状态:
2020-07-14| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-07-21| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2021-09-08| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|Free format text: NOTIFICACAO DE DEVOLUCAO DO PEDIDO EM FUNCAO DA REVOGACAO DO ART. 229-C DA LEI NO 9.279, DE 1996, POR FORCA DA LEI NO 14.195, DE 2021 |

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2021-09-21| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2022-03-08| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US201161566851P| true| 2011-12-05|2011-12-05|

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US61/566851|2011-12-05|

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PCT/EP2012/073843|WO2013083460A1|2011-12-05|2012-11-28|Robust controlled-release formulations|

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