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    • 专利摘要:
    The present invention relates to solid instant release dosage forms (IR dosage forms) comprising lipid conjugates of nucleosides having gel-like properties in the active substance or active concentrate of the treatment, in particular in an aqueous medium, and methods for their preparation.
    公开号:KR19990082039A
    申请号:KR1019980705759
    申请日:1997-01-24
    公开日:1999-11-15
    发明作者:롤프-디터 가벨；알렉산더 비를；하인리히 보그
    申请人:로셰 디아그노스틱스 게엠베하；
    IPC主号:
    专利说明:

    Solid Instant Release Dosage Forms and Methods for Making the Same
    The present invention relates to solid instant release dosage forms (IR dosage forms) comprising lipid concentrates of nucleosides having gelling properties in aqueous media, especially concentrates of therapeutic agents or active substances. The present invention also relates to a process for the production of such quick release forms.
    The drug (active substance) is not made in a special form and is used only in rare cases. Auxiliary materials can be used to convert to solid IR dosage forms with traditional gelling processes.
    In general, the IR dosage form must disintegrate very rapidly to obtain the required high dissolution rate in vitro of the active substance. Rapid disintegration of the dosage form is determined on the one hand by the choice of auxiliary substances and manufacturing processes, and on the other hand by the dissolution properties of the active substance itself. The active materials used do not usually form gels or gel-like structures during dissolution in aqueous media to possibly rule out mutual adhesion of the particles of the active material.
    However, numerous active materials with lipophilic residues, when processed to form solid IR dosage forms using traditional gelling processes, tend to form gels or gel-like structures when dissolved in, for example, aqueous media. There is an active material from the group of lipid conjugates that are present, and therefore does not achieve a moderately fast dissolution rate of the active material in vitro. This applies to combinations of active substances (concentrates of active substances) which contain the active substances in high concentrations. This disadvantage is particularly evident, particularly when a high dose of massed dosage forms (eg tablets) are desired, and as the concentration of the active substance increases, the desired effect increases. The in vitro dissolution rate and in vivo dissolution rate and resorption rate of these formulations are greatly reduced compared to liquid dosage forms.
    Within the meaning of the present invention, the term “gel forming active substance” is understood to include active substances which form gel-like phases at 20 ° C., at a concentration of less than 20% (w / v%) in aqueous systems. , The solution obtained here does not exhibit Newtonian fluid behavior. Such a fluid is called a Newtonian fluid whose flow resistance at a given temperature, defined by the Newton's equation t = h · D (where t is the shear stress, D is the velocity gradient and h is the kinematic viscosity).
    Such active materials and their preparation are described, for example, in WO 92/03462, WO 93/16092, WO 93/16091, WO 94/03465, PCT / EP94 / 02123; DE 4402492, DE 4418690 and WO 91/19726, EP 0 350 287, US 5,223,263, US 5,194,654, US 4,921,951, US 4,622,392, US 4, 291,024, US 4,283,394. In the case of antivirally active nucleoside derivatives, EP 0 350 287 and US 5,223,263 describe lipid derivatives (diacylglycerol nucleosides) and their use in liposome form.
    Active materials that are absorbent, unstable, compatible with many conventional auxiliary materials, and are prone to gel formation in aqueous media, are processed into rapid solid, rapid disintegrating forms of administration with the aid of significant addition of auxiliary materials. Can't be. When the active substance-adjuvant mixture or the dosage form prepared therein is introduced into the aqueous release medium, a high viscous gel layer forms immediately on the boundary which makes rapid dissolution more impossible. These gel layers dissolve very slowly just like the hydrocolloidal matrix and thus exhibit undesirable delay effects.
    Although this delaying effect may be partially offset by dilution with a suitable adjuvant, the large amount of adjuvant required will result in an unsuitable dosage for tablets, and the bulky dosage forms at higher doses of the active substance It cannot be manufactured anymore.
    In addition, where the formulations are the same, the rate of dissolution in vitro depends on the degree of compression of the form of administration, so that a suitable rate of dissolution in vitro cannot be achieved in the case of compressed dosage forms (eg tablets) and in the case of capsule fillings. In addition, tablets made in this way have inadequate hardness and excessive wear loss, so wear losses are high when film coated tablets are prepared by grinding tablets in the coating used.
    Traditional manufacturing processes are more disadvantageous. Due to the dispersion of the active substance in the auxiliary substance necessary for aqueous granulation, the active substance is also brought into contact with the incompatible auxiliary substance, and thus a sufficiently high stability of the form of administration cannot be achieved. It has also been found that the homogeneous distribution of the absorbent active substance in the form of administration is not always ensured because the particles of the active substance aggregate to form large units in the wet medium. However, the heterogeneous distribution of the active substance in pharmaceutical mixtures with other auxiliary substances is problematic because, when further processed into each dosage form such as tablets or capsules, the amount of active substance in the form of administration will be different. . In addition, different portions of the in vitro dissolution rate of each form of administration result in the construction of a large amount of technical preparation that exceeds conventional variations despite the same composition and the same processing steps of the formulation.
    However, for essential pharmaceutical stability, such risks should be ruled out as far as possible when developing pharmaceutical formulations.
    For the above reasons, using a standard gelling method of mixing, granulating, spray drying, spray solidifying or press granulating the active substance with the auxiliary substance, reaching a single dosage form at a desired dosage with a moderately fast in vitro dissolution rate It is not possible in the usual way. In addition, the granular structure adversely affects the stability of the active substance, that is, a satisfactory solution cannot be obtained by the conventional method.
    Accordingly, it is an object of the present invention to develop improved IR dosage forms of active substances or active concentrates which form gels in aqueous media.
    OBJECT OF THE INVENTION The object of the present invention relates to an IR dosage form wherein the gelling active substance or active concentrate is inserted into an envelope that controls swelling consisting of compatible auxiliary substances that inhibit or offset gel formation.
    Surprisingly, it has been found that selected groups of auxiliary substances are suitable within the scope of the present invention to reduce, inhibit or offset the gel formation of active substances or active concentrates in aqueous media. In addition, such dosage forms can be stored for a long period of time without detectable degradation products of the active or auxiliary substances used, which are stable and due to the probable interaction of the active substances with the auxiliary substances. Suitable auxiliary substances within the scope of the present invention are macromolecules such as polyvinylpyrrolidone, gelatin, gelatin derivatives, starch, starch derivatives, cellulose, cellulose derivatives, macrogol, polyvinyl alcohol and polyacrylic acid, and auxiliary substances Such as sugars, sugar alcohols, glycerides, salts of fatty acids, fats, waxes, surfactants, silicates or highly dispersible silicone dioxides and combinations thereof. Auxiliary materials Highly dispersible silicone dioxide, polyvinyl pyrrolidone, cellulose and sugars are particularly suitable. These auxiliary substances are compatible with the active substance. They can be formed separately or in combination to form a swelling control envelope. The envelope of the active material particles is in this regard that each active material particle is surrounded by a first coating of auxiliary material and the active material particles themselves are not in direct contact.
    Macromolecules (e.g., polyvinylpyrrolidone, gelatin, gelatin derivatives, starch, starch derivatives, cellulose, cellulose derivatives, macrogol, polyvinyl alcohol and polyacrylic acid), sugars, sugar alcohols, salts of fatty acids, fats, It is known that waxes, surfactants, silicates or highly dispersible silicone dioxide can form gels with water or increase the viscosity in aqueous media. Glycerides have the same effect. Moreover, it is known that the active substance forms a gel with an aqueous medium. Due to this fact, it was expected that after the active material was completely dissolved in the aqueous medium, the addition of the auxiliary material increased the viscosity of the solution.
    However, the unexpected addition of the auxiliary material in the form of the first coating reduces the viscosity, i.e. the expected addition effect of the auxiliary material and the active material with increasing viscosity does not occur. Surprisingly, the desired rapid in vitro dissolution was achieved. In addition, compressed dosage forms (tablets) have the necessary physical properties such as moderate hardness and low wear loss.
    In a preferred aspect of the present invention, the active substance or active concentrate may be surrounded by another envelope (second envelope) (cf. FIG. 1) in addition to the swelling control first envelope. The same auxiliary material for the first envelope is suitable for inserting particles provided with a second envelope or first envelope separately or in combination.
    The solid IR dosage form according to the invention is a particle having a first envelope (first particle), a particle having a first envelope and a second envelope (second particle), or a first particle having an external phase (inner). Phase) or second particles (inner phase) having an external phase. The external phase contains auxiliary substances suitable for preparing tablets starting with the active substance / adjuvant granules. The external phase may be a conventional dissolving and / or conventional agent such as fillers and / or agents to aid flow agents, lubricants or separators such as microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, silicone dioxide or surfactants. Pharmaceutical auxiliary substances.
    According to the invention, the ratio of active substance to auxiliary substance with respect to the IR dosage form is 1: 0.01 to 1: 100, preferably 1: 0.05 to 1: 5 with respect to the first envelope. In an IR dosage form having a first and a second envelope, the weight ratio of active substance to auxiliary substance is from 1: 0.01 to 1:10 for the first envelope and 1: 0.1 to 1: 100 for the second envelope, It is preferably in the range of 1: 1 to 1:10. The content of the active substance of the IR dosage form according to the invention is 0.5 to 90%, preferably 5 to 50%. The average particle size (d ') of the active substance or active concentrate ranges from 10 μm to 3 mm. The lower limit is preferably 50 µm, 100 µm or 200 µm. The upper limit is preferably 500 µm, 700 µm or 1 mm.
    It is understood that the gelling active substance within the scope of the present invention is an active substance which increases the viscosity of the solution when dissolved in water or a buffer containing aqueous system at a concentration of less than 20%, preferably about 2 to 10%. The viscosity of such solutions is, for example, levels above 5 mPas * sec, in particular above 100 mPas * sec, preferably above 500 mPas * sec.
    According to the invention, the active substance or salt or concentrate thereof that forms a gel in an aqueous medium is, for example, a compound of formula (I):
    L-B-D (I)
    Wherein D represents a pharmaceutically active substance (medicament), L represents a lipophilic residue and B represents a linking group linking groups L and D).
    In particular B represents a bridge —O — [(PO) (OH) O] n −, where n is 1,2 or 3, and L represents the lipid moiety of the formula (II):
    {Wherein R 1 may be optionally substituted once or several times with C 3 -C 8 cycloalkyl or substituted phenyl, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkylmercapto, C 1 -C A straight or branched, saturated or unsaturated alkyl chain having 1-30 carbon atoms, which may be optionally substituted by a 6 alkoxycarbonyl, C 1 -C 6 alkylsulfinyl or C 1 -C 6 alkylsulfonyl group ,
    R 2 is hydrogen, a straight or branched chain, saturated or unsaturated alkyl chain having 1 to 20 carbon atoms (halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkylmercapto, C 1 -C 6 alkoxycarbonyl , C 1 -C 6 alkylsulfinyl or C 1 -C 6 alkyl may be optionally substituted once or several times by a sulfonyl), and
    X represents a valence dash, oxygen, sulfur, oxycarbonyl, carbonyloxy, carbonyl amido, amidocarbonyl, sulfinyl or sulfonyl groups,
    Y is valent dash, oxycarbonyl, carbonyloxy, carbonyl amido, amidocarbonyl, oxygen or sulfur atom,
    m is an integer from 1 to 5}.
    R 1 in formula II preferably represents a straight or branched C 8 -C 15 alkyl group which may be optionally substituted by C 1 -C 6 alkoxy or C 1 -C 6 alkylmercapto groups. R 1 is in particular a saturated alkyl chain optionally substituted by C 3 -C 8 cycloalkyl or an optionally substituted phenyl group. R 1 in particular represents a nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, cyclohexyl-hexyl or phenyl-hexyl group, wherein the phenyl group is optionally substituted by C 1 -C 6 alkyl or halogen . The methoxy, ethoxy, butoxy and hexyl groups can be considered as C 1 -C 6 alkoxy substituents of R 1 . If R 1 is substituted by a C 1 -C 6 alkylmercapto residue, it is in particular a methyl-mercapto, ethyl mercapto, propylmercapto, butylmercapto and hexyl mercapto residue.
    R 2 represents a straight or branched C 8 -C 15 alkyl group which may be further substituted by a C 1 -C 6 alkoxy group or a C 1 -C 6 alkylmercapto group. R 2 particularly represents an octyl, nonyl, decyl, undecyl, dodecyl, tridecyl or tetradecyl group. The methoxy, ethoxy, propoxy, butoxy and hexoxy groups are preferably contemplated as C 1 -C 6 alkoxy substituents of R 2 . R 2 especially represents a C 8 -C 15 alkyl group, preferably an octyl, nonyl, decyl, undecyl, dodecyl, tridecyl or tetradecyl group.
    If R 2 is substituted by a C 1 -C 6 alkylmercapto residue, it is in particular understood as methylmercapto, ethylmercapto, butylmercapto and hexylmercapto residue.
    X is preferably sulfur, sulfinyl or sulfonyl and Y is oxygen. In special cases, the heteroatoms X and Y in the lipid moiety L can be replaced by known carboxylic esters from lecithin such that the hydrolysis to form the corresponding lysolecithin derivatives or glycerol esters is It occurs frequently in serum or liver (drug first pass effect) with a corresponding rapid clearance. Thioether lipids and ether lipids (X, Y = 0, S) do not exhibit this degradation in various species, including humans.
    In the compound, X and Y represents a valencene during the dash, R 2 is hydrogen, R 1 is C 1 -C 30 alkoxy or C 1 -C 6 C 1 -C 30 alkyl optionally substituted by alkyl mercapto Represents a chain.
    m is preferably 1 or 2, in particular 1.
    If the phenyl group is substituted, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylmercapto, C 1 -C 6 alkoxycarbonyl or C 1 -C 6 alkylsulfonyl group It is preferably considered as a substituent.
    Leg B is represented by the following formula:
    -O-[(PO) (OH) O] n-
    (Where n can be 1, 2 or 3, but is preferably 0, 1 or 2, in particular 1).
    Lipid moiety L and phosphate bridge B have the same meaning as above, where L is preferably a residue of formula II and B is preferably a phosphate bridge. In the phosphate bridge, n is preferably 1, and in the lipid portion of formula II, R 1 and R 2 are alkyl residues having 8 to 15 carbon atoms, X is sulfur and Y is oxygen. .
    The term "pharmacologically active substance" (D of formula I) means an active substance in the legal pharmaceutical sense. Such active substance can be the active substance of a medicament already introduced and registered by the authority or the active substance currently registered as a medicament. The definition of “pharmacologically active substance” also refers to those that can be chemically modified by introducing one or several functional groups (eg, groups in which D can be bound to a lipid carrier moiety L, such as a hydroxy or amino group). Derivatives of the same active substance. The definition also includes prodrug forms formed from active substance D which is physiologically active. In particular, the pharmacologically active substance D has not started its clinical progress or has not begun due to unwanted side effects, or has only a very small dose-effect spectrum, so that the dose required for treatment is at high risk or uncontrolled. Practically impossible.
    The therapeutic range of the pharmacologically active substance is significantly improved when the substance is combined with a carrier molecule similar to a lipid. Conjugates prepared in this way are used as new active substances for the preparation of pharmaceutical forms of administration. As a result of the binding as a whole, the increase in the activity of the pharmaceutically active substance D in vivo is due to the drug delivery transfer system formed, whereby the pharmacologically active substance is localized to the target cell, thus increasing the efficiency of the pharmacologically active substance. This is because the amount of pharmacologically active substance to be administered on the one hand is reduced, or on the other hand the increased pharmacological effect is achieved while maintaining the same effective amount.
    The chemical structure of the pharmacologically active substance D may be modified such that the substance changes in terms of physical or chemical properties and, for example, has essentially the same properties as substance D, which has a higher or lower lipophilic but is not denatured with respect to the therapeutic effect. Can be. In particular, it is advantageous if the substance D is chemically modified by the introduction of a functional group in such a way that it can be bound via a bridge suitable for the lipid moiety L. This is achieved, for example, by the introduction of a hydroxy group which is bound to the lipid via phosphate group B. If the active substance already has a phosphate group, for example as in the case of the active substance Foscarnet (HO-P (O) (OH) -COOH), it can also be used directly for binding to lipids. In such a case, n in the definition of B represents 0 (zero).
    The pharmacologically active substance D is chemically produced by the introduction of a chemical or biological substrate substance (antibody, peptide, protein, hormone, toxin, etc.) having a biological effect (INDEX NOMINUM, International Drug Directory, Medpharm) and a functional group (e.g., a hydroxy group). Derivatives thereof.
    It is contemplated that within the scope of the present invention all pharmacologically active substances are effective in the laboratory but toxic in vivo in the therapeutic range, ie all such substances have narrow treatments with chemical functional groups for covalent binding to phosphates. Has a range. In addition, such materials may have what can be used and can be introduced by chemical denaturation without loss of the effect of the material, but initially they do not contain functional groups in pharmacologically active forms.
    Such pharmacologically active substances are preferably used for conjugation with lipid residues L which normally reach the active form after phosphorylation (eg in the case of nucleosides). The pharmacologically active substance phosphate is then released from the conjugate by enzymatic hydrolysis of the conjugate. The release of phosphorylated material is particularly important because this process can also occur in cells that normally do not have the enzymes (kinases) needed to phosphorylate pure pharmacologically active substances. Conjugated pharmacologically active substances released by degradation of intracellular enzymes may have, for example, cell proliferation inhibitory, cytotoxic, antitumor, antiviral, antiretroviral, immunosuppressive or immunostimulatory effects.
    If the compounds of the formula I contain protic degradation residues such as one or several carboxy, phosphate or sulfonyl groups, the corresponding esters with alcohols and pharmacologically resistant salts of these acids, such as alkali or alkaline earth salts, are It can be used in the scope of the invention. Corresponding esters are in particular C 1 -C 6 alkyl esters such as methyl or ethyl esters. Pharmacologically acceptable salts are especially the sodium and potassium salts.
    For example, a compound suitable as a pharmaceutically active substance D that can be optionally converted into a derivative capable of binding by the introduction of a functional group that does not significantly affect tumor slowing action, inhibits topoisomerases I and II and , Substances that can be inserted into DNA and / or RNA, and are also as follows: tubulin inhibitors, alkylating agents, ribosomal inactive compounds, tyrosine phosphokinase inhibitors, differentiation inducers, hormones, hormone agonists or hormone antagonists, pleiotropic Substances that change resistance to cytostatic agents, calmodulin inhibitors, protein kinase C inhibitors, p-glycoprotein inhibitors, regulators of mitochondrial bound hecokinase, γ-glutamylcysteine synthetase or glutathione-S transferase Inhibitors of superoxy dismutase, inhibitors of HIV-1 and HIV-2 reverse transscriptase Inhibitors.
    The pharmacologically active substance D may have anti-inflammatory, antirheumatic, anti-inflammatory, analgesia, or antipyretic action. It may also be an antiarrhythmic agent, calcium antagonist, antihistamine, phosphodiesterase or sympathetic stimulant or parasympathetic stimulant.
    All substances are suitable as pharmacologically active substances D with short half-lives, in particular these compounds have different organ, tissue or cellular half-lives, inferior (drug) bioavailability, ie inferior resorption, high hepatic degradation or rapid elimination, inferior Transmembrane (eg, cell membrane, blood-brain barrier), bone marrow toxicity or other restricted organ toxicity (eg, cardiotoxicity, hepatotoxicity, nephrotoxicity, neurotoxicity, etc.) My active concentration is very low. Also suitable are substances, which in particular interact with the cell nucleus of the target cell and which can interfere with molecular processing or be used for gene therapy at the DNA or RNA level (eg antisense oligonucleotides, DNA fragments).
    The pharmacologically active substance D in formula I is as follows: AZT (azidothymidine), FLT (fluorothymidine), 5-FU (5-fluorouridine), 6-MPR, fludarabine, Cladribine, pentostatin, ara-C, ara-A, ara-G, ara-R, acylclovir, gancyclovir, poscarnet, doxorubicin, 4'-epidoxorubicin, 4'-de Oxy-doxorubicin, etoposide, daunomycin, idarubicin, epirubicin, mitoxantrone, vincristine, vinblastine, taxol, colchicine, melphalan, 3'-deoxy-2-fluoro- Adenosine, FdA, 5-ethynyluracil-9-β-D-arabino-furanoside, 5-propynuracilyl-9-β-D-arabino-furanoside, d4T, ddU, ddI, ddA, d2T, 2'-deoxy-2 ', 2'-difluorocytidine, 5-trifluoromethyl-2'-deoxyuridine, 5-chloro-2', 3'-dideoxy-3 ' -Fluorouridine, 3'-deoxy-3'-fluoro myoinositol, neplanosin A, ribavirin, myorinositol, pialu Dean, 3TC, Lamivudine, Doxyfluidine, Tegapur, Hypericin, Similar Hypericin, Ucevir, Famicyclobivir, Pencyclovir, Carvedilol, Actinomycin A, Bleomycin, Daunoru Bicine, phloxuridine, mitramycin, mitomycin C, mitoxantrone, streptozotocin, bindecine, netylmycin, amikacin, gentamicin, streptomycin, kanamycin A, tobramycin, neomycin B, plicamycin Lysine, papamycin, amphotericin B, vancomycin, poscarnet, idoxuridine, trifluridine, vidarabine and morphine, prostaglandin, leukotriene or cyclosporine. In addition, terpenadine, dexamethasone, terbutalin, prednisolone, phenoterol, orsiprenalin, salbutamol, isoprenin, muscarinic, bufranolol, oxyfenbutazone, oestrogene, salicolipoic acid, propranotol, Ascorbic acid, spongiadiol, diclofenac, isosphoniadiol, flufenamic acid, digoxin, 4-methyl-aminophenazone, allolfurinol, theophylline, epoprostenol, nifedipine, quinine, reserpin, mesotrec Also contemplated are acetate, chloroambucil, sperguarine, ibuprofen, indomethacin, sulfasalazine, penicillinamine, chloroquine.
    Preferred pharmacologically active substances include, for example, peptides, proteins and oligonucleotides such as corticotropin, calcitonin, desmopressin, gonadotropin, goserelin, insulin, gipressin, beta-melanotropin, Alpha-melanopropine, muramildipeptide, oxytocin, vasopressin, FK-506, octreotide or enalkyrene.
    Within the scope of the present invention, lipid conjugates of nucleosides are preferred active substances. In this connection, azidothymidine conjugates, fluorothymidine conjugates and 5-fluorouridine conjugates are particularly preferred. Sodium salt of 3'-azido-3'-deoxy-5'-thymidylic acid-mono- [3- (dodecylthio) -2-decyloxy-propyl] -ester, 3'-fluoro-3 Sodium salt of '-deoxy-5'-thymidylic acid-mono- [3- (dodecylthio) -2-decyloxy-propyl] -ester, and 5-fluoro-5'-uridic acid-mono [ 3- (dodecylthio) -2-decyloxypropyl] -ester is particularly preferred. Also preferred lipid conjugates are (3-dodecylmercapto-2-decyloxy) -propoxy-phosphinylhydroxy-formic acid and sodium salts and alkyl esters thereof.
    The above pharmacologically active substances and the conjugates that can be prepared therein are merely illustrative and do not limit the scope of the invention.
    The content of the gelling active substance for each formation (eg tablet) of administration is 1-500 mg, preferably 10-300 mg, in particular about 100-250 mg, so that the weight of each dosage form is 100 mg. Do not exceed If each dosage form is a tablet, they are provided with a film forming coating to achieve a taste control effect or an effect that affects the release of the active substance.
    The preparation process of the IR form of administration of the present invention is carried out by the following method:
    1) The swelling control first envelope is mixed or granulated (all variants of composition or decay granulation), preferably wet or spray granulation, dry granulation, with said compatible auxiliary material, alone or in combination of auxiliary materials. Or by granulation, spray drying, spray solidification or by press granulation of the active substance or active concentrate.
    The ratio of active material to auxiliary material is 1: 0.01 to 1: 100, preferably 1: 0.05 to 1: 5 in this process.
    2) The application of the second envelope alone, in combination or in combination with the auxiliary material, granulation (all variants of composition or decay granulation), preferably wet or spray granulation, dry granulation, spray drying, Spray solidification or granulation of the first particles produced according to 1).
    The ratio of active material to auxiliary material is 1: 0.1 to 1: 100, preferably 1: 1 to 1:10 in this process.
    Optionally, the first or second particles are mixed in a conventional manner with a conventional pharmaceutical auxiliary material such as a filler and / or disintegration aid and / or an external phase consisting of a flow agent, lubricant or separator.
    IR dosage forms according to the invention have a beneficial active substance release of greater than 35% after 30 minutes or greater than 70% after 1 hour. The active substance release is preferably at least 80-95%, in particular at least 90% after 1 hour.
    An IR dosage form according to the invention, having a first envelope around an active substance particle, has the following advantages:
    1) When the active substance particles are dissolved in an aqueous medium, the rate of dissolution in the test tube is enhanced in the final formation of administration due to the prevention or reduction of gel formation.
    2) Avoid sticking of the active material particles during processing in wet medium (granular preparation) and in late dissolution of the dosage form in an aqueous medium.
    3) acts to protect the active substance-decomposition auxiliary substance in any second envelope.
    4) Block active material from moisture during the manufacturing process and during storage of the form of administration.
    5) The hardness of the compressed material is increased by improved linkage of the active material with other auxiliary materials.
    In addition, the second envelope (or insertion of the active substance particles provided with the first envelope) has the following additional advantages over the IR dosage form:
    1. Significantly improved disintegration of the compacted material in the enveloped first particle (internal phase). As a result, after the surface is first enlarged, the active material particles are provided with a first envelope to form a gel.
    2. Physical protection of auxiliary substances in the external phase which degrade the active substance.
    3. Guarantee of external appearance effects (eg disintegrant effects).
    4. Ability to connect each enveloped particle during tableting.
    5. Plastic masking of the active material to ensure complete compression independent of the compressive forces resulting from high hardness and low wear loss of the compressed material.
    For the preparation of IR dosage forms, the preferred process of the present invention is that a first envelope which inhibits gelation of the active substance is applied to the surface of the active substance using the auxiliary substance of the invention as the first step. This is preferably carried out by mixing, granulating, spray drying, spray solidifying, or press granulating of the active material with the macromolecular auxiliary material and any pharmaceutical auxiliary material. The active material particles used preferably have a diameter of 10 to 500 μm. The particles formed in this step have a diameter of more than 10 μm, 50-700 μm. In the second step, the second coating or insertion of the particles obtained in the first step is carried out using the auxiliary substances or pharmaceutical additives of the invention. This process step may likewise be carried out by mixing, granulating, spray drying, spray solidifying, or press granulating of the particles, optionally using granulation adducts. The particles obtained in this way have a two layer structure, wherein the particle core is formed by the active material itself, and the inner envelope (first envelope) is an envelope of the auxiliary material containing the auxiliary material according to the invention or Consists of layers. The other auxiliary material is then contained in a second envelope (second envelope) applied to the first envelope. The ratio of active substance to auxiliary substance is preferably in the range from 1: 0.01 to 1:10 for the first envelope. The ratio of active material to auxiliary material in the second envelope is preferably from 1: 0.1 to 1: 100. Then, in the third process step, the trauma (eg tableting aid) can be mixed with the second particles so that the tableting mass produced in this way can be pressed directly into tablets. Tablets made in this way may optionally be coated with a neutral film or with a film that controls the taste or release of the active substance.
    Subsequently, the following examples illustrate, but do not limit, the present invention.
    Example 1
    Variables A and B are traditional dosage forms and variable C is a dosage form according to the invention.
    positionsportABC One)Active substance206 mg206 mg206 mg 2)Silicon dioxide, highly dispersed--14 mg 3)Microcrystalline Cellulose142 mg-- 4)Lactose300 mg442 mg300 mg 5)Polyvidone K254 mg4 mg20 mg 6)Microcrystalline Cellulose--176 mg 7)Sodium carboxymethyl starch120 mg120 mg- 8)Poly (vinylpyrrolidone), crosslinked--40 mg 9)Silicon dioxide, highly dispersed8 mg8 mg4 mg 10)Magnesium stearate20 mg20 mg20 mgFinal weight of core800 mg800 mg780 mgHardness40 N28 N142 NWear lossCappingCapping0.1% Active substance: Na salt of 3'-azido-3'-deoxy-5'-trimidylic acid-mono [3- (dodecylthio) -2-decyloxypropyl] -ester
    Gelling Properties of Active Material: When a 7% aqueous solution of the active material is prepared, the viscosity of the solution is 500-600 mPa * sec (initial value: 1 mPa * sec).
    The first coating is prepared in the first step by coating the active material particles 1) with an aqueous suspension of the auxiliary material. In the second step, the second coating is prepared by wet granulation of the particles obtained in the first step together with the positions 3) -5). The trauma is made by mixing positions 6) -10). The pharmaceutical mass obtained in this way is then compressed to determine the hardness and wear loss of the tablets obtained. In variants A and B, the preparation of the first envelope is omitted.
    The examples show that the IR dosage forms according to the invention, with the first and second coatings of the active material, are not capped and show very low wear losses and moreover have significantly increased hardness. In variants A and B, the gelling active material is traditionally processed to form granules with a large amount of disintegration promoting aids (microcrystalline cellulose and lactose) and binder PVP (Polyvidon K 25). In variant 3, the amount of disintegration promoting aid is reduced by approximately one third, but there is an auxiliary material aerosil (largely dispersed dispersed silicon dioxide). In addition, the coating process used is surrounded by a continuous coating (first coating) of active material particles. Tablets with good physical properties are obtained from variant C, the release of which is suitable for the conditions. During tableting, the capping of the tablet can be reduced to a low value of less than 1%. In addition, the IR dosage form according to the invention shows 90% release of the active substance after 1 hour.
    Example 2
    The following three variant dosage forms of administration are prepared analogously to Example 1: Variant A and B are traditional dosage forms and variant C is a dosage form according to the invention.
    positionsportABC One)Active substance100 mg100 mg100 mg 2)Silicon dioxide, highly dispersed--13 mg 3)Microcrystalline Cellulose116 mg-- 4)Lactose200 mg316 mg200 mg 5)Polyvidone K254 mg4 mg20 mg 6)Microcrystalline Cellulose--120 mg 7)Sodium carboxymethyl starch60 mg60 mg- 8)Poly (vinylidone), crosslinked--30 mg 9)Silicon dioxide, highly dispersed5 mg5 mg2 mg 10)Magnesium stearate15 mg15 mg15 mgFinal weight of core500 mg500 mg500 mgHardness45 N17 N150 NWear lossCappingCapping<1% Active substance: R, S- (3-dodecylmercapto-2-decyloxy) -propoxy-phosphinyl formic acid (disodium salt or methyl ester)
    This example shows that there is no capping and very low abrasion loss with the IR dosage form according to the invention with the first and second envelopes around the active material and is also quite hard. In addition, the IR dosage form according to the invention already has 80% release of the active substance after 1 hour.
    Example 3
    The following dosage forms are prepared analogously to Example 1, wherein variants A and B are traditional dosage forms and variant C is a dosage form according to the invention:
    positionsport:ABC One)Active substance150 mg150 mg150 mg 2)Silicon dioxide, highly dispersed--10 mg 3)Microcrystalline Cellulose136 mg-- 4)Lactose203 mg336 mg218 mg 5)Polyvidone K253 mg3 mg15 mg 6)Microcrystalline Cellulose--129 mg 7)Sodium carboxymethyl starch87 mg90 mg- 8)Poly (vinylpyrrolidone), crosslinked--30 mg 9)Silicon dioxide, highly dispersed6 mg6 mg3 mg 10)Magnesium stearate15 mg15 mg15 mgFinal weight of core600 mg600 mg570 mgHardness33 N15 N160 NWear lossCappingCapping<0.5% Active substance: Na salt of 3'-fluoro-3'-deoxy-5'-thymidylic acid-mono [3- (dodecylthio) -2-decyloxypropyl] -ester
    Viscosity of 2% aqueous solution of active material: 6 mPas * sec.
    This example shows that there is no capping with the first and second envelopes and the IR dosage form according to the invention with slight wear, and also with significantly better hardness.
    权利要求:
    Claims (22)
    [1" claim-type="Currently amended] A solid immediate release dosage form comprising an active concentrate or active concentrate of treatment having gelling properties in an aqueous medium in an envelope comprising auxiliary substances which inhibit or offset gel formation.
    [2" claim-type="Currently amended] The instant release dosage form of claim 1, wherein the active substance or active concentrate is surrounded by another envelope (second envelope) made of a suitable auxiliary material in addition to the swelling control first envelope.
    [3" claim-type="Currently amended] The method of claim 1, wherein the auxiliary material is a macromolecule (e.g., polyvinylpyrrolidone, gelatin, gelatin derivatives, starch, starch derivatives, cellulose, cellulose derivatives, macrogol, polyvinyl alcohol and polyacrylic acid), sugars, Immediate release dosage forms selected from sugar alcohols, salts of fatty acids, fats, waxes, surfactants, silicates or highly dispersible silicon dioxide, which form an envelope alone or in combination with each other.
    [4" claim-type="Currently amended] Instant release dosage forms. 3. The immediate release dosage form of claim 2 wherein the second envelope consists of each auxiliary substance or combinations thereof.
    [5" claim-type="Currently amended] The instant release dosage form according to any one of claims 1 to 4, further having trauma.
    [6" claim-type="Currently amended] 6. The immediate release dosage form according to claim 5, wherein the trauma consists of conventional pharmaceutical auxiliary substances such as fillers and / or disintegration aids and / or flow agents, lubricants or separators.
    [7" claim-type="Currently amended] The instant release dosage form according to any one of claims 1 to 3, wherein the ratio of active substance or active concentrate to auxiliary substance is from 1: 0.01 to 1: 100.
    [8" claim-type="Currently amended] The instant release dosage form according to claim 7 wherein the ratio is from 1: 0.05 to 1: 5.
    [9" claim-type="Currently amended] The method according to any one of claims 1 to 4, wherein the ratio of the active substance or the active concentrate to the auxiliary substance is from 1: 0.01 to 1:10 with respect to the first envelope, and the ratio with respect to the second envelope is 1: 0.1. Immediate release dosage form from 1: 100, preferably 1: 1 to 1:10.
    [10" claim-type="Currently amended] 10. The immediate release dosage form according to any one of the preceding claims, wherein the content of the active substance is 0.5 to 90%, preferably 5 to 50%.
    [11" claim-type="Currently amended] The instant release dosage form according to any one of claims 1 to 10, wherein the average particle size (d ') of the active substance or concentrate of the active substance is from about 0.01 mm to 3 mm.
    [12" claim-type="Currently amended] The immediate release dosage form according to any one of claims 1 to 11 containing an active substance or active concentrate of Formula I:
    [Formula I] L-B-D (I)
    Wherein D represents a pharmaceutically active substance, L represents a lipophilic residue, and B represents a linking group that binds groups L and D).
    [13" claim-type="Currently amended] The immediate release dosage form of claim 12, wherein:
    D is a pharmacologically active substance,
    B is a bridge -O-[(PO) (OH) O] n- , where n is 1, 2, or 3
    L is the lipid moiety of the formula:
    [Formula II]
    {here,
    R 1 may be optionally substituted once or several times by C 3 -C 8 cycloalkyl or substituted by a phenyl group, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkylmercapto, C 1 -C 6 alkoxy Straight or branched, saturated or unsaturated alkyl chains having 1-30 carbon atoms, which may be optionally substituted by carbonyl, C 1 -C 6 alkylsulfinyl or C 1 -C 6 alkylsulfonyl groups,
    R 2 is hydrogen, a straight or branched chain, saturated or unsaturated alkyl chain having 1 to 20 carbon atoms (halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkylmercapto, C 1 -C 6 alkoxycarbonyl , C 1 -C 6 alkylsulfinyl or C 1 -C 6 alkyl may be optionally substituted once or several times by a sulfonyl), and
    X represents a valence dash, oxygen, sulfur, oxycarbonyl, carbonyloxy, carbonyl amido, amidocarbonyl, sulfinyl or sulfonyl groups,
    Y is valent dash, oxycarbonyl, carbonyloxy, carbonyl amido, amidocarbonyl, oxygen or sulfur atom,
    m is an integer from 1 to 5}.
    [14" claim-type="Currently amended] The instant release dosage form of claim 13 comprising the following active substance or active concentrate:
    R 1 represents a straight or branched C 8 -C 15 alkyl chain or an optionally substituted phenyl group which may be substituted by C 3 -C 8 cycloalkyl,
    R 2 represents a straight or branched C 8 -C 15 alkyl chain,
    X represents a sulfur, sulfinyl or sulfonyl group,
    Y represents oxygen,
    X and Y may be known carboxylic esters from lecithin.
    [15" claim-type="Currently amended] The immediate release dosage form of claim 14 wherein:
    R 1 represents a nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, cyclohexyl-hexyl or phenyl-hexyl group,
    R 2 is an octyl, nonyl, decyl, undecyl, dodecyl, tridecyl or tetradecyl group (these are C 1 -C 6 alkoxy substituents such as methoxy, ethoxy, propoxy, butoxy or hexyl groups or CC alkyls) Mercapto residues, such as methylmercapto, ethyl mercapto, butyl mercapto or hexyl mercapto residues).
    [16" claim-type="Currently amended] The instant release of claim 14, wherein R 1 and R 2 represent alkyl residues having 8 to 15 carbon atoms, X represents sulfur, Y represents oxygen, and n in the phosphate bridge is 0 or 1 Dosage forms.
    [17" claim-type="Currently amended] 15. The compound of claim 14, wherein R 1 is a C 1 -C 30 alkyl chain which may be substituted by a C 1 -C 6 alkoxy or C 1 -C 6 alkylmercapto group, R 2 is hydrogen, and X and Y are An immediate release dosage form wherein valence dash is indicated and m is 1 or 2, preferably 1.
    [18" claim-type="Currently amended] 18. The immediate release dosage form according to any one of claims 1 to 17, containing the active substance or active concentrate from the group of lipid conjugates of nucleosides.
    [19" claim-type="Currently amended] The immediate release dosage form of claim 18 which contains an azidothymidine conjugate, a fluorothymidine conjugate and a 5-fluorouridine conjugate.
    [20" claim-type="Currently amended] The instant release dosage form according to claim 12, wherein n represents 0 and D represents the groups —P (O) (OH) —COOH and esters and pharmacologically resistant salts thereof.
    [21" claim-type="Currently amended] Instantly by mixing, granulating, spray drying, spray solidifying or pressing granulation of the active substance or concentrate of the active substance with gelling properties in an aqueous medium, alone or in combination with auxiliary substances Methods of Making Release Dosage Forms.
    [22" claim-type="Currently amended] In the first process step, the active material particles are coated with the first first envelope of the auxiliary material which inhibits gel formation, in the second process step the particles obtained in the first step are coated with the second envelope of the auxiliary material, The particles thus prepared are compressed into tablet form, wherein the auxiliary material of the first envelope and the second envelope has gelling properties.
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    同族专利:
    公开号 | 公开日
    AU1594897A|1997-08-20|
    HU224953B1|2006-04-28|
    CN1214629A|1999-04-21|
    NO323625B1|2007-06-18|
    HU9902415A3|1999-12-28|
    AT226065T|2002-11-15|
    US20020122817A1|2002-09-05|
    DE19602757A1|1997-07-31|
    WO1997026867A2|1997-07-31|
    MX9805939A|1998-11-30|
    WO1997026867A3|1997-09-25|
    NZ331051A|2000-01-28|
    RU2175547C2|2001-11-10|
    NO983437D0|1998-07-24|
    ZA97596B|1998-07-24|
    AU717456B2|2000-03-23|
    HU9902415A2|1999-11-29|
    US6521262B2|2003-02-18|
    IL125474D0|1999-03-12|
    BR9707083A|1999-03-23|
    ES2184987T3|2003-04-16|
    PL328157A1|1999-01-18|
    ZA9700596B|1998-07-24|
    EP0877605A2|1998-11-18|
    IL125474A|2001-12-23|
    NO983437L|1998-09-28|
    CZ298897B6|2008-03-05|
    JP2000506512A|2000-05-30|
    CZ232098A3|1998-10-14|
    CA2243964A1|1997-07-31|
    EP0877605B1|2002-10-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-01-16|Priority to DE99602757.8
    1996-01-26|Priority to DE19602757A
    1997-01-24|Application filed by 로셰 디아그노스틱스 게엠베하
    1997-01-24|Priority to PCT/EP1997/000329
    1999-11-15|Publication of KR19990082039A
    优先权:
    申请号 | 申请日 | 专利标题
    DE99602757.8|1996-01-16|
    DE19602757A|DE19602757A1|1996-01-26|1996-01-26|Solid instant release dosage forms and processes for their manufacture|
    PCT/EP1997/000329|WO1997026867A2|1996-01-26|1997-01-24|Solid instant-release forms of administration and process for producing the same|
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