anesthetic or sedative composition

专利摘要:
HOSTED COMPOSITION / SEDATIVE OR ANESTHETIC DELIVERY GUEST, ANESTHETIC OR SEDATIVE COMPOSITION, ANESTHETIC OR SEDATION COMPOSITION, INDUCTION OR MAINTENANCE METHOD FOR ADMINISTRATION OF AN INTERMITTENT CAKE OR AN INFOUSION, ANESTHESIA OR STEAM SENTION, ANESTHETIC OR HYDRAULATION A MODIFIED FORM OF THE SAME IN THE MANUFACTURING OF A MEDICINE TO INDUCT ANESTHESIA IN AN INDIVIDUAL AND METHOD OF INDUCTION OR MAINTENANCE BY ADMINISTRATION OF A BITTER CAUSE OR INFUSION, SEDATION IN A HUMAN INDIVIDUAL The present invention generally refers to the field of delivery systems. of drug for neuroactive steroid anesthetic agents. More particularly, anesthetic and sedative formulations are provided in the form of host / guest preparations comprising one or more neuroactive steroid anesthetics and a cyclodextrin. Particular cyclodextrins contemplated include sulfoalkyl ether cyclodextrins and modified forms thereof.
公开号:BR112012017800B1
申请号:R112012017800-8
申请日:2011-01-19
公开日:2020-12-08
发明作者:Juliet Marguerite Goodchild；Colin Stanley Goodchild；Benjamin James Boyd
申请人:Drawbridge Pharmaceuticals Pty Ltd；
IPC主号:

专利说明:

DEPOSIT DATA
[001] This application is associated with, and claims the priority of Provisional Patent Application No. US 61 / 297,249, filed on January 21, 2010, entitled "Anesthetic Formulation" and Provisional Patent Application No. US 61 / 385,318 filed on 22 September 2010, entitled "Anesthetic formulation", in which the contents of these are incorporated in this document as a reference in their entirety. FIELD
[002] The present invention relates in general to the field of drug delivery systems for neuroactive steroid anesthetic agents. More particularly, sedative and anesthetic compositions are provided in the form of host / guest preparations that comprise one or more neuroactive steroid anesthetics and a cyclodextrin or a modified form thereof. BACKGROUND
[003] The bibliographic details of references provided in the relevant specification are listed at the end of the specification.
[004] Reference to any prior technique is not and should not be understood as an acknowledgment or any form of suggestion that this prior technique is part of the common general knowledge in any country.
[005] Drug delivery systems aim to deliver the required amount of drug systematically or to a targeted site for a time and under sufficient conditions to have the desired effect. Some drug delivery systems require carrier materials to mitigate particular undesirable drug properties. One type of carrier molecule is a cyclodextrin which acts as a host for a selected guest molecule.
[006] Cyclodextrins are cyclic oligosaccharides with hydroxyl groups on their outer surface and an empty central cavity which has a lipophilic character. Cyclodextrins are capable of forming inclusion complexes with hydrophobic molecules. The stability of the resulting host / guest complex depends on how the guest molecule occupies the host's central cavity.
[007] The most common cyclodextrins are α-, β- and Y- cyclodextrins which consist of 6, 7 and 8 glucose units linked by α-1,4-, respectively. Cyclodextrins have relatively low solubility in water and organic solvents and this limits their use in pharmaceutical formulations. For a description of the general chemistry of cyclodextrin, reference can be made to Fromming and Szejtlic (eds), Cyclodextrins in Pharmacy, Kluwer: Dordrecht, The Netherlands, 1994; Atwood, Davies, MacNicol and Vogtie (Eds), Comprehensive Supramolecular Chemistry Vol 4, Pergamon: Oxford UK, 1996; and Thomason, Crit Rev Ther Pharmaceutical Carrier Syst 14: 1, 1997.
[008] Alphaxalone [Alfaxalone or 3-α-hydroxy-5-α-, pregnan-11,20-diona] is a potent neuroactive steroid anesthetic currently used in veterinary medicine (Child et al., British Journal of Anesthesia 43 : 2 to 13, 1971).
[009] Alphaxalone has been used widely around the world as an intravenous anesthetic along with alfadolone [Altesina; Alfatesina] in human patients until 1983. Although these anesthetics have a high therapeutic index, they were nevertheless withdrawn from clinical practice due to occasional, unpredictable and still serious anaphylactoid reactions for a polyethoxylated castor oil excipient (Cremophor EL [Brand Registered]).
[0010] Currently, a lipid formulation of diisopropyl phenol (propofol) is the most highly used anesthetic agent. Propofol, however, may be contraindicated in certain patients at risk due to its blood pressure lowering effect, the effect it has on reducing cardiac output and may adversely affect respiratory control. In particular, propofol is formulated in a lipid emulsion which can support microbial growth if contaminated. The formulation cannot actually be sterilized. There have been cases where microbially contaminated propofol formulations have resulted in a patient becoming infected. Another problem with the current propofol formulation is the pain induced following or during intravenous injection. Attempts to reformulate in a water-based preparation led to increased injection pain. Propofol can also lead to cardiovascular and respiratory depression has a low therapeutic index of 5, that is, only 5 times the normal anesthetic dose can lead to death. In addition, the anesthetic is incompatible with plastic storage receptacles and plastic syringes which complicate syringe delivery equipment which is often in a standard for anesthesia and intravenous sedation. The drug can also cause hyperlipidemia and can induce toxicity when used in a larger dose by infusion. This is particularly problematic in the intensive care setting.
[0011] A neuroactive steroid anesthetic has the potential to be more effective with fewer side effects than propofol.
[0012] Therefore, there is a need to develop a suitable formulation to enable the use of a neuroactive steroid anesthetic agent in patients. SUMMARY
[0013] Throughout this specification, unless the context requires otherwise, the word "understands", or variations such as "understands" or "understands", will be understood to imply the inclusion of an indicated element or integer or method step or group of elements or whole numbers or method steps but not the exclusion of any other element or whole number or method step or group of elements or whole numbers or method steps.
[0014] The present invention provides a host / guest complex formulation comprising a neuroactive steroid anesthetic and a cyclodextrin or modified form thereof for use in inducing anesthesia or sedation in mammalian individuals. Generally, the neuroactive steroid anesthetic is poorly soluble. The host / guest complex formulation is, therefore, a drug delivery system for a neuroactive steroid anesthetic. In one embodiment, the cyclodextrin is a modified polyanionic β-cyclodextrin and the neuroactive steroid anesthetic is selected from alfaxalone, alfadolone, acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxydone, minaxolone, Org20599, Org20599, Org20599, Org2 salt, form of prodrug or pharmacologically acceptable derivative thereof. However, all cyclodextrins are covered in this document which includes y and α cyclodextrins or their modified forms as well as their salts. The term "derivative" includes deuterated derivatives of the neuroactive steroid anesthetic. Deuterated derivatives are contemplated for use as improved drugs. One or more hydrogen atoms can be replaced with deuterium. Modified forms of cyclodextrins include anionic, acylated, alkylated, branched, hydroxyalkylated and methylated cyclodextrins. By "alkylated" it includes an alkyl ether derivative as well as an alkyl ether-alkyl ether cyclodextrin. The "alfadolone" agent includes its salt, alfadolone acetate. Reference to a cyclodextrin or a modified form thereof includes its salts (for example, sodium salt).
Accordingly, an aspect of the present invention is directed to an anesthetic or sedative composition comprising a neuroactive steroid anesthetic formulated with a cyclodextrin or modified form thereof.
[0016] The anesthetic or sedative formulation of the present invention exhibits features such as being sterilizable, causes reduced incidence of pain on injection, has a higher therapeutic index compared to propofol (which includes a therapeutic index greater than 5), is capable of storage in a plastic receptacle and induces a rapid induction of anesthesia to surgical levels with a similar or faster awakening time than propofol or Altesin (alfaxalone and alfadolona).
[0017] Therefore, another aspect of the present invention provides an anesthetic or sedative composition comprising a neuroactive steroid anesthetic and a cyclodextrin or modified form thereof in which the anesthetic and cyclodextrin are formulated to provide an anesthetic composition which exhibits a property selected from being sterilizable, exhibiting minimal pain on intravenous injection, having a therapeutic index greater than 5 and being storable in a plastic receptacle. In one embodiment, the formulation has one, two, three or all four of these properties.
[0018] In a related embodiment, the present invention provides a sedative or anesthetic delivery host / guest composition comprising a cyclodextrin host or a modified form thereof with a neuroactive steroid drug guest anesthetic, the host composition / guest is formulated to be sterilizable, manageable by intravenous injection with minimal pain and to exhibit a therapeutic index of more than 5. The formulation can also be storable in a plastic receptacle.
[0019] More particularly, the present invention provides an anesthetic or sedative composition comprising a neuroactive steroid anesthetic selected from alfaxalone, alfadolone, acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxidione, minaxolone, Org20599, Org21465 and tetrahydrode and salts, forms of prodrug and pharmacologically acceptable derivatives thereof formulated with a cyclodextrin or modified form thereof.
[0020] Even more particularly, the present invention is directed to an anesthetic or sedative composition comprising a neuroactive steroid anesthetic selected from alfaxalone, alfadolone, acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxidione, minaxolone, Org20599, Org21465 and tetrahydrodeoxycorticosterone and salts, prodrug forms and pharmacologically acceptable derivatives thereof formulated with a cyclodextrin or a modified form thereof in which the composition exhibits a property selected from being sterilizable, exhibiting minimal pain on intravenous injection, having a therapeutic index greater than 5 and be storable and a plastic receptacle.
[0021] A particular cyclodextrin useful in the practice of the present invention is a sulfoalkyl ether cyclodextrin such as (7) sulfobutyl β-cyclodextrin ether. Such a compound can be prepared as described in U.S. Patent No. 5,376,645. Another useful cyclodextrin is an alkyl ether derivative that includes a sulfoalkyl ether-alkyl ether cyclodextrin. However, the present invention extends to other cyclodextrin derivatives such as anionic, acylated, branched, hydroxyalkylated and methylated forms. The anesthetic formulation of the present invention enables injectable administration to mammalian individuals and in particular human patients.
[0022] Another aspect of the present invention provides an anesthetic or sedative composition that comprises a neuroactive steroid selected from alfaxalone, alfadolone, acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxydione, minaxolone, Org20599, Org21465 and a tetrahydrodeoxicorticosterone and a tetrahydrodeoxicorticosterone and a tetrahydrodeoxicorticosterone and a tetrahydrodeoxicorticosterone. , prodrug form or pharmacologically acceptable derivative thereof formulated with a sulfoalkyl ether cyclodextrin or modified form thereof to generate a sterilizable composition with a therapeutic index of more than 5.
[0023] In one embodiment, the composition is also storable in a plastic receptacle.
[0024] The formulation can comprise a buffer to maintain the pH within a range of about pH 5.5 to pH 8. Alternatively, the formulation cannot be buffered, where the pH of the formulation can be about pH3 for about pH 9.5. The formulation can also comprise a preservative, antimicrobial agent and / or an agent which reduces toxicity. In addition, to improve solubility and / or stability, a copolymer can be included. Examples of suitable copolymers include hydroxyl propyl methyl cellulose (HPMC), polyvinyl pyrrolidone (PVP), and carboxymethyl cellulose (CMC).
[0025] The present invention additionally contemplates inducing or maintaining by infusion or administration of intermittent bolus, anesthesia or sedation in an individual, the method which comprises the administration of an anesthetic-effective amount of a neuroactive steroid anesthetic formulated with a cyclodextrin , for a time and under conditions to induce anesthesia or sedation.
[0026] More particularly, the present invention provides a method of induction or preservation by infusion or administration of intermittent bolus, anesthesia or sedation in an individual, the method comprising administering an anesthetic-effective amount of a neuroactive steroid anesthetic selected from alfaxalone, alfadolone, acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxydione, minaxolone, Org20599, Org21465 and tetrahydrodeoxycorticosterone and pharmacologically acceptable derivatives, salts or forms of the same formulated with a cyclodic form or with a cyclodic form. same for a time or under conditions sufficient to induce anesthesia or sedation, in which the anesthetic or sedative formulation exhibits a property selected from being sterilizable, exhibiting minimal pain on intravenous injection and having a therapeutic index greater than 5.
[0027] In one embodiment, the formulation is also storable in a plastic receptacle.
[0028] Generally, the molar ratio of neuroactive steroid anesthetic to cyclodextrin is about 1: 1 to about 1: 6, more particularly about 1: 1 to about 1: 4, even more particularly about 1: 1 to 1: 3 and even more particularly about 1: 2.
[0029] These aspects of the present invention extend to induce or maintain by infusion or administration of intermittent bolus, anesthesia or sedation or both in individuals.
[0030] The formulation can be packaged for sale with a set of instructions. The instructions may include a patient management protocol that comprises administering to the patient an effective amount of neuroactive steroid anesthetic as selected from alfaxalone, alfadolone, acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxidione, minaxolone, Org20599, Org21465 and tetrahydrodeoxycorticosterone and salts, prodrug forms and pharmacologically acceptable derivatives thereof formulated with a cyclodextrin for a time and under conditions sufficient to induce anesthesia. As indicated above, a suitable cyclodextrin includes a sulfoalkyl ether dextrin, such as (7) sulfobutyl ether β-cyclodextrin as well as alkyl ether derivatives such as sulfoalkyl-alkyl ether cyclodextrins. Other derivatives include anionic, acylated, alkylated, branched, hydroxyalkylated and methylated cyclodextrins.
[0031] The present invention additionally contemplates the use of a neuroactive steroid anesthetic and the cyclodextrin or modified form thereof, in the manufacture of a drug to induce anesthesia in an individual. In a particular modality, the neuroactive steroid anesthetic is selected from alfaxalone, alfadolone, acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxydione, minaxolone, Org20599, Org21465 and tetrahydrodeoxicorticosterone and salts, forms of pro-pharmaceutics acceptable values.
[0032] Kits comprising, in the form of a compartment, form a neuroactive steroid anesthetic in a first compartment and a cyclodextrin, such as a sulfoalkyl ether cyclodextrin, in a second compartment and optionally excipients and / or copolymers in a third or other compartment are also covered in this document. The kit may be in the form of a modified syringe.
[0033] Labeled forms of the neuroactive steroid anesthetic are also useful in monitoring and tracking the anesthetic during sedation or anesthesia. Kits and devices are therefore provided in this document to assist in monitoring labeled neuroactive steroid anesthetics. Labeled derivatives include deuterated, tritiated and other labeled agents. BRIEF DESCRIPTION OF THE FIGURES
[0034] Some figures contain representations in color or entities. Color photographs are available from the Patent upon request or from a Patent Office. A fee may be imposed if obtained from a Patent Office.
[0035] Figures 1a through 1f are graphical representations of experiments in male Wistar mice implanted with intravenous catheters of internal jugular vein residing under halothane anesthesia and then supplied with propofol (a, b), Altesin [alphaxalone and alfadolone acetate] ( c, d) or PhaxanCD [alphaxalone in a 1: 2 molar complexation ratio with (7) sulfobutyl ether β-cyclodextrin] (e, f).
[0036] Figure 2 is a graphical representation of the lethal dosage of two alfaxalone preparations [PhaxanCD and Altesina in mice].
[0037] Figure 3 is a graphical representation of a probit plot to measure the lethality of an Altesin Preparation in mice.
[0038] Figure 4 is a graphical representation of resting time in mice using repeated doses of PhaxanCD (alphaxalone in a molar complexation ratio of 1: 2 with (7) sulfobutyl ether β-cyclodextrin).
[0039] Figure 5 is a graphical representation of time response reflex curves of straightening in mice using pregnanolone in a (7) sulfobutyl β-cyclodextrin ether.
[0040] Figure 6 is a graphical representation of the tail pinching time response curve in mice using pregnanolone in a (7) sulfobutyl β-cyclodextrin ether.
[0041] Figure 7 is a graphical representation of a rotating cylinder test response curve in mice using pregnanolone in a (7) sulfobutyl β-cyclodextrin ether.
[0042] Figure 8 is a graphical representation of straightening reflex time response curves in mice using alfadolone in a (7) sulfobutyl β-cyclodextrin ether.
[0043] Figure 9 is a graphical representation of tail pinching time response curves in mice using alfadolone in a (7) sulfobutyl β-cyclodextrin ether.
[0044] Figure 10 is a graphical representation of the rotating cylinder test response curve in mice using alfadolone in a (7) sulfobutyl β-cyclodextrin ether.
[0045] Figure 11 is a graphical representation of percentage change in medium cystolic blood pressure in mice after injection with propofol, Altesin or PhaxanCD.
[0046] Figure 12 is a graphical representation of percentage change in medium diastolic blood pressure in mice after injection with propofol, Altesin or PhaxanCD.
[0047] Reference to "PhaxanCD" means an alphaxalone preparation with (7) sulfobutyl ether β-cyclodextrin. DETAILED DESCRIPTION
[0048] The present invention provides a drug delivery system for a neuroactive steroid anesthetic. Generally, the neuroactive steroid anesthetic is poorly soluble in water. The drug delivery system comprises a host carrier in the form of a cyclodextrin or a modified form thereof. Reference to "cyclodextrin" includes in one embodiment an a-, β- or y-cyclodextrin or a modified or derived form thereof. Reference to "cyclodextrin" in another embodiment includes sulfoalkyl ether dextrin such as (7) sulfobutyl ether β-cyclodextrin or an alkyl ether derivative thereof such as a sulfobutyl ether alkyl cyclodextrin. Derivatives of cyclodextrins include anionic, acylated, alkylated, branched, hydroxyalkylated and methylated cyclodextrins. "Alkylated" includes an alkyl ether derivative such as an alkyl ether-alkyl ether cyclodextrin. Particular cyclodextrins contemplated in this document are shown in Table 7 [Uekama et al., Chem. Rev. 98: 2.045 to 2.076, 1998] and include β-cyclodextrin sulfobutyl ethers, ethyl β-cyclodextrin sulfobutyl ethers (smooth), Y-cyclodextrin sulfobutyl ethers and α-cyclodextrin sulfobutyl ethers and their salts (for example, salts of sodium).
[0049] The drug delivery system of the present invention enables a neuroactive steroid anesthetic to be administered to an individual in a sterile form. In addition, delivery itself is less painful compared to intravenous propofol administration. The formulation of the present invention additionally has a therapeutic index greater than 5 (which means that administration of more than 5 times the anesthetic dose can lead to death in a test animal). By "greater than 5" means a therapeutic index of between 5 and 200 that includes 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170 , 180, 190 and 200 as well as whole numbers or fractions between them. The formulation of the present invention is also storable in a plastic receptacle and is compatible for use in a plastic delivery device.
Accordingly, an aspect of the present invention provides a sedative or anesthetic delivery host / guest composition comprising a cyclodextrin host or modified form thereof with a neuroactive steroid drug guest anesthetic, the formulated host / guest composition to be sterilizable, manageable by intravenous injection with minimal pain and to exhibit a therapeutic index of more than 5. In one embodiment, the formulation can also be storable in a plastic receptacle. The formulation can exhibit one, two, three or all four of these properties.
[0051] By "reduced pain" means compared to a formulation that comprises propofol as a reference.
[0052] The formulation is useful to induce anesthesia or sedation in mammalian individuals and, in particular, human individuals.
[0053] In one embodiment, the neuroactive steroid is selected from alfaxalone, alfadolone, acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxydione, minaxolone, Org 20599, Org 21465 and tetrahydrodeoxycorticosterone and a salt, pro-drug form or pharmacologically acceptable derivative thereof.
[0054] An example of a pharmacologically acceptable salt is alfadolone acetate, which is encompassed by the present invention. An example of a derivative of a neuroactive steroid anesthetic is a deuterated derivative. A "modified" cyclodextrin includes a cyclodextrin derivative.
Consequently, another aspect of the present invention is directed to a host / guest drug delivery composition comprising a cyclodextrin host or modified form thereof with a neuroactive steroid drug guest anesthetic selected from alphaxalone, alfadolone , acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxydione, minaxolone, Org 20599, Org 21465 and tetrahydrodeoxycorticosterone and a salt, form of prodrug or pharmacologically acceptable derivative thereof, the formulation of which exhibits properties that include being sterilizable, induce reduced pain on intravenous administration and have a therapeutic index of more than 5 and / or be storable in a plastic receptacle. The formulation can also initiate rapid induction of anesthesia to surgical levels with a similar or faster wake-up time compared to propofol. As indicated above, the formulation can exhibit one, two, three or all of these properties.
[0056] The composition of the present invention can be referred to as a formulation, host / guest composition, drug delivery system, medication, anesthetic or sedative as well as more descriptively such as an anesthetic formulation or sedative formulation.
[0057] Another aspect of the present invention provides an anesthetic or sedative formulation comprising a neuroactive steroid anesthetic and a cyclodextrin or modified form thereof, the formulation of which exhibits properties that include being sterilizable, inducing reduced pain on intravenous administration and having a therapeutic index of more than 5 and / or be storable in a plastic receptacle.
[0058] More particularly, the present invention relates to an anesthetic or sedative formulation comprising a neuroactive steroid anesthetic selected from alfaxalone, alfadolone, acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxydone, minaxolone, Org 20599, Org 21465 and tetrahydrodeoxycorticosterone and a salt, form of prodrug or pharmacologically acceptable derivative thereof, the formulation exhibiting properties that include being sterilizable, inducing reduced pain in intravenous administration and having a therapeutic index of more than 5.
[0059] In one embodiment, the formulation is also storable in a plastic receptacle.
The present invention extends to mixtures of two or more neuroactive steroid anesthetic drugs such as a composition comprising alfaxalone and alfadolone and / or alfadolone acetate or its pharmacologically acceptable derivatives, salts or forms of prodrug.
[0061] A "pharmacologically acceptable derivative" is a derivative that still induces anesthesia while not increasing adverse side effects. The term "derivative" includes deuterated derivatives in which one or more hydrogen atoms are replaced by deuterium. This can lead to improved effectiveness. In addition, anesthetic agents can be subjected to alkylation, alkoxylation, acetylation and / or phosphorylation to generate other derivatives. Other types of derivatives include deuterated or tritiated or other labeled forms useful for monitoring and tracking the anesthetic in the body. The terms "derived" and "modified form" are used interchangeably in this document. Alfadolone salts include alfadolone acetate. Reference to prodrugs includes transported prodrugs.
[0062] In one embodiment, cyclodextrin is a β-cyclodextrin or a modified form thereof, such as, but not limited to, a sulfoalkyl ether dextrin. A particularly useful sulfoalkyl ether dextrin is (7) sulfobutyl β-cyclodextrin ether. Alkyl ether derivatives are also contemplated such as a sulfoalkyl ether-alkyl ether cyclodextrin. An example of an alkyl ether derivative is a sulfobutyl ether-alkyl ether cyclodextrin. Other cyclodextrins contemplated in this document are listed in Table 7 and include anionic, acylated, branched, alkylated, hydroxyalkylated and methylated derivatives.
[0063] Consequently, an aspect of the present invention provides a sedative or anesthetic delivery host / guest composition comprising a host of sulfoalkyl ether dextrin or modified form thereof with a neuroactive steroid drug guest anesthetic, a host / guest formulated to be sterilizable, manageable by intravenous injection with minimal pain, exhibits a therapeutic index of more than 5. In one embodiment, the formulation can also be storable in a plastic receptacle.
[0064] Another aspect of the present invention is directed to a host / guest drug delivery composition comprising a host of sulfoalkyl ether dextrin or modified form thereof with a neuroactive steroid drug guest anesthetic selected from alphaxalone, alfadolone , acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxydione, minaxolone, Org 20599, Org 21465 and tetrahydrodeoxycorticosterone and a salt, form of prodrug or pharmacologically acceptable derivative thereof, the host / guest composition to be sterilizable, administrable by intravenous injection with minimal pain and exhibiting a therapeutic index of more than 5.
[0065] In one embodiment, the composition is also storable in a plastic receptacle.
[0066] Another aspect of the present invention provides an anesthetic or sedative formulation that comprises a neuroactive steroid anesthetic and a sulfoalkyl ether dextrin or modified form thereof, the formulation exhibiting properties that include being sterilizable, inducing reduced pain in intravenous administration, being that it has a therapeutic index of more than 5 and / or is storable in a plastic receptacle.
[0067] As indicated above, a particularly useful sulfoalkyl ether dextrin is (7) sulfobutyl β-cyclodextrin ether. Of the properties displayed, in a particular mode, the formulation displays two or more, three or more or all of the properties. These properties include imitation of rapid anesthesia induction to surgical levels with a faster or similar awakening time or as compared to propofol.
[0068] The formulation between the neuroactive steroid and cyclodextrin is generally in a molar ratio of from 1: 1 to 1: 6 (neuroactive steroid: cyclodextrin), more particularly from about 1: 1 to 1: 4, yet more particularly about 1: 1 to 1: 3 and even more particularly about 1: 2. The 1: 1 to 1: 6 range includes 1: 1, 1: 1.1, 1: 1.2, 1: 1.3, 1: 1.4, 1: 1.5, 1: 1.6 , 1: 1,7, 1: 1,8, 1: 1,9, 1: 2, 1: 2,1, 1: 2,2, 1: 2,3, 1: 2,4, 1: 2 , 5, 1: 2,6, 1: 2,7, 1: 2,8, 1: 2,9, 1: 3, 1: 3,1, 1: 3,2, 1: 3,3, 1 : 3.4, 1: 3.5, 1: 3.6, 1: 3.7, 1: 3.8, 1: 3.9, 1: 4, 1: 4.1, 1: 4.2 , 1: 4.3; 1: 4.4, 1: 4.5, 1: 4.6, 1: 4.7, 1: 4.8, 1: 4.9, 1: 5, 1: 5.1, 1: 5, 2, 1: 5.3, 1: 5.4, 1: 5.5, 1: 5.6, 1: 5.7, 1: 5.8, 1: 5.9 and 1: 6.
Accordingly, the present invention provides a drug delivery host / guest composition comprising a cyclodextrin host or modified form thereof with a neuroactive steroid drug guest, wherein the molar ratio of neuroactive steroid to cyclodextrin is about 1: 1 to about 1: 6 and where the composition is formulated to be sterilizable, manageable by intravenous injection with minimal pain and exhibiting a therapeutic index of more than 5. In one embodiment, the formulation can also be storable in a plastic receptacle.
[0070] More particularly, the present invention is directed to a drug delivery host / guest composition comprising a cyclodextrin selected from an α-, β- or Y — cyclodextrin or a modified form thereof that includes a sulfoalkyl ether dextrin or sulfoalkyl ether-alkyl ether derivative or other derivatives listed in Table 7 and a neuroactive steroid drug guest selected from alfaxalone, alfadolone, acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxydone, minaxolone, Org 205 Org 21465 and tetrahydrodeoxycorticosterone and a salt, form of prodrug or pharmacologically acceptable derivative thereof, wherein the molar ratio of a neuroactive steroid to cyclodextrin is from about 1: 1 to about 1: 6 and where the composition is formulated to be sterilizable, administrable by intravenous injection with minimal pain and to exhibit a therapeutic index of more than 5. In one embodiment, (7) sulfobutyl ether β -cyclodextrin comprises less than 100ppm of a phosphate and has an absorption of less than 0.5AU due to a drug degradation enzyme, as determined by UV / v is spectrophotometry at a wavelength from 245nm to 270nm for an aqueous solution that contains 300 mg of dextrin per ml of solution in a cell that has a path length of 1 cm. In one embodiment, the formulation can also be storable in a plastic receptacle.
[0071] The anesthetic composition of the present invention may, in one embodiment, comprise a buffer such as a phosphate or tris or citrate-phosphate buffer to maintain the pH from about 5.5 to about pH 8. This includes pH values from 5.5, 6, 6.5, 7, 7.5 and 8. Alternatively, the composition does not comprise a buffer and the pH is from about pH 3 to about pH 9.5 such as pH 3, 3, 5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9 or 9.5.
[0072] In a further aspect, the formulations of the present invention also include one or more agents such as excipients and / or preservatives, microbial retardants. Other agents can also be included to reduce toxicity. The agents include, for example, EDTA, benzyl alcohol, bisulfites, lauric acid monoglyceryl ester (Monolaurin), capric acid and / or its soluble alkaline salts or its monoglyceryl ester (Monocaprin), edetate, and capric acid and / or its salts soluble alkali or its monoglyceryl ester (Monocaprin) and edentate. The formulation can also contain one or more copolymers to aid in the solubility or stability of the anesthetic agent. Examples include hydroxy propyl methyl cellulose (HPMC), polyvinyl pyrrolidone (PVP) and / or carboxymethyl cellulose (CMC).
[0073] Conveniently, the neuroactive steroid anesthetic is supplied in a concentration of from about 0.5 to 100 mg / ml in a saline suspension comprising cyclodextrin. Such concentration includes 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 , 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 , 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 , 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and 100 mg / ml of drug. As indicated above, the composition is generally formulated so that the molar ratio of neuroactive steroid to cyclodextrin is from about 1: 1 to about 1: 6, particularly from about 1: 1 to 1: 4, even more particularly from about 1: 1 to 1: 3 and with maximum detail 1: 2.
[0074] Reference to any particular neuroactive steroid or its salts includes a racemic mixture of enantiomers for each anesthetic as well as a single enantiomer of the agent.
[0075] In a particular modality, the neuroactive steroid is alfadolone acetate, alfaxalone and / or alfadolone. In one embodiment, alfaxalone is in the formulation at a concentration of from 1 to 100 mg / ml such as 10 mg / ml. In another embodiment, alfadolone or alfadolone acetate is present in 0.5 to 50 mg / ml such as 3 mg / ml.
[0076] The formulations in this document are for in vivo delivery, which means that the anesthetic neuroactive steroid is delivered intravenously, subcutaneously, intraperitoneally, intrathecally, intramuscularly, intravitreally, transdermally, suppository (rectal), pessary (vaginal), inhalation, intranasal and the like. More effectively, the formulation is an intravenous (iv) formulation.
Consequently, another aspect of the present invention provides an injectable formulation of an anesthetic neuroactive steroid selected to be sterilizable and manageable by intravenous injection with minimal pain, which exhibits a therapeutic index greater than 5 and storable in a plastic receptacle formulated with cyclodextrin , such as (7) sulfobutyl ether β-cyclodextrin or an alkyl ether derivative.
[0078] The anesthetic neuroactive steroid can be used alone or in combination with another anesthetic or sedative or another active agent. In one embodiment, it is used with alfadolone or its salt, alfadolone acetate. Therefore, in reference to "alfadolone" includes alfadolone acetate. The composition can then comprise alfaxalone or alfadolone alone or a combination of alfaxalone and alfadolone or any of its derivatives, salts or forms of prodrugs.
[0079] Therefore, in a particular embodiment, the present invention further provides a composition comprising alphaxalone or a pharmacologically acceptable derivative, salt or prodrug thereof and / or alfadolone or a pharmacologically acceptable derivative, salt or prodrug thereof. formulated with a sulfoalkyl ether dextrin, such as (7) sulfobutyl ether β-cyclodextrin in which the molar ratio of alfaxalone and / or alfadolone to dextrin is from about 1: 1 to about 1: 6. Reference can be conveniently made to Remington's Pharmaceutical Sciences, Mack Publishing Company, Eaton, USA, 1990 and Rowe's Handbook of Pharmaceutical Excipients, 2009 for formulation methods and reagents.
[0080] The present invention contemplates to induce or maintain by infusion or administration in bolus intermittently, anesthesia in a human individual, the method comprising administering an effective amount of anesthetic of an anesthetic neuroactive steroid formulated with a cyclodextrin, such as sulfoalkyl ether dextrin, for a time and under conditions of anesthesia induction.
[0081] More particularly, the present invention provides a method of intermittently inducing or maintaining by infusion or bolus administration, anesthesia in a human individual, the method comprising administering an effective amount of anesthetic to a selected anesthetic neuroactive steroid to starting from alfaxalone, alfadolone, acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxydione, minaxolone, Org20599, Org21465 and tetrahydrodeoxycorticosterone and a pharmacologically acceptable derivative, salt or prodrug of the same, formulated with a cyclod, formulated with a cyclod ) sulfobutyl β-cyclodextrin ether, for a time and under conditions sufficient to induce anesthesia, in which the anesthetic formulation is sterilizable, can be administered by intravenous injection with minimal pain and exhibits a therapeutic index greater than 5. Additionally, the formulation can start rapid anesthesia with faster or similar awakening time compared to propofol l or Althesin (registered trademark). The formulation can also be storable in a plastic container.
[0082] The present invention extends to induce or maintain by sedimentation or infusion intermittently, sedation. Therefore, another aspect of the present invention provides a method of inducing or maintaining by infusion or bolus administration intermittently, sedation in an individual, the method comprising administering an effective amount of sedation of an anesthetic neuroactive steroid formulated with a cyclodextrin as sulfoalkyl ether dextrin, for example, (7) sulfobutyl ether β-cyclodextrin, for a time and under sufficient conditions to induce sedation.
[0083] The reference to "(7) sulfobutyl ether β-cyclodextrin" includes methylated, hydroxyalkylated, branched, alkylated, alkylated and anionic derivatives thereof such as sulfobutyl ether-alkyl ether β-cyclodextrin. Other derivatives include β-cyclodextrin sulfobutyl ethers, ethyl ethers, β-cyclodextrin sulfobutyl ethers (flat), y-cyclodextrin sulfobutyl ethers and α-cyclodextrin sulfobutyl ethers and their salts (for example, sodium salts).
[0084] As indicated above, a particular individual is a human individual.
[0085] The anesthetic formulation can be packaged for sale with instructions for use. The use includes a patient management protocol that comprises administering to the patient an effective amount of anesthetic neuroactive steroid as selected from alphaxalone, alfadolone and salts, prodrug forms and pharmacologically acceptable derivatives thereof, formulated with a cyclodextrin as a sulfoalkyl ether dextrin, for example, (7) sulfobutyl ether β-cyclodextrin, for a time and under sufficient conditions to induce anesthesia.
[0086] The present invention further contemplates the use of an anesthetic neuroactive steroid and a cyclodextrin, such as a sulfoalkyl ether dextrin, for example, (7) sulfobutyl β-cyclodextrin ether, in the manufacture of a drug to induce anesthesia in an individual as a human individual. In a particular modality, the anesthetic neuroactive steroid is selected from alfaxalone, alfadolone and salts, forms of prodrug and pharmacologically acceptable derivatives thereof. In another modality, the anesthetic is selected from acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxydione, minaxolone, Org20599, Org21465 and tetrahydrodeoxycorticosterone and salt, as a prodrug or pharmacologically acceptable derivative thereof.
[0087] In terms of an effective amount of anesthetic, it is generally around 0.25 mg / kg to about 100 mg / kg in body weight. An effective amount of sedative is provided in similar or lesser amounts and includes from about 0.05 mg / kg to about 10 mg / kg in body weight.
[0088] The present invention still provides a kit. The kit can be in any form that includes a modified syringe or syringe. A kit may comprise alfaxalone and / or alfadolone or another anesthetic neuroactive steroid or its derivatives, salts or forms of prodrugs in one or more compartments and a sulfoalkyl ether dextrin in an additional compartment as well as excipients in subsequent compartments. The contents of the compartments can be mixed by addition before use.
[0089] In a particular embodiment, the present invention provides a formulation comprising alphaxalone and / or alfadolone and / or pharmacologically acceptable derivatives, salts or forms of prodrugs thereof complexed with the sulfobutyl cyclodextrin ether, for use in inducing or maintaining by infusion or intermittent bolus administration, anesthesia or sedation in a human subject.
[0090] Anesthetic forms can be identified as deuterated or tritiated forms or by other identifications to facilitate monitoring and tracking of anesthetics in the body. Kits and apparatus are then provided to monitor identified anesthetic neuroactive steroids.
[0091] While the present invention is particularly directed to anesthetic formulations for use in humans, the formulations can also be used in animals such as for clinical trials or veterinary use. Non-human animals contemplated in this document include rats, mice, guinea pigs, hamsters, sheep, pigs, dogs, cats, horses, cows, goats, camels and non-human primates.
[0092] Therefore, the present invention provides an anesthetic or sedative composition comprising an anesthetic neuroactive steroid and a cyclodextrin or modified form thereof where the composition has the following properties: (i) the neuroactive steroid and cyclodextrin are formulated in a ratio molar about 1: 1 to about 1: 6; (ii) the neuroactive steroid is selected from alfaxalone, alfadolone, acebrocol, alopregnanolone, eltanolone (pregnanolone), ganaxolone, hydroxydione, minaxolone, Org20599, Org21465 and tetrahydrodeoxychorticosterone and a derivative, salt or pro-pharmaceutically acceptable form of the pharmaceutical agent. formulated; (iii) cyclodextrin is selected from an α-, β-, and Y — cyclodextrin or a modified form thereof; (iv) a buffer is optionally present and when present, the pH of the formulation is about pH 5.5 to about pH 8.0 and in the absence of buffer, the pH is about pH 3 to about pH 9.5 ; (v) the formulation is sterilizable; (vi) intravenous injection of the formulation induces less pain than from a propofol formulation; (vii) the therapeutic index of the formulation is greater than 5; (viii) the formulation can be stored in a plastic container; and (ix) the formulation can initiate rapid induction of anesthesia at surgical levels with a faster or similar awakening time compared to propofol.
[0093] In a particular embodiment, an anesthetic or sedative formulation is provided as it comprises a sulfoalkyl ether or sulfoalkyl ether-alkyl ether dextrin, a neuroactive anesthetic steroid such as alfaxalone or alfadolone and one or more copolymers such as HPMC, PVP and / or CMC.
[0094] In a particular embodiment, the anesthetic neuroactive steroid is formulated with a sulfoalkyl ether dextrin such as (7) sulfobutyl ether β-cyclodextrin.
[0095] The present invention also contemplates a method for formulating an anesthetic or sedative composition, the method of which generates a host / guest composition comprising a cyclodextrin and a neuroactive steroid. In one embodiment, the cyclodextrin is a sulfoalkyl ether or sulfoalkyl ether-alkyl ether dextrin such as (7) sulfobutyl or β-cyclodextrin or sulfobutyl ether-alkyl ether β-cyclodextrin. Other cyclodextrins include β-cyclodextrin sulfobutyl ether-ethyl ether, β-cyclodextrin sulfobutyl ether (flat), Y-cyclodextrin sulfobutyl ether, α-cyclodextrin sulfobutyl ether and its sodium salts.
[0096] The present invention is further described by the following non-limiting examples. When an anesthetic neuroactive steroid is formulated with a cyclodextrin, it is referred to as "anesthetic neuroactive steroid CD". An example is PhaxanCD, which comprises alphaxalone formulated with a cyclodextrin which in this case is (7) sulfobutyl ether β-cyclodextrin. Other examples include pregnanoloneCD and alfadoloneCD. EXAMPLE 1
[0097] Anesthetic effects of alfaxalone at 30% by weight by volume of (7) sulfobutyl ether β-cyclodextrin
[0098] Alfaxalone was formulated as 6 ml of clear colorless liquid containing: • 60 mg (10 mg / ml) alphaxalone; • (7) 1,800 mg sulfobutyl β-cyclodextrin ether; • Saline solution (0.9% by weight by volume) of 6ml.
[0099] This is a ratio of molar complexation of alphaxalone to (7) sulfobutyl β-cyclodextrin ether of 1: 4.6. Male Wistar rats (weight [] 270 to 315 g) with resident jugular intravenous catheters were placed in a Perspex limiter and injections were obtained with the attached observations under the limiter shown in Table 1. TABLE 1


[00100] The rats that had 25 and 100 mg / kg in body weight recovered in 60 minutes; they did not die or suffer any adverse effects at these doses. In these experiments, it can be seen that the intravenous injection of 10 mg / ml alfaxalone dissolved in (7) sulfobutyl ether β-cyclodextrin caused loss of consciousness at doses above 10 mg / kg and there was a dose-related anesthetic effect with a wide range of security; the rats that received 25 and 100 mg / kg in body weight (twice and ten times the anesthetic dose) did not die, which indicates a wide range of safety for the preparation. This is clearly different from an alphaxalone formulation in hydroxypropyl β-cyclodextrin. Such preparation (AlfaxanCD-RTU) made by Jurox Pty, Newcastle NSW Australia has a published LD50, the dose of alphaxalone that causes death in 50% of the rats when obtained intravenously, of 19 mg / kg in body weight of a very significantly below, showed here alphaxalone formulated in sulfobutyl ether β-cyclodextrin [Alfaxan CD-RTU Material safety data Sheet; Jurox Pty, Newcastle NSW, Australia]. EXAMPLE 2 Pharmacokinetics in the rat
[00101] Two groups of ten rats with implanted internal jugular and intra-arterial carotid catheters receive an intravenous bolus injection via a jugular vein of 10 mg / kg in body weight of (7) formulation of sulfobutyl ether alpha-cyclodextrin β-cyclodextrin (n = 10 rats) or a mixture of alphaxalone and alfadolone in CremoforEL (a polyethoxylated castor oil), 1.1 ml / kg (n = 10 rats). Blood obtained from the carotid artery or tail at a number of intervals after this injection is analyzed for blood levels with alfaxalone. They are fitted to a three-compartment pharmacokinetic model and the standard error of the mean (without) for key parameters is calculated for the two steroid anesthetic preparations.
[00102] It is expected that there will be no significant difference between the PK parameters calculated for the (7) formulation of sulfobutyl ether β-cyclodextrin and the formulation of Althesin (registered trademark). This should indicate that the new formulation is expected to behave in a manner similar to the way Althesin (a trademark) has behaved in the past, particularly with regard to the doses required for anesthesia and sedation and also the speed of recovery. A Table of sample blood levels that can be expected from experiments appears in Table 2. TABLE 2
EXAMPLE 3 Anesthetic effects of Alfaxalone in (7) sulfobutyl ether β-cyclodextrin compared to alphaxalone such as Althesin (trademark) and propofol
[00103] Male Wistar rats (weighing 150 to 220 g by weight) were implanted with intravenous catheters of an internal jugular vein resident under halothane anesthesia. Twenty-four hours later, each rat received an intravenous injection of a dose range or: propofol (10 mg / ml in 10% by weight by volume of Intralipid emulsion; Diprivan [trademark]); Althesin (registered trademark) (alphaxalone 9 mg / ml plus alfadolone acetate of 3 mg / ml in 20% by weight by volume of CremoforEL); or PhaxanCD (alphaxalone of 10 mg / ml in a molar complexation ratio of 1: 2 with Captisol (trademark) - (7) sulfobutyl ether β-cyclodextrin). The following were evaluated at regular intervals after an intravenous injection: 1. straightening reflex: classified as: 1 normal; 2 slow; 3 any attempt; 4 none - this was a measure of onset and duration of unconsciousness; 2. responses to tail clamping: classified as: 1 normal; 2 weak; 3 only present; 4 none - this was a measure of onset and duration of surgical anesthesia; and 3. time when the rat was able to walk on the rotating cylinder (a rotating cylinder) measured in seconds: the maximum normal dwell time is 120 seconds in non-sedated rats - to reach the value, there was a measure of time taken to achieve complete recovery from the sedation effects of anesthetic injections.
[00104] Results of groups of ten rats treated with the same anesthetic and dose were combined for statistical purposes. Rats that achieved a score of 4 for loss of straightening reflexes were considered to have lost consciousness and those who scored 4 for loss of responses to tail pinching were considered to be surgically anesthetized. The number of rats in each group of 10 similarly treated animals that scored 4 were subjected to probit regression analysis using SPSS 18 statistics to produce log dose v graphs of probit value (probit plot) and also to calculate the estimated dose that caused anesthesia in 50 and 95% of individuals (AD50 and AD95, respectively) for unconsciousness (straightening reflex medications) and surgical anesthesia (responses to tails clamping). The walking times on the rotating cylinder were also plotted for each dose and treatment. It was used as a complete recovery medication. The results are shown in Figures 1a to 1f, with rotating cylinder performance for each anesthetic, n = 10 rats per dose.
[00105] Table 3 below summarizes the results of this series of experiments. It can be seen as PhaxanCD being equipotent with Althesin (trademark), causing unconsciousness and surgical anesthesia, and both are more potent than propofol in this respect. The recovery from unconsciousness caused by PhaxanCD is as fast as with propofol. However, recovery of PhaxanCD is slightly slower than propofol, but it is faster than Althesin (trademark), if the depth of anesthesia is taken at a surgical level. Control experiments revealed that vehicles obtained alone, intravenously, 20% of CremoforEL, 10% of Intralipid and 13% of Captisol, had no sedation or anesthetic effects. TABLE 3

[00106] It can be concluded from this set of experiments that: • PhaxanCD is an effective intravenous anesthetic that causes rapid onset of general anesthesia after intravenous injection. • It is equipotent with Althesin and twice as potent as propofol. EXAMPLE 4 Lethal dose revealed for anesthetic preparations for alfaxalone
[00107] This series of experiments was responsible for determining the doses of LD50 and LD95 for alfaxalone formulated in CremoforEL [Althesin (registered trademark)] and (7) sulfobutyl ether β-cyclodextrin (PhaxanCD); that is, the doses of alfaxalone in Captisol (trademark) that caused the death of 50% and 95% of the individuals. Male Wistar rats (weight 150-220 g weight) were implanted with resident internal jugular vein catheters under halothane anesthesia. Twenty-four hours later, each rat received an intravenous injection of a dose range or: Althesin (trademark) (9 mg / ml alphaxalone plus 3 mg / ml alfadolone acetate in 20% CremoforEL); or PhaxanCD (10 mg / ml alphaxalone in a 1: 2 molar complexation ratio with Captisol (trademark) - (7) sulfobutyl ether β-cyclodextrin). The number of mice that died was recorded for each group of 10 mice that received the same dose of drug. Results from groups of ten rats treated with the same anesthetic and dose were combined for statistical purposes. The raw data graph is shown in Figure 2 [% of rats that died at each dose in group v of dosage].
[00108] At doses of alfaxalone between 50 and 60 mg / kg, all rats in the Althesin (trademark) groups died, whereas, in the PhaxanCD groups that received the same doses of alfaxalone, none died. The lethality values for PhaxanCD showed a ceiling of 20%; with no more than 20% of the mice dying even if the dose of alphaxalone mixed by addition like PhaxanCD has been increased. The percentages of mice that died in all different dosage treatment groups were subjected to probit regression analysis using SPSS 18 statistics and the probit values were plotted against the anesthetic dose log; it is called a probit plot. The same is shown in Figure 3.
[00109] The probit plot for Althesin (trademark) was used to calculate the dose of alfaxalone in this formulation that caused death in 50% and 95% of the rats; LD50 and LD95 respectively). These values were 43.6 mg / kg [LD50] and 51.5 mg / kg [LD95]. As the dose of alfaxalone was increased, the number of mice that died increased in proportion when alfaxalone was obtained as Althesin (trademark). In contrast, there was a ceiling effect of the lethality of alfaxalone in the (7) formulation of sulfobutyl ether β-cyclodextrin (PhaxanCD). Alphaxalone was much less toxic as assessed for lethality compared to alphaxalone formulated with CremoforEL (Althesin [trademark]). A dose of 52 mg / kg of alfaxalone like Althesin (trademark) caused all 10 rats in the group to die, but 64 mg / kg of alfaxalone did not cause any death in the 10 rats that received the dose of alfaxalone formulated with (7 ) sulfobutyl β-cyclodextrin ether (PhaxanCD). Furthermore, in contrast, the probit plot for Althesin (trademark), which showed a direct proportional relationship of increasing lethality with increasing dose alphaxalone, formulated in (7) sulfobutyl ether β-cyclodextrin (PhaxanCD), showed a ceiling effect for lethality; when the dose of alfaxalone in this preparation was increased to 71, 78 and then 84 mg / kg, with only 20% of the rats dying in each group. Therefore, it was not possible to find the dose of alfaxalone in this formulation that caused death in 50% and 95% of the rats (the LD50 and LD95, respectively). In any event, the two values are greater than 84 mg / kg, that is, it is more than twice the equivalent values for Althesin (registered trademark) and four times the LD50 value for alphaxalone formulated in manufactured hydroxypropyl β-cyclodextrin by Jurox [Alfaxan CD-RTU Material Safety Data Sheet. Jurox Pty, Newcastle NSW, Australia].
[00110] These results make the therapeutic index (dose ratio that causes death in 50% of individuals (LD50) divided by the dose that causes anesthesia in 50% of individuals (the AD50)) as being 14.8 for Althesin (registered trademark ) and> 30.2 for alfaxalone formulated in (7) sulfobutyl β-cyclodextrin ether (Captisol [registered trademark] PhaxanCD). This difference is not due to differences in toxicity of the excipients. Table 4 below shows the results of experiments on 10 rats with resident jugular intravenous catheters. Five rats received a 20% solution of Cremofor EL intravenously and another five rats received a solution of (7) sulfobutyl ether β-cyclodextrin, both being administered in a dose and volume equal to that mixed by addition in the above experiments in the highest dose. high level of alfaxalone. No excipients caused death in any rat, which indicates that the difference in safety / lethality of the two formulations of alfaxalone did not occur due to the dose-related toxicity of the excipients.

EXAMPLE 5 Demonstration of the limitation of alphaxalone toxicity by Captisol [trademark] (sulfobutyl ether β-cyclodextrin)
[00111] Since the potency in causing anesthesia is the same for an alphaxalone bolus dose if obtained in 20% CremoforEL (Althesin [Trademark]) or (7) sulfobutyl β-cyclodextrin ether (PhaxanCD), then the ceiling effect for toxicity should be related to (7) sulfobutyl ether β-cyclodextrin when higher doses of alfaxalone in (7) formulation of sulfobutyl β-cyclodextrin are mixed by addition. Such a property has not been described for intravenous anesthetics before. In addition, this property has not been described before for alphaxalone formulated in other cyclodextrins.
[00112] To test whether the low toxicity of PhaxanCD was due to the excipient Captisol, twenty rats with resident jugular intravenous catheters were divided into two groups of 10 rats each. They all received intravenous injections of alfaxalone formulated in 20% Cremophor in a dose that, in previous experiments that were reported in example 4, caused the death of all rats (Althesin [trademark]; dose of alfaxalone iv 52.5 mg / kg - this is 16 times the AD95 for Althesin (trademark) where it is expected in a very high proportion or all the mice will die). Sixty seconds before the injection of Althesin (registered trademark), a premedication injection was obtained: • Group 1 (10 rats) received 5.3 ml / kg of 0.9% sodium chloride solution 60 seconds before 52.5 mg / kg of alfaxalone as Althesin (registered trademark); • Group 2 (10 rats) received 5.3 ml / kg of 13% of the solution of (7) sulfobutyl ether β-cyclodextrin in 0.9% of the sodium chloride solution 60 seconds before 52.5 mg / kg alfaxalone as Althesin (registered trademark).
[00113] The number of rats that died in each group was recorded as shown in Table 5. All 20 rats were anesthetized by injecting 52.5 mg / kg of alfaxalone as Althesin (registered trademark). However, the presence of (7) sulfobutyl β-cyclodextrin ether caused a statistically and clinically significant reduction in mortality caused by alfaxalone. TABLE 5 ALL RATS THAT SURVIVED WERE ANESTHESIAED <1 HOUR
[00114] Pre-drug obtained 60 seconds before Althesin @ 16x AD95

[00115] Study of the effect of Captisol on the rate of Althesin
[00116] Fisher's exact test
[00117] P value P on two sides is 0.0230, considered significant.
[00118] The row / column association is statistically significant.
[00119] This is a more unexpected result. EXAMPLE 6 The effect on repeated dosing sleep times with PhaxanCD
[00120] The mechanism responsible for the fact that (7) sulfobutyl ether β-cyclodextrin causes the ceiling effect on alphaxalone toxicity is unknown. It is known that alfaxalone is very poorly soluble in water and therefore the vast majority of alfaxalone molecules are complexed with cyclodextrin molecules in the ratio of 1: 2 (the complexation ratio). It is known that some of the alphaxalones will be dissociated from the cyclodextrin complex when PhaxanCD is injected intravenously. The question posed by the unique property of the sulfobutyl alphaxalone complex cyclodextrin that exhibits a ceiling effect for toxicity is whether it is caused by limiting the amount of alphaxalone released from the complex or whether a "cleansing" of the alphaxalone molecules occurs they could otherwise penetrate the brain to cause toxicity, due to an excess of uncomplexed cyclodextrin molecules released by alphaxalone metabolism by the liver. The effect of the latter should be anticipated to cause a progressive decrease in the level of free alphaxalone as the concentration of uncomplexed sulfobutyl ether cyclodextrin increased as a result of: • liver metabolism of alfaxalone; • more doses of PhaxanCD that are mixed by addition, which then create more non-complexed cyclodextrin available.
[00121] If someone were to predict tolerance to repeated doses of alfaxalone formulated in (7) sulfobutyl ether β-cyclodextrin, that is, repeated injections of PhaxanCD would cause sedation and anesthetic effect less progressively.
[00122] To test, these five rats with resident jugular intravenous catheters received repeated injections of the minimum dose of alphaxalone in (7) sulfobutyl ether β-cyclodextrin (5 mg / kg PhaxanCD) which caused 10/10 rats to be anesthetized , as judged, by the complete loss of the straightening reflex. The time was measured for each rat to initiate recovery of the straightening reflex (progressing from a score of 4 to a score of 3 in the straightening reflex, as described in example 2 above) and then another dose of 5 mg / kg of PhaxanCD was obtained. The time to start the recovery of the straightening reflex after the second dose of anesthetic was measured and then another dose of 5 mg / kg of PhaxanCD was mixed by adding iv and the process was repeated eight more times. The progressive recovery times from the first to the tenth dose are shown in the histogram (Figure 4) and in Table 6 below as the mean (without) for those five rats. It can be seen that there was a significant progressive increase in recovery times after each of the first four doses. In addition, doses of 5 to 10 did not cause any significant additional increase and, more importantly, no decrease in the time of sleep. These results indicate that the ceiling effect of alphaxalone toxicity caused by (7) sulfobutyl ether β-cyclodextrin probably occurred due to the controlled release of alfaxalone from the complex at a rate sufficient to cause anesthesia, but no more than same, since it doesn't matter how much of the complex is obtained. This is a unique balance between the chemical relationship of alfaxalone and (7) sulfobutyl β-cyclodextrin ether, the low solubility of alfaxalone in water environments, including biological fluids, the amount of alfaxalone needed to penetrate the brain causing anesthesia and pharmacokinetics of alfaxalone. The results are shown in Figure 4 and Table 6. None of them were expected, nor could they be predicted from the prior art. TABLE 6


[00123] The ANOVA [Tukey Kramer Post hoc] Variance analysis applied to the data of sleep times after X, 10 repeated dosages of 5 rats with PhaxanCD 5 mg / kg revealed that there was a statistically significant progressive increase in time of sleep from the first to the second, from the second to the third and from the third to the fourth, but no increase in sleeping times after that. In addition, it is important to note that there was no progressive decrease in sleeping times that would be predicted if the mechanism for low toxicity and the ceiling effect of PhaxanCD were due to the uncomplexed "free" sulfobutyl cyclodextrin ether [Captisol (trademark) ], cleaning the alphaxalone from the blood. If that were the case then, the amount of free uncomplexed Captisol would increase as more doses were obtained and as the alphaxalone was metabolized by the liver, leading then to a progressive increase in uncomplexed free Captisol as the experiment repeated exposure has progressed. If alphaxalone was cleaned by it, then less sleep time would be expected with each successive dose. In contrast, the time to fall asleep increased with each of the first four doses and then remained constant subsequently with each subsequent dose. EXAMPLE 7 Ceiling toxicity
[00124] The following assumption is made: A. Such an intravenous injection of Althesin (trademark) leads to an instant dispersion of alfaxalone in the plasma, but, since anesthesia is caused by injection of drug into a circulation and also the alphaxalone is discharged from the blood to the liver in the first step, the level reached by mixing in plasma will only reach 30% of the theoretical maximum assumed by the instantaneous mixture.
[00125] The following is considered: 1. alfaxalone is soluble in water at 0.03 mg / ml; 2. alphaxalone is 35% protein bound in plasma; 3. plasma volume is 31 ml / kg in rat (Davies and Morris, Pharmaceutical Research, 10 (7): 1093 to 95, 1993); 4. both Althesin (trademark) and PhaxanCD have alphaxalone concentrations of 10 mg / ml; 5. for anesthesia induction, Althesin (registered trademark) and PhaxanCD are equipotent; a minimum of 4.3 mg / kg of alfaxalone also per preparation causes numbness in the majority (95%) of the rats; 6. after an initial bolus injection, a drug preparation will be balanced with the volume of plasma during the first sleep cycle, but then the drug will be dispersed in the extracellular fluid [ECF] which is = 297 ml / kg (Davies and Morris , 1993 supra); 7. Captisol is distributed to ECF and is restricted to that space; and 8. Alfaxalone is only released from Captisol in an aqueous environment if the level of free alphaxalone in the aqueous environment is less than saturation, that is, <0.3 mg / ml [fact 1].
[00126] It is proposed in this document that: I. From A and 5 above, the drug plasma level necessary to cause numbness = mixed dose by addition as volume of Althesin / plasma = 4.3 / 31 = 0, 14 mg / ml. II. Apply A, the plasma concentration being expected to be 30% of the same when the blood has circulated to mix the drug efficiently = 0.046 mg / ml. III. Thereafter, the level of free unbound alphaxalone in plasma associated with induction of anesthesia after a single bolus injection iv = 65% of the total (from fact 2) = 0.045 x 0.65 = 0.03 mg / ml. IV. Proposition III above is exactly the known solubility of alfaxalone in water. V. By combining points 5 and 8 with proposition IV, it is proposed in this document, that the first induction dose of PhaxanCD caused anesthesia by releasing all alfaxalone from the complex reaching only the anesthetic level and alphaxalone saturation level free. SAW. When the second dose of anesthetic was mixed by addition in Example 9, the rat began to recover from the anesthetic because some free alphaxalone was metabolized by the liver, some free alphaxalone was redistributed to the ECF and some of the Captisol containing alfaxalone was also redistributed to the ECF. Thus, the level of free alphaxalone dropped and the alphaxalone left the brain, causing it to awaken. Thus, an additional dose was obtained. Unlike the first dose, there was still alphaxalone in the blood, so only some of the alphaxalone was released from the complex to bring the free alphaxalone level back to 0.03 mg / ml; in this way, the brain is recharged and the sleep continues. VII. However, the sleep continues for a longer time after the second dose and the third and also the fourth, and until the ECF is loaded with 0.03 mg / ml of alfaxalone and alfaxalone / Captisol complex [oints 6 and 7]. Subsequently, additional doses of Captisol simply fill the blood level with free alfaxalone and maintain them until the liver's metabolism determines the dose of alfaxalone. VIII. Once the free alphaxalone level reaches 0.03 mg / ml, the brain is anesthetized. The brain will only absorb more alphaxalone if the level of free alphaxalone increases. This is possible with Althesin (trademark) and death occurs when the anesthetic dose of the drug is mixed 15 times by addition as a cake, leading to a theoretical free alphaxalone level of 0.45 mg / ml. In contrast, when the dose of alfaxalone is obtained as PhaxanCD, in a complex with Captisol (trademark), alphaxalone is not released from the complex, since the free alphaxalone level reaches 0.03 mg / ml [oint 1]. This explains the ceiling effect on lethality with alphaxalone when formulated in 13% sulfobutyl-7-ether β-cyclodextrin. IX. Since no further increase in sleeping time occurs after the fifth dose of 5 mg / kg of PhaxanCD and subsequent doses of the same magnitude, then the alphaxalone gap should be in balance with the dose delivery rate. The equilibrium clearance of alfaxalone is then 5 mg / kg / 4.2 min. Since the plasma concentration is approximately 0.04 mg / ml, then the equilibrium plasma clearance rate = ((5 ^ 4.2) -r 0.04) = 30 mls / kg / min. It is inserted in the known values of hepatic blood flow (Davies and Morris, 1993 supra). It is well known that alphaxalone is primarily discharged from plasma by first-pass hepatic metabolism. X. The latter means that this particular formulation of alphaxalone in sulfobutyl ether β-cyclodextrin controls the level of free unbound anesthetic that penetrates the brain up to, but not above, a level that causes anesthesia; Captisol cannot release any additional compound above the level at which the plasma water is saturated with alphaxalone and therefore, higher levels of blood that would cause toxicity are not achieved.
[00127] This property has not been described for intravenous anesthetics or intravenous cyclodextrins previously. This happens from a unique set of circumstances not described or previously revealed: 1. A unique host / guest interaction. The evidence for this is the fact that the same guest [alphaxalone] formulated in another host cyclodextrin (AlfaxanCD-RTU; hydroxypropyl β-cyclodextrin - the Jurox preparation) does not have a toxicity ceiling with a cited LD50 of 19 mg / kg iv in rats, a dose that is 75% lower than the dose of alfaxalone in (7) sulfobutyl ether β-cyclodextrin causes only 20% lethality; 2. The guest is a compound that causes anesthesia at a free drug level that is equal to its aqueous solubility; and 3. The guest is a compound that has a high therapeutic index so that the level of free drug is well below the toxic level. EXAMPLE 8 Formulation of pregnanolone
[00128] The anesthetic neuroactive steroid pregnanolone was mixed with 13% w / v sulfobutyl ether β-cyclodextrin (Captisol [Trademark]) in 0.9% saline to form pregnanoloneCD. Pregnanolone incompletely dissolved in a concentration of 10 mg / ml, and unlike alfaxalone, only went into the solution after 4 hours of continuous stirring. The solution was opalescent. This observation indicates that no neuroactive steroid interacts with (7) sulfobutyl β-cyclodextrin in the same way. Fifteen male Wistar rats (weight 150 to 200) with surgically implanted internal jugular intravenous catheters were used for these experiments in which they received intravenous pregnanoloneCD injections: 2.5 mg / kg (n = 5); 5 mg / kg (n = 5); and 10 mg / kg (n = 5).
[00129] They were evaluated for anesthesia by the straightening reflex that was scored: 1 normal; 2 slow; 3 any attempt; 4 none. A score of 4 means that a state of unconsciousness (anesthesia) has been achieved. Figure 5 below shows the results of this test for rats in the three groups that received 2.5, 5 and 10 mg / kg of pregnanolone. The results shown are the meanings of the readings from all 5 rats at each time point after the intravenous injection of pregnanolone.
[00130] The rats were also evaluated for surgical anesthesia using punctuated tail clamp responses: 1 normal; 2 weak; 3 only present; 4 none. A score of 4 indicates that surgical anesthesia has been achieved. Figure 6 shows the results of this test for rats in the three groups that received 2.5, 5 and 10 mg / kg of pregnanoloneCD. The results shown are the meanings of the readings from all 5 rats at each time point after the intravenous injection of pregnanoloneCD.
[00131] The time to complete recovery from the sedative effects of pregnanoloneCD was evaluated with the time spent in the rotating cylinder - normal non-sedated rats remained in the accelerated rotating drum for 120 seconds; the rats are fully recovered when they can walk on the rotating roller mat for 120 seconds. Figure 7 below shows the results of this test for rats in the three groups that received 2.5, 5 and 10 mg / kg of pregnanoloneCD. The results shown are the meanings of the readings from all 5 rats at each time point after the intravenous injection of pregnanoloneCD. Conclusions
[00132] PregnanoloneCD is an intravenous anesthetic, but of long duration. The same causes induction of anesthesia immediately after the intravenous injection. This effect is dose related and it is possible to cause enough CNS depression to lead to surgical anesthesia. EXAMPLE 9 Alfadolone formulation
[00133] The neuroactive steroid anesthetic alfadolone was mixed with 13% w / v sulfobutyl ether β-cyclodextrin (Captisol) in 0.9% w / v saline to form alfadoloneCD. Alfadolone completely dissolved in a concentration of 10 mg / ml, but unlike alfaxalone, it only went into the solution after 4 hours of continuous stirring. This observation indicates that no neuroactive steroid interacts with (7) sulfobutyl β-cyclodextrin in the same way. Fifteen male Wistar rats (weight 150 to 200) with surgically implanted internal jugular intravenous catheters were used for these experiments in which they received intravenous dealfadolone CD injections: 10 mg / kg (n = 5); 20 mg / kg (n = 5); and 40 mg / kg (n = 5).
[00134] They were evaluated for anesthesia by the straightening reflex that was scored: 1 normal; 2 slow; 3 any attempt; 4 none. A score of 4 means that a state of unconsciousness (anesthesia) has been achieved. Figure 8 shows the results of this test for rats in the three groups that received 10, 20 and 40 mg / kg of alfadoloneCD. The results shown are the meanings of the readings from all five rats at each time point after the intravenous injection of alfadolone.
[00135] The rats were also evaluated for surgical anesthesia using punctuated tail clamp responses: 1 normal; 2 weak; 3 only present; 4 none. A score of 4 indicates that surgical anesthesia has been achieved. Figure 9 shows the results of this test for rats in the three groups that received 10, 20 and 40 mg / kg of alfadoloneCD. The results shown are the meanings of the readings from all five rats at each time point after the intravenous injection of alfadolonaCD.
[00136] The time to complete recovery from the sedative effects of alfadolonaCD was evaluated with the time spent in the rotating cylinder - normal non-sedated rats remained in the accelerated rotating drum for 120 seconds; the rats are fully recovered when they can walk on the rotating roller mat for 120 seconds. Figure 10 shows the results of this test for rats in the three groups that received 10, 20 and 40 mg / kg alfadolonaCD. The results shown are the meanings of the readings of all 5 rats at each time point after the intravenous injection of alfadolonaCD. Conclusions
[00137] AlfadoloneCD is a short-lived intravenous anesthetic. It causes induction of anesthesia immediately after intravenous injection. This effect is dose related and it is possible to cause enough CNS depression to lead to surgical anesthesia. EXAMPLE 10 Cardiovascular Effects of PhaxanCD compared to Althesin and Propofol
[00138] Fifteen male Wistar rats (weight 150 to 200) with surgically implanted internal jugular intravenous catheters were used for these experiments in which the rats in three groups received intravenous injections of anesthetic doses of AD95 equipotent propofol (6.6 mg / kg; Diprivan 10 mg / ml propofol in 10% Intralipid emulsion), Althesin (3.28 mg / kg alfaxalone; Althesin 9 mg / ml alfaxalone plus 3 mg / ml alfadolone dissolved in 20% Cremofor EL), or PhaxanCD (3.23 mg / kg of alfaxalone; 10 mg / ml of alphaxalone dissolved in Captisol [(7) sulfobutyl ether β-cyclodextrin] 13%); n = 5 rats per group. Systolic and diastolic blood pressures were measured before and after these injections. Each measurement was calculated as a percentage change from pre-anesthetic levels for that rat. Figures 11 and 12 show the percentage changes against time for each of the cardiovascular parameters in each treatment group. Conclusion
[00139] The two formulations of alfaxalone (Althesin / 20% Cremofor EL; PhaxanCD / sulfobutyl ether β-cyclodextrin (Captisol [Trademark])) caused less cardiovascular disorder than an equianesthetic dose of propofol and in one measurement (blood pressure diastolic) the formulation of sulfobutyl ether β-cyclodextrin alfaxalone (PhaxanCD) caused less cardiovascular disturbance compared to the preparation of Cremofor EL (Althesin [Trademark]). EXAMPLE 11 A Phase 1 / 2a Clinical Trial
[00140] In these experiments on human volunteers, propofol and (7) sulfobutyl ether β-cyclodextrin / alfaxalone formulation are compared in a double blind mode. Each volunteer is prepared in a fully equipped anesthesia room. The dosage with propofol or alfaxalone is determined by a randomization schedule for propofol or alfaxalone. An anesthetist assigned to provide the anesthetic opens an envelope to check which drug should be provided to that patient. The dose of drug is determined from a calculation schedule (see below) that is based on the patient's response prior to the last dose of that drug used - anesthesia achieved or not based on a measurement of 50 for the electroencephalogram bispectral index ( BIS value). The patient has an intravenous cannula in his right hand to administer the drug and another to draw blood for samples to measure blood levels of the drug. The arm and the anesthetist who administers the anesthetic have no communication with the test subject or a second anesthetist who is in contact with the individual and who is responsible for the individual's general care, as well as physiological monitoring. The arm and the anesthetist who administers the drug are separated by a curtain between the anesthetist responsible for the individual, as well as between the individual and the anesthetist nurse present. The first, anesthetist who administers the drug, only communicates that the anesthetic injection will start by ringing a bell and the responsible anesthetist only communicates with the anesthetist who administers the drug to say if a BIS value of 50 or less was reached after this the individual leaves the room at the end of the experiment. Measurements and evaluations made: • Individual's weight in kg. This is written in the case record before passing it on to the anesthetist who administers it. • The responsible anesthetist asks the patient to report pain during the injection and a positive or negative report is recorded. • The presence or absence of abnormal movements is noted by the responsible anesthetist.4 • The time from the ring of the bell that indicates the injection of anesthetic to the individual who drops a syringe with 20 ml of water kept between the index and the thumb in the left arm straight. • The time from the ring of the bell that indicates the injection of anesthetic to the loss of verbal contact with the patient and time for the return of that contact. • The time from the ring of the bell that indicates the injection of anesthetic to the individual who loses the eyelash reflex and the time for the return of that reflex. • The BIS value and if a value of 50 or below is reached, when and for how long after the intravenous injection. • Blood pressure, systolic and diastolic, and pulse rate using non-invasive methods measured every 1 minute for 5 minutes, every 2.5 minutes for an additional 10 minutes and every 5 minutes thereafter. • Blood oxygen saturation measured with a pulse oximeter probe placed on the lobe of the left ear. The individual breathes air unless the oxygen saturation levels drop below 93% in that oxygen time is provided by a face mask and anesthetic circuit. Breathing is assisted if apnea occurs and persists for more than 30 seconds. The occurrence of low oxygen saturation and apnea is noted. • The total recovery time indicated by normal performance in a digital replacement test • Blood drawn for analysis of blood levels of alfaxalone at 0.5, 1.0, 1.5, 2, 5 10, 15, 30 and 60 minutes after anesthetic injection. • Blood drawn before the experiment, one hour after the experiment and 24 hours and a week later for:
[00141] Complete hematological analysis.
[00142] Liver function tests.
[00143] Kidney function tests.
[00144] Dose programming
[00145] When the envelope is opened by the anesthetist who administers the randomized instruction it will be to provide propofol or alfaxalone. If this is the first individual to receive the drug, it is provided with: propofol 2 mg / kg; alfaxalone 0.5 mg / kg. • The dosage for the next patient to receive that drug is determined by the response of the first individual who received the drug.
[00146] If the first individual did not reach a BIS of 50 or less, then for propofol the dose would be 3 mg / kg and for alphaxalone 0.75 mg / kg.
[00147] If the first individual did not reach a BIS of 50 or less, then for propofol the dose would be 1 mg / kg and for alphaxalone 0.25 mg / kg. • Thereafter, the dosage is: a 25% dose decrease if all individuals previously treated with that drug achieve a BIS of 50 or, a 25% dose increase if all individuals previously treated with that drug have not have all reached a BIS of 50 or,
[00148] In case there have been some individuals treated with this drug who have reached BIS values of 50 or less and others with BIS values that have not dropped to 50 or less then:
[00149] In case the last answer is a BIS of 50 or less, then the drug dose for the next individual who receives that drug will be halfway between the dose and the dose for the last individual who received the drug and the dose provided to the most recent previous individual who received that drug and who did not achieve a BIS of 50 or below.
[00150] In case the last response is a BIS greater than 50, then the drug dose for the next individual who receives that drug will be halfway between dose and dose for the last individual who received the drug and the dose provided to the most recent previous individual who received that drug that achieved a BIS of 50 or below.
[00151] The last case is repeated for each drug series until the dose range variations have become small and six subjects have reached a BIS value of 50 or less having received the same dose of ± 10% drug. These 6 doses that reach anesthetic levels of BIS are combined to calculate the standard error of the mean induction dose.
[00152] The following results are expected: • Alfaxalone causes general anesthesia with BIS values <50 achievable in the circulation time of an arm / brain. • The quality of induction is at least as good as with propofol, but with the added advantage that there is no pain during the injection. • In the “induction dose”, propofol causes greater drops in blood pressure, an increased incidence of apnea and decreased oxygen saturation than alfaxalone. • After administering the “induction dose” the speed and quality of recovery are faster for alfaxalone. • The pharmacokinetics of alfaxalone after intravenous administration is the same for the Figures of alfaxalone in the literature after administration of Althesin (Trademark).
[00153] Those skilled in the art will find that the invention described in this document is susceptible to variations and modifications other than those specifically described. It should be understood that the invention includes all these variations and modifications. The invention also includes all the steps, resources, compositions and compounds referred to, or indicated in this specification, individually or collectively, and any and all combinations of any two or more among said steps or resources.


[00154] From Uekama et al., 1998 supra. BIBLIOGRAPHY
[00155] Atwood, Davies, MacNicol and Vogtie (Eds), Comprehensive Supramolecular Chemistry Volume 4, Pergamon: Oxford UK, 1996
[00156] Child et al., British Journal of Anesthesia 43: 2 to 13, 1971
[00157] Davies and Morris, Pharmaceutical Research, 10 (7): 1093 to 95, 1993
[00158] Fromming and Szejtlic (eds), Ciclodextrins in Pharmacy, Kluwer: Dordrecht, Netherlands, 1994
[00159] Remington's Pharmaceutical Sciences, Mack Publishing Company, Eaton, USA, 1990
[00160] Rowe's Handbook of Pharmaceutical Excipients, 2009
[00161] Thomason, Crit Rev Ther Drug Carrier Syst 14: 1, 1997
[00162] Uekama et al., Chem. Rev. 98: 2.045 to 2.076, 1998

权利要求:
Claims (14)
[0001]
1. ANESTHETIC OR SEDATIVE COMPOSITION, characterized by comprising a neuroactive steroid anesthetic formulated with a cyclodextrin, in which the neuroactive steroid anesthetic is selected from alfaxalone, alfadolone and alfadolone acetate or a salt thereof, and in which cyclodextrin is ( 7) sulfobutyl β-cyclodextrin ether or an alkyl ether derivative thereof, and in which the molar ratio of neuroactive steroid anesthetic to cyclodextrin is 1: 1 to 1: 6.
[0002]
2. COMPOSITION according to claim 1, characterized in that the molar ratio of neuroactive steroid anesthetic to cyclodextrin is 1: 1 to 1: 4.
[0003]
COMPOSITION according to either of claims 1 or 2, characterized in that the molar ratio of neuroactive steroid anesthetic to cyclodextrin is 1: 1 to 1: 3.
[0004]
COMPOSITION according to either of claims 2 or 3, characterized in that the molar ratio of neuroactive steroid anesthetic to cyclodextrin is 1: 2.
[0005]
COMPOSITION according to any one of claims 1 to 4, characterized in that it further comprises one or more of an antimicrobial agent, a preservative, a buffer and / or a copolymer.
[0006]
6. COMPOSITION according to claim 5, characterized in that the copolymer is selected from hydroxy propyl methyl cellulose, polyvinyl pyrrolidone and carboxymethyl cellulose.
[0007]
7. COMPOSITION according to claim 5, characterized in that, if a buffer is present, the pH is from pH 5.5 to pH 8.
[0008]
COMPOSITION according to any one of claims 1 to 7, characterized in that the derivative is sulfobutyl ether-alkyl ether β-cyclodextrin.
[0009]
COMPOSITION according to claim 8, characterized in that the cyclodextrin is sulfobutyl ether-ethyl ether β-cyclodextrin or sodium salt thereof.
[0010]
COMPOSITION according to any one of claims 1 to 9, characterized in that it comprises alphaxalone and alfadolone or alfadolone acetate or salts thereof.
[0011]
11. ANESTHETIC OR SEDATIVE COMPOSITION, as defined in any of claims 1 to 10, characterized by being for use in inducing or maintaining anesthesia or sedation in an individual, wherein said composition is for administration by infusion or intermittent bolus.
[0012]
12. COMPOSITION, according to claim 11, characterized in that alfaxalone is used in an anesthetic concentration of 0.25 mg / kg to 100 mg / kg of body weight.
[0013]
13. COMPOSITION according to claim 12, characterized in that alfaxalone is used in a sedative concentration of 0.05 mg / kg to 10 mg / kg of body weight.
[0014]
COMPOSITION according to any one of claims 1 to 13, characterized in that the individual is a human.

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法律状态:
2018-07-24| 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 |

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2018-07-31| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-08-14| B25A| Requested transfer of rights approved|Owner name: DRAWBRIDGE PHARMACEUTICALS PTY LTD (AU) |

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2018-09-04| B25G| Requested change of headquarter approved|Owner name: DRAWBRIDGE PHARMACEUTICALS PTY LTD (AU) |

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2019-12-03| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2019-12-17| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2020-04-07| B07A| Application suspended after technical examination (opinion) [chapter 7.1 patent gazette]|

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2020-09-01| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-12-08| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 19/01/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US29724910P| true| 2010-01-21|2010-01-21|

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US61/297,249|2010-01-21|

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US38531810P| true| 2010-09-22|2010-09-22|

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US61/385,318|2010-09-22|

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PCT/AU2011/000050|WO2011088503A1|2010-01-21|2011-01-19|Anaesthetic formulation|

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