JP6323846B2 - Abuse prevention formulation containing opioid - Google Patents

Abuse prevention formulation containing opioid Download PDF

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JP6323846B2
JP6323846B2 JP2017075857A JP2017075857A JP6323846B2 JP 6323846 B2 JP6323846 B2 JP 6323846B2 JP 2017075857 A JP2017075857 A JP 2017075857A JP 2017075857 A JP2017075857 A JP 2017075857A JP 6323846 B2 JP6323846 B2 JP 6323846B2
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tablet
solid preparation
powder
oxycodone hydrochloride
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JP2017190328A (en
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亮 河合
亮 河合
善三 交久瀬
善三 交久瀬
健至 船木
健至 船木
全 真下
全 真下
健佑 堀内
健佑 堀内
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塩野義製薬株式会社
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  The present invention relates to an oxycodone abuse prevention preparation characterized by containing oxycodone hydrochloride trihydrate. The present invention also relates to an opioid abuse-preventing preparation that contains an opioid and polyoxyalkylene, has no irregularities on the tablet surface, and does not crack in the film.

  Many pharmaceutical active ingredients have the potential for abuse in addition to having excellent activity in suitable applications. That is, they can be used by abusers to produce effects other than those intended. For example, opioids that work in treating severe pain from severe pain are often used by abusers to induce anesthesia or euphoria.

  In order to allow abuse, the corresponding dosage form, such as a tablet or capsule, is crushed by the abuser, for example, crushed in a mortar, preferably extracting the active ingredient from the powder obtained using an aqueous liquid Then, the obtained solution is filtered parenterally, particularly intravenously, after filtering with absorbent cotton or cellulose filling as necessary. Controlled release dosage forms containing active ingredients that may be abused will not behave as desired by abusers even if they are illegally inoculated orally, so these dosage forms are also abused Is crushed and extracted.

In order to prevent such abuse of opioids, preparations for preventing opioid abuse (oxycodone tamper resistant, hereinafter sometimes abbreviated as “OTR”) have been developed. Patent Document 1 discloses an abuse-preventing agent characterized by exhibiting one or a plurality of active ingredients that may be abused, a thermoplastic polyalkylene oxide having a molecular weight of at least 500,000, and a breaking strength of at least 500 N The shape is disclosed. Patent Documents 2 to 4 disclose a method for producing an opioid abuse-preventing preparation containing an opioid and a thermoplastic polyalkylene oxide.
Patent Documents 2 and 3 disclose a method for producing an abuse-preventing formulation, but do not disclose a method for producing a formulation that has no irregularities on the tablet surface, is smooth, and does not cause cracks in the coating film. Patent Documents 4 and 5 disclose that a free acid or an antioxidant is added in order to improve the stability of the opioid and prevent a decrease in the content of the opioid. Is not disclosed.

Japanese Patent No. 4939218 Japanese Patent No. 5069300 U.S. Pat. No. 8,894,988 Special table 2012-533585 Special table 2012-533586

  One of the opioid analgesics, oxycodone is a semi-synthetic narcotic synthesized from the alkaloid thebaine in opium, and is a strong opioid used in WHO cancer pain therapy. Since this oxycodone can also be abused, it is necessary to manufacture an anti-abuse formulation. In Japanese pharmacopoeia, oxycodone hydrochloride trihydrate is listed as oxycodone. The present inventors have found that oxycodone hydrochloride trihydrate has poor content uniformity in the preparation compared to oxycodone hydrochloride monohydrate listed in the United States Pharmacopeia.

  As an excipient of an opioid abuse-preventing preparation, a thermoplastic polyalkylene oxide that has a very high hardness when cured is used in order to make the preparation difficult to break. In order to increase the crushing resistance of the polyalkylene oxide, it is necessary to carry out an operation of curing, in which the preparation is brought to a temperature higher than the melting point at the time of production and then cooled. On the other hand, in order to identify the preparation, the surface of the preparation may be coated with a pigmented coating agent. In this case, the preparation may be exposed to high-temperature heat in order to dry the coating agent. Depending on the curing and coating operation, the preparations may be exposed to high temperatures, causing the preparations to adhere to and separate from each other, which may cause irregularities on the tablet surface or cracks in the coating film. I found it.

  Therefore, it is necessary to find a preparation with high uniformity of oxycodone content in an anti-abuse preparation containing oxycodone hydrochloride trihydrate. In addition, in an anti-abuse preparation containing an opioid and a polyoxyalkylene and coated with a coating film, it is necessary to find a preparation that does not have irregularities on the tablet surface and does not crack in the coating film.

As a result of intensive studies in order to develop the preparation, the present inventors have found an optimal formulation and have completed the present invention. Specifically, 1) Oxycodone hydrochloride trihydrate by mixing oxycodone hydrochloride trihydrate powder and polyoxyalkylene powder with high shearing force and / or dry granulating the mixed powder. A solid preparation containing oxycodone hydrochloride trihydrate and polyoxyalkylene was found, characterized in that the relative standard deviation of the content of oxycodone was within 8.5%, preferably within 5%.
In addition, 2) (i) a step of coating a tablet containing oxycodone hydrochloride trihydrate and polyoxyalkylene with a coating agent, and (ii) curing a tablet coated with the coating agent by the step of (i). It has been found that a preparation with no irregularities on the tablet surface and cracks in the coating film can be produced by performing the step of coating the tablet cured by the steps of (iii) and (ii) with a coating agent. It was.

That is, the present invention
(1) By mixing oxycodone hydrochloride trihydrate powder and polyoxyalkylene powder with high shear force, the relative standard deviation of the content of oxycodone hydrochloride trihydrate in the content uniformity test is 8.5. %, A solid preparation containing oxycodone hydrochloride trihydrate and polyoxyalkylene,
(2) By dry granulating oxycodone hydrochloride trihydrate powder and polyoxyalkylene powder, the relative standard deviation of the content of oxycodone hydrochloride trihydrate in the content uniformity test is within 8.5% A solid preparation containing oxycodone hydrochloride trihydrate and polyoxyalkylene, characterized in that
(3) The solid preparation according to (2) above, wherein the dry granulation is a slag tableting method,
(4) The solid preparation according to any one of (1) to (3), wherein the relative standard deviation of the content of oxycodone hydrochloride trihydrate in the content uniformity test is within 5%,

(5) The solid preparation according to any one of (1) to (4), wherein the content of oxycodone hydrochloride trihydrate per solid preparation is 0.1 to 10% by weight,
(6) The solid preparation according to any one of (1) to (5), further containing a free acid,
(7) The solid preparation according to the above (6), wherein the free acid is citric acid,
(8) The solid preparation according to any one of (1) to (7), further containing an antioxidant,
(9) The solid preparation according to (8), wherein the antioxidant is α-tocopherol,
(10) The solid preparation according to any one of (1) to (9), which is a granule,
(11) A solid preparation containing the granule according to (10) above,
(12) The solid preparation according to any one of (1) to (9), which is a tablet,
(13) A coated solid preparation produced by a production method comprising the following steps:
(I) coating a tablet containing an opioid and polyoxyalkylene with a coating agent;
(Ii) curing the tablet coated with the coating agent by the step (i), and (iii) coating the tablet cured by the step (ii) with the coating agent,
(14) The coating according to (13), wherein the step (ii) is a step of exposing the tablet coated with the coating agent in the step (i) to 55 to 90 ° C and then cooling to 45 to 55 ° C. Solid formulations,
(15) The coated solid preparation according to (13) or (14) above, wherein the solid preparation described in (12) is used as a tablet containing an opioid and polyoxyalkylene.
(16) Coated solid preparation produced by a production method comprising the following steps:
(I) mixing opioid powder and polyoxyalkylene powder, and slag tableting the resulting mixed powder;
(ii) a step of tableting the granule obtained by the step (i),
(Iii) a step of coating the tablet obtained by the step (ii) with a coating agent;
(Iv) curing the tablet coated with the coating obtained by the step (iii), and (v) coating the cured tablet obtained by the step (iv) with the coating,
(17) A solid preparation containing oxycodone hydrochloride trihydrate and polyoxyalkylene.
(17-1) The solid preparation according to the above (17), further comprising a free acid.
(17-2) The solid preparation according to the above (17-1), wherein the free acid is citric acid.
(17-3) The solid preparation according to (17) or (17-1), further containing an antioxidant.
(17-4) The solid preparation according to the above (17-3), wherein the antioxidant is α-tocopherol.
(18) A method for producing a solid preparation comprising any one of the following steps and containing an opioid and a polyoxyalkylene and having a relative standard deviation of the opioid content in the content uniformity test within 8.5%:
a) mixing the opioid powder and the polyoxyalkylene powder with high shear force, or b) dry granulating the opioid powder and the polyoxyalkylene powder,
(19) A method for producing a solid preparation containing an opioid and polyoxyalkylene, comprising the following steps:
(I) coating a tablet containing an opioid and polyoxyalkylene with a coating agent;
(Ii) curing the tablet coated with the coating agent by the step (i), and (iii) coating the tablet cured by the step (ii) with the coating agent;
About.

  When the active ingredient is oxycodone hydrochloride trihydrate, the solid preparation of the present invention (hereinafter sometimes referred to as “the present preparation”) has a relative standard deviation of 8.5% or less. Or a coated solid preparation containing opioids and polyoxyalkylene, having no irregularities on the surface of the preparation, and having no cracks in the coating film. The present invention makes it possible for the first time to produce a solid preparation containing oxycodone hydrochloride trihydrate and polyoxyalkylene.

: Production method of Example 1 preparation : Production method of Comparative Examples 1 and 2 : Comparative Example 3 Preparation Method : Production method of Example 2 preparation : Examples 3 and 4 Production method of preparation : Production methods of Examples 5 and 6 : Tablet surface of Examples 3 to 6 : Tablet surface of Comparative Example 4 preparation (after initial and curing) : Tablet surface of Comparative Example 5 preparation (after initial and curing)

The dosage form of the present invention is very suitable for preventing the abuse of opioids selected from the group comprising: Specifically as an opioid,
N- {1- [2- (4-Ethyl-5-oxo-2-tetrazolin-1-yl) ethyl] -4-methoxymethyl-4-piperidyl} propionanilide (alfentanyl), allylprozin, alphaprozin, Anilidine, bemidone, benzylmorphine, vegitramide, 17-cyclopropylmethyl-4,5α-epoxy-7α [(S) -1-hydroxy-1,2,2-trimethyl-propyl] -6-methoxy-6,14- Endo-ethanomorphinan-3-ol (buprenorphine), butorphanol, carfentanil, clonitazene, (−)-methyl- [3β-benzoyloxy-2β (1αH, 5αH) -tropanecarboxylate] (cocaine), 4,5α -Epoxy-3-methoxy-17-methyl-7-morphinene-6α -Ol (codeine), desomorphin, dextromoramide, (+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl) propionate (dextropropoxyphene), dezocine, dianpromide, diamorphone, 4,5α-epoxy-3-methoxy-17-methyl-6α-morphinanol (dihydrocodeine), 4,5α-epoxy-17-methyl-3,6a-morphinandiol (dihydromorphine), dimenoxadol, dimephetal Nord, dimethylthianbutene, dioxafetil butyrate, dipipanone, dihydromorphone, eptazocine, etoheptadine, ethylmethylthianbutene, 4,5α-epoxy-3-ethoxy-17-methyl-7-morphinene-6α-ol (ethylmol) Fin), etnitazene, 4,5α-epoxy-7α- (1-hydroxy-1-methylbutyl) -6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol (etorphine), fempipramide, N- (1-phenethyl-4-piperidyl) propionanilide (fentanyl), heroin, 4,5α-epoxy-3-methoxy-17-methyl-6-morphinanone (hydrocodone), 4,5α-epoxy-3-hydroxy- 17-methyl-6-morphinanone (hydromorphone), hydroxypetidin, isomethadone, hydroxymethylmorphinan, 1- [4- (3-hydroxyphenyl) -1-methyl-4-piperidyl] -1-propanone (ketobemidone), ( 3S, 6S) -6-Dimethylamino-4,4-di Enylheptan-3-ylacetate (levacetyl mesador), (−)-6-dimethylamino-4,4-diphenol-3-heptanone (levomethadone), (−)-17-methyl-3-morphinanol ( Levorphanol), levofenacil morphane, levoxemacin, lofentanil, meperidine, 2-methyl-2-propyltrimethylene dicarbamate, meptazinol, metazosin, methadone, methylmorphine, metapone, 3-methylfentanyl, 4 -Methylfentanyl, 4,5α-epoxy-17-methyl-7-morphinene-3,6α-diol (morphine), morphine-6-glucoronide, myrophine, nalbufen, nalorphine, narcein, nicomorphine, 6-dimethylamino -4,4-diphenyl-3-hexanone (normesadone), normorphin, norpipanone, plant secretions (opium) belonging to Papaver somniferum species, 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl- 6-morphinanone (oxycodone), oxymorphone, plants belonging to Papaver soniferum species (including subspecies setigerum) and plant parts (Papaver soniferum), papaveretam, 1,2,3,4,5,6-hexahydro-6 11-dimethyl-3- (3-methyl-2-butenyl) -2,6-methano-3-benzazocin-8-ol (pentazocine), ethyl- (1-methyl-4-phenyl-4-piperidinecarboxylate) (Petidine), Fena Xone, phenomorphan, phenazosin, phenoperidine, pinomidine, forcodeine, 1 '-(3-cyano-3,3-diphenylpropyl) [1,4'-bipiperidine] -4'-carboxamide (pyritramide), proheptadine, promedol , Propridine, propoxyphene, methyl {3- [4-methoxycarbonyl-4- (N-phenylpropanamido) piperidino] propanoate} (remifentanyl), N- {4-methoxymethyl-1- [2- (2- Thienyl) ethyl] -4-piperidyl} propionanilide (sufentanyl), ethyl (2-dimethylamino-1-phenyl-3-cyclohexene-1-carboxylate (tyridine, cis and trans), thebaine, tramadol, (1R, 2R, 4S) -2- (Di Tylamino) methyl-4- (p-fluorobenzyloxy) -1- (m-methoxy-phenyl) cyclohexanol, (1R, 2R) -3- (2-dimethylaminomethyl-cyclohexyl) phenol, (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methyl-propyl) phenol, (2R, 3R) -1-dimethylamino-3 (3-methoxyphenyl) -2-methyl-pentan-3-ol, (1RS, 3RS, 6RS) -6-dimethylaminomethyl-1- (3-methoxyphenyl) -cyclohexane-1,3-diol, preferably as a racemic compound, 3- (2-dimethylaminomethyl-1-hydroxy -Cyclohexyl) phenyl 2- (4-isobutoxy-phenyl) propionate, 3- (2-dimethylaminomethyl) Til-1-hydroxy-cyclohexyl) phenyl 2- (6-methoxy-naphthalen-2-yl) propionate, 3- (2-dimethylaminomethyl-cyclohex-1-enyl) -phenyl 2- (4-isobutyl-phenyl) Propionate, 3- (2-Dimethylaminomethyl-cyclohex-1-enyl) -phenyl 2- (6-methoxy-naphthalen-2-yl) propionate, (RR-SS) -2-acetoxy-4-trifluoromethyl- Benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2-hydroxy-4-trifluoromethyl-benzoic acid 3- (2-dimethylaminomethyl-1- Hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -4-chloro 2-hydroxy-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2-hydroxy-4-methyl-benzoic acid 3- (2-dimethylaminomethyl) -1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2-hydroxy-4-methoxy-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) ) -2-Hydroxy-5-nitro-benzoic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl) -phenyl ester, (RR-SS) -2 ′, 4′-difluoro-3-hydroxy-biphenyl -4-carboxylic acid 3- (2-dimethylaminomethyl-1-hydroxy-cyclohexyl)- Phenyl esters and corresponding stereoisomeric compounds, in each case corresponding derivatives thereof, in particular amides, esters or ethers, and in each case physiologically acceptable compounds thereof, in particular salts and solvates thereof, in particular Preferred are hydrochloride, sulfate, saccharin salt, active metabolite, diphenoxylate, levomethadone, nortilidine, pyritramide and biminol.

The dosage forms of the present invention are particularly suitable for preventing abuse of opioid active ingredients selected from the group comprising: Oxycodone, hydromorphone, morphine, oxymorphone, tramadol and their physiologically acceptable derivatives or compounds, preferably their salts and solvates, preferably their hydrochlorides, sulfates, saccharin salts, and / or their Stereoisomers or corresponding compounds and / or derivatives, more preferably oxycodone hydrochloride hydrate, more preferably oxycodone hydrochloride monohydrate or trihydrate, particularly preferably oxycodone hydrochloride trihydrate It is a Japanese product.

  The content of the active ingredient (drug) in this preparation may be an amount that produces a medicinal effect. For example, it is 0.01 to 90% by weight, preferably 0.025 to 80% by weight, more preferably 0.05 to 70% by weight, based on the total amount of the preparation. If the content is higher than these, it may be difficult to add an anti-abuse function to the tablet, and if it is less, the preparation itself may be enlarged or a large amount of tablets may be taken.

In order to achieve the required breaking strength of the dosage form according to the present invention, at least one synthetic or natural polymer having a breaking strength of at least 250 N is used, as measured using the method disclosed herein. Polyalkylene oxide, preferably selected from the group comprising polymethylene oxide, polyethylene oxide, polypropylene oxide, polyethylene, polypropylene, polyvinyl chloride, polycarbonate, polystyrene, polyacrylate, copolymers thereof and mixtures of at least two of the polymers mentioned At least one polymer is preferably used for this purpose. High molecular weight thermoplastic polyalkylene oxide is preferred. High molecular weight polyethylene oxide having a molecular weight of at least 500,000, preferably at least 1,000,000 to 1,500,000, as measured by rheological measurements, is particularly preferred. These polymers have viscosities of 4500-17600 cP at 25 ° C. when measured in a 5 wt% aqueous solution using a model RVF Brookfield viscometer (spindle no. 2 / rotation speed 2 rpm). Having a viscosity of 400-4000 cP when measured with a 2% by weight aqueous solution using a viscometer (spindle no. 1 or 3 / rotation speed 10 rpm), and the viscometer described (spindle no. 2 / rotation speed) Having a viscosity of 1650-10000 cP when measured with a 1% by weight aqueous solution using 2 rpm).

  The polymer is preferably used in powder form. They may be soluble in water.

  The polymer content may be any amount that achieves the required breaking strength of the dosage form. For example, an amount of 20 to 99.9% by weight, preferably at least 30% by weight or more, more preferably at least 40% by weight or more based on the total amount of the preparation. If the content is less than these, the breaking strength of the dosage form may be reduced.

  Auxiliary substances that can be used in addition to the active ingredient and the polymer are auxiliary substances necessary for the formulation of solid dosage forms and auxiliary substances necessary for the stability of the active ingredient. Auxiliary substances necessary for the preparation of solid dosage forms include plasticizers, auxiliary substances that affect the release of active ingredients, hydrophobic or hydrophilic polymers, and specifically include hydroxypropylcellulose, hypromellose and the like. It is done. Supplementary substances necessary for the stability of the active ingredient include antioxidants and free acids. Specific examples of antioxidants include sodium nitrite, α-tocopherol and its derivatives, -L-ascorbic acid stearate, butylhydroxyanisole, butylhydroxytoluene, dibutylhydroxytoluene, ascorbic acid and its salts, monothio Glycerol, phosphorous acid, sodium hydrogen sulfite, sodium sulfite, sodium pyrosulfite, alphathioglycerin, sodium edetate hydrate, erythorbic acid, potassium dichloroisocyanurate, L-cysteine hydrochloride hydrate, soy lecithin, thio Sodium glycolate, sodium thiomalate, 1,3-butylene glycol, benzotriazole, preferably α-tocopherol. Specific examples of the free acid include citric acid, adipic acid, gluconic acid, succinic acid, tartaric acid, lactic acid, maleic acid, and malic acid, and preferably citric acid.

  The content of the antioxidant may be an amount that can prevent the decomposition of the active ingredient. For example, an amount of 0.01 to 10% by weight, preferably 0.03 to 5% by weight, more preferably 0.05 to 4% by weight is used with respect to the total amount of the preparation. If the content is less than these, the active ingredient may be decomposed, and if it is more, toxicity may occur.

  The content of the free acid may be an amount that can prevent the decomposition of the active ingredient. For example, an amount of 0.01 to 10% by weight, preferably 0.03 to 5% by weight, more preferably 0.05 to 4% by weight is used with respect to the total amount of the preparation. If the content is less than these, the active ingredient may be decomposed, and if it is more, toxicity may occur.

If necessary, this preparation may contain additives other than those mentioned above. Additives listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Pharmaceutical Standards, the Pharmaceutical Additives Standard, and the Food Additives Official Standard Can be used. Moreover, the content of these additives may be an arbitrary ratio. Examples of additives other than those described above include lubricants, coating agents, colorants, fragrances, binders, and corrigents.
Examples of the lubricant include sodium stearyl fumarate, sucrose fatty acid ester, stearic acid, magnesium stearate, calcium stearate, talc, hydrous silicon dioxide and the like, preferably magnesium stearate.
As coating agents, for example, hypromellose, polyvinyl alcohol, ethyl cellulose, carboxymethyl ethyl cellulose, carmellose, carmellose sodium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, PVA copolymer, ethyl acrylate / methyl methacrylate copolymer dispersion, aminoalkyl Methacrylate copolymer, Opadry, carnauba wax, carboxyvinyl polymer, dry methacrylic acid copolymer, dimethylaminoethyl methacrylate / methyl methacrylate copolymer, stearyl alcohol, shellac, cetanol, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose phthalate, fumar Acid / stearic acid / polyvinyl acetal diethylaminoacetate / hydroxypropyl methylcellulose mixture, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol, methacrylic acid copolymer, 2-methyl-5-vinylpyridine methyl acrylate / methacrylic acid copolymer, etc., preferably hypromellose is there.
Examples of colorants include yellow sesquioxide, sesquioxide, edible red No. 3, edible yellow No. 5, edible blue No. 1 and the like, brown iron oxide, black iron oxide, copper chlorophyll, copper chlorophyllin sodium, riboflavin , Riboflavin butyric acid ester, powdered green tea powder, etc., preferably yellow ferric oxide and ferric oxide.
The fragrance includes what is called a flavoring agent, such as sugar flavor, banana flavor, sunfix banana, orange essence, orange oil, caramel, camphor, cinnamon oil, spearmint oil, strawberry essence, chocolate essence, cherry flavor, Spruce oil, pine oil, mint oil, vanilla flavor, bitter essence, fruit flavor, peppermint essence, mixed flavor, mint flavor, menthol, lemon powder, lemon oil, rose oil, and the like, preferably sugar flavor.
Examples of binders include hydroxypropylcellulose, corn starch, pregelatinized starch, partially pregelatinized starch, gum arabic, gum arabic powder, gelatin, agar, dextrin, pullulan, povidone, polyvinyl alcohol, crystalline cellulose, methylcellulose, ethylcellulose, carboxy Examples thereof include methyl ethyl cellulose, carmellose, carmellose sodium, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hypromellose and the like.
As a corrigent, for example, ascorbic acid and its salt, aspartame, sucralose, glycine, sodium chloride, magnesium chloride, hydrochloric acid, dilute hydrochloric acid, citric acid and its salt (sodium citrate), anhydrous citric acid, L-glutamic acid and its salt, Succinic acid and its salt, acetic acid, tartaric acid and its salt, sodium hydrogencarbonate, fumaric acid and its salt, malic acid and its salt, glacial acetic acid, disodium inosinate, honey and the like.

  Due to their hardness, the dosage form according to the present invention is difficult to grind with, for example, a mortar and pestle, and even if it can be ground, it is very difficult to grind into a powder form. This can substantially prevent abuse, either orally or parenterally, particularly intravenously or via the nasal passages. However, in order to prevent any possible abuse of the dosage form according to the invention, the dosage form according to the invention, in a preferred embodiment, contains, in addition to the polymer, further substances which make abuse difficult or prevent. be able to. The hardness (measured by a tablet hardness meter) of this preparation may be a hardness that cannot be normally broken, and is about 250 to 700N.

Apart from one or more active ingredients that may be abused, the anti-abuse dosage forms of the present invention comprising at least one cured polymer and optionally at least one wax are therefore as auxiliary substances: May contain at least one of the components (a) to (e).
(A) at least one substance that stimulates the nasal cavity and / or pharynx,
(B) at least one viscosity-increasing agent that forms a gel with the extract obtained from the dosage form with the help of the minimum amount of aqueous liquid, the gel preferably being introduced into a further amount of aqueous liquid. A viscosity-increasing agent that is visually identifiable,
(C) at least one antagonist of each of the potentially abused active ingredients,
(D) at least one emetic,
(E) at least one dye as an aversive agent;
(F) at least one bitter substance;

  The components (a) to (f) are each independently suitable as an addition to prevent abuse of the dosage form according to the present invention. Accordingly, component (a) is preferably suitable for protecting the dosage form from nasal, oral and / or parenteral, preferably intravenous abuse, and component (b) is preferably parenteral Particularly preferably suitable for protecting against abuses via intravenous and / or nasal passages, component (c) preferably protecting against nasal and / or parenteral, particularly preferably via intravenous abuse. Component (d) is preferably parenterally, particularly preferably suitable for protecting against intravenous and / or oral and / or nasal abuse, and component (e) is Suitable as a visual hindrance to abuse via oral or parenteral, component (f) is preferred to protect against abuse via oral or nasal passages. The combined use according to the invention of at least one of the above components makes it possible to more effectively prevent the abuse of the dosage form according to the invention.

  In one embodiment, the dosage form according to the invention comprises a combination of two or more of components (a) to (f), preferably (a), (b) and optionally (c) and / or ( f) and / or (e) or (a), (b) and optionally (d) and / or (f) and / or (e).

When oxycodone is used as an active ingredient, a hydrate of oxycodone hydrochloride may be used. Examples of the hydrate of oxycodone hydrochloride include oxycodone hydrochloride monohydrate and trihydrate. However, although oxycodone hydrochloride monohydrate is listed in the US Pharmacopeia, it is not listed in the Japanese Pharmacopeia and cannot be used in Japan. Oxycodone hydrochloride trihydrate is listed in the Japanese Pharmacopoeia and can be used in Japan. However, when the preparation is produced, the content uniformity of the oxycodone hydrochloride trihydrate in the preparation is poor and needs to be improved. “Content uniformity” is determined from the relative standard deviation of the content of oxycodone. The relative standard deviation of the content is obtained by the following formula.

Relative standard deviation of content (formula) = standard deviation of content × 100 / average value of content

According to the present invention, the relative standard deviation of the content of oxycodone hydrochloride trihydrate can be within 8.5%, preferably within 5%.

  In order to improve content uniformity, it has been found that when oxycodone hydrochloride trihydrate and additives are mixed, they are mixed with high shearing force. In order to mix by applying a high shearing force, mixing is performed using a mixer having a stirring blade (agitator). Specific examples of the mixer include a super mixer, a high speed mixer, a ribbon mixer, an orbital screw blender, a V-type mixer with an agitator, a Forberg blender, a planetary blender, and a double arm blender.

  When mixing with a mixer, for example, when mixing an active ingredient oxycodone hydrochloride trihydrate and other additives (total amount: 20 to 30 kg) with a 40 L high speed mixer (high shear type mixer) If the rotation speed of the stirring blade (agitator) is 100 to 200 revolutions / minute and the mixing time is 10 seconds to 10 minutes, the relative standard deviation of the content is within 8.5%, preferably within 5%, more preferably Is within 4%.

  The active ingredient and other additives may be mixed by a mixer without a stirring blade before mixing by a mixer having a stirring blade (agitator), for example, a bin blender, a V-type mixer, a double cone, etc. A blender, inclined cone blender, cube blender, drum blender, or the like may be used.

  Furthermore, in order to improve the content uniformity of oxycodone hydrochloride trihydrate in this preparation, after producing granules containing oxycodone hydrochloride trihydrate, the granules are tableted, and when manufactured, Content uniformity is further improved. The granule production method may be any of a wet granulation method, a dry granulation method, and any granulation method, but a dry granulation method is preferred in order to increase production efficiency. Examples of the dry granulation method include a slag tableting method, an extrusion granulation method, and a roller compression method, and the slag tableting method is particularly preferable. The slag tableting method is a technique for producing granules by making slag tablets by tableting and crushing the slag tablets.

For example, a solid preparation containing an opioid and polyoxyalkylene and having a relative standard deviation of the opioid content in the content uniformity test within 8.5% can be produced by a production method including any of the following steps: it can.
a) a step of mixing the opioid powder and the polyoxyalkylene powder with high shear force, or b) a step of dry granulating the opioid powder and the polyoxyalkylene powder.

In addition, a coated solid preparation can be produced by a production method including any of the following steps.
(I) mixing opioid powder and polyoxyalkylene powder, and slag tableting the resulting mixed powder;
(ii) a step of tableting the granule obtained by the step (i),
(Iii) a step of coating the tablet obtained by the step (ii) with a coating agent;
(Iv) curing the tablet coated with the coating agent obtained by the step (iii), and (v) coating the cured tablet obtained by the step (iv) with the coating agent.

  The average particle size of the granules may be an average particle size that is satisfactory in content uniformity and easy to handle, but is 50 to 1000 μm, preferably 100 to 750 μm, and more preferably 200 to 500 μm.

  As a method for producing a tablet, there are a direct tableting method in which a powder is directly compressed, and an indirect tableting method in which a granule is produced and then the granule is produced and then the granule is produced.

  When a polymer such as polyoxyalkylene is blended in the preparation, when the polymer is once heated to the melting point or higher and then cooled, so-called curing is performed, the strength of the polymer increases. Curing is an essential process. On the other hand, in order to distinguish tablets with different contents, a pigmented coating agent may be coated on the tablet surface, but the temperature of the coating agent is increased in the drying step. However, when the coating agent is coated after curing the tablet after tableting, the preparations may adhere to each other, and the preparation surface may be uneven. On the other hand, when the tablet after tableting is coated and then cured, the polymer may expand due to the high temperature during curing, and the coating film may crack.

  In order to solve the above problems, the coating surface is partially coated with a coating agent, then cured, and then coated with a coating agent. In addition, the preparation can be produced without causing cracks in the coating film. When coating the coating agent in two stages, the amount of the first coating agent coating (hereinafter sometimes referred to as “primary coating”) is 5 to 50%, preferably 7 to 40%, more preferably 10 to 30%. Thereafter, the curing is performed by heating to a temperature higher than the melting point of the polymer and cooling. In the case of polyoxyalkylene, the heating temperature is 50 ° C. or higher, preferably 60 ° C. or higher, more preferably 63 ° C. or higher. Cool at temperature. The amount of coating of the second coating agent (hereinafter sometimes referred to as “secondary coating”) is 50 to 95%, preferably 60 to 93%, more preferably 70 to 90% with respect to the total coating amount. %.

It can be manufactured by a manufacturing method including the following steps.
(I) coating a tablet containing an opioid and polyoxyalkylene with a coating agent;
(Ii) a step of curing the tablet coated with the coating agent by the step (i), and (iii) a step of coating the tablet cured by the step (ii) with the coating agent.
The step (ii) is preferably a step in which the tablet coated with the coating agent in the step (i) is exposed to 55 to 90 ° C and then cooled to 45 to 55 ° C.

  In a solid preparation before coating with a coating agent, particularly a tablet (hereinafter sometimes referred to as “plain tablet”), preferred drug and additive combinations include opioids, polyoxyalkylenes, free acids, antioxidants and lubricants. Combinations of agents, more preferred drugs, combinations of additives are oxycodone hydrochloride, polyoxyalkylenes, free acids, antioxidants and lubricants, more preferred drugs, combinations of additives are oxycodone hydrochloride trihydrate , Polyoxyalkylenes, free acids, antioxidants and lubricants, particularly preferred drugs, additives combinations are oxycodone hydrochloride trihydrate, polyoxyalkylene, citric acid, vitamin E (α-tocopherol) and stearin The combination of acid metal salt, most preferred drug and additive is oxycodone hydrochloride Trihydrate, polyoxyethylene, citric acid, a combination of vitamin E (alpha-tocopherol) and magnesium stearate.

  In a solid preparation after coating with a coating agent (hereinafter referred to as “coated solid preparation”), particularly a tablet coated with a coating film (hereinafter sometimes referred to as “coated tablet”), a preferable combination of drugs and additives is , Opioids, polyoxyalkylenes, free acids, antioxidants, lubricants, coatings and dye combinations, more preferred drugs, additive combinations are oxycodone hydrochloride, polyoxyethylene, citric acid, vitamin E (α -Tocopherol) a combination of metal stearate, hypromellose and iron oxide, particularly preferred drugs, additives are oxycodone hydrochloride trihydrate, polyoxyethylene, citric acid, vitamin E (α-tocopherol) and stearic acid Magnesium, hypromellose, yellow ferric oxide and three It is a combination of iron dioxide.

  The dosage form of this preparation may be any dosage form that can be taken by the patient, but is preferably a tablet defined in the Japanese Pharmacopoeia General Rules for Preparation.

  Although the diameter of this formulation should just be a magnitude | size which a patient can take, it is 3-20 mm, Preferably it is 4-15 mm, More preferably, it is 5-10 mm.

  Although the thickness of this formulation should just be a magnitude | size which a patient can take, it is 1-9 mm, Preferably it is 1.5-7 mm, More preferably, it is 1.75-6 mm.

  EXAMPLES Hereinafter, although an Example, a comparative example, and a reference example are given and this invention is demonstrated in detail, this invention is not restrict | limited by these. The tablet of an Example, a comparative example, and a reference example was manufactured by the following method.

(Manufacturing method of tablet powder)
Table 1 shows the formulation of the tablet powder. The tableting powder represents a mixed powder before tableting. As the drug, oxycodone hydrochloride trihydrate (manufactured) was used. Polyoxyethylene as excipient, POLYOX WSR 301 LEO NF (Dow Chemical), citric acid as stabilizer, Citric Acid Anhydrous fine F3500 (Jungbunzlauer), vitamin E, vitamin E Vegetable magnesium stearate (manufactured by Taihei Chemical Co., Ltd.) was used as dry powder (manufactured by Merck) and magnesium stearate.
The manufacturing method of Example 1 is shown in FIG. Specifically, in Table 1 below, oxycodone hydrochloride trihydrate, polyoxyethylene, citric acid, and vitamin E are mixed into a container mixer (model: PM100 type Bole container mixer (100 L container), container rotating type mixer, life span. And magnesium stearate was further mixed by a container mixer. The rotation speed of the container mixer was 12 times / minute, and the mixing time was about 47 minutes. The mixed powder was further mixed by a high speed mixer with a stirring blade (type: FS-GS-40J type high speed mixer, manufactured by Earth Technica), and the mixed powder was mixed by a container mixer to obtain a tablet powder. . The rotation speed of the stirring blade of the high speed mixer was 160 rotations / minute, the mixing time was 5 minutes, the rotation speed of the container mixer was 12 times / minute, and the mixing time was about 30 seconds. The content of oxycodone hydrochloride trihydrate in the tablet powder was measured. The content of Example 1 and the relative standard deviation of the content indicate values of 3 lots.
The production methods of Comparative Examples 1 to 3 are shown in FIG. 2 (Comparative Examples 1 and 2) and FIG. 3 (Comparative Example 3). Specifically, in Table 1 below, oxycodone hydrochloride trihydrate, polyoxyethylene, citric acid and vitamin E are mixed into a container mixer (model: PM100 type Bole container mixer (100L container), container rotating type mixer, life span. A mixed powder produced by spinning and mixing for about 17 minutes by Kogyo Co., Ltd. was designated as Comparative Example 1. Furthermore, the tableting powder manufactured by putting magnesium stearate into a container mixer and rotating and mixing with the container mixer for about 12 minutes was used as Comparative Example 2. Also, oxycodone hydrochloride trihydrate, polyoxyethylene, citric acid, and vitamin E are rotated and mixed in a container mixer for about 42 minutes, and magnesium stearate is added to the container mixer and rotated and mixed for about 73 minutes. The tablet powder produced in this manner was designated as Comparative Example 3. The number of rotations of the container mixer was 12 times / min.
The content of oxycodone hydrochloride trihydrate in the mixed powder and tablet powder of each Example and Comparative Example was measured.

(Measurement method of oxycodone hydrochloride trihydrate content)
Oxycodone hydrochloride trihydrate was measured by high performance liquid chromatography (HPLC). The measurement conditions are as follows.
Wavelength: 230nm
Column: Capsule pack UG120 (Shiseido) 4.6 mm x 15 cm, 5 μm
Column temperature: 25 ° C
Mobile phase: 0.05 mol / L phosphate buffer / acetonitrile mixture at pH 8.0 (4: 3)
Liquid flow rate: 1.0 mL / min

The measurement results of the content of oxycodone hydrochloride trihydrate in Example 1 and Comparative Examples 1 to 3 are shown in Table 2 and Table 3. As a result, the relative standard deviation of the tablet powder mixed by a high speed mixer with stirring blades was less than 8.5% for all 3 lots (Table 2). On the other hand, the relative standard deviation of the mixing powder and tableting powder mixed by a container mixer not using a stirring blade exceeded 8.5% at any mixing time (Table 3). From this result, the high speed mixer having a high shearing force was able to uniformly mix oxycodone hydrochloride trihydrate as compared with the container mixer having no shearing force.


(Granule production method)
The granule formulation is the same as in Table 1. The mixture was mixed with a container mixer in the same manner as in Example 1 to obtain a mixed powder. The mixed powder was produced by granulating by a slag tableting method (Example 2). The manufacturing method is shown in FIG. Specifically, as in the slag tableting method, as in Example 1, oxycodone hydrochloride trihydrate, polyoxyethylene, citric acid, and vitamin E were mixed into a container mixer (type: PM100 type Bole container mixer (100 L container). Mixed with a mold mixer, manufactured by Kotobuki Kogyo Co., Ltd., and magnesium stearate was further mixed with a container mixer to obtain a mixed powder. The rotation speed of the container mixer was 12 times / minute, and the mixing time was about 47 minutes. The mixed powder was compressed by a tableting machine (type: VIRGO 0512SS2AZ type tableting machine, manufactured by Kikusui Seisakusho Co., Ltd.) to produce a slag tablet. The slag tablets were pulverized by a granulator (type: WP120 × 40V type roller compactor, manufactured by Alexander Ewrk) to obtain granules. The obtained granules were mixed by a container mixer (type: PM100 type Boule container mixer (100 L container) container rotating type mixer, manufactured by Kotobuki Kogyo Co., Ltd.), and the produced tablet granules were designated as Example 2. The rotation speed of the container mixer was 12 times / minute, and the mixing time was about 5 minutes. The content of oxycodone hydrochloride trihydrate in the tablet granules was measured. The content of Example 2 was measured for 3 lots.

The results of measurement of the content of oxycodone hydrochloride trihydrate in Example 2 are shown in Table 4. As a result, the granules were more uniform in content than the mixture by the high shear force in Example 1, and the relative standard deviations were all 5% or less. From this result, it was possible to produce a preparation with higher content uniformity by mixing granules containing oxycodone hydrochloride trihydrate.

(Method for producing coated tablet)
Table 5 shows the formulation per coated tablet containing oxycodone hydrochloride trihydrate. As the drug, oxycodone hydrochloride trihydrate (manufactured) was used. Polyoxyethylene as excipient, POLYOX WSR 301 LEO NF (Dow Chemical), citric acid as stabilizer, Citric Acid Anhydrous fine F3500 (Jungbunzlauer), vitamin E, vitamin E Dry powder (Merck), magnesium stearate, vegetable magnesium stearate (Taihei Chemical Co., Ltd.), Opadry OY-LS-28902 (hypromellose, Nippon Colorcon Co., Ltd.) as coating agent, yellow iron sesquioxide (as pigment) Hana Kasei Co., Ltd.) and iron sesquioxide (Hana Kasei Co., Ltd.) were used.
Manufacturing methods of Examples 3 to 6 are shown in FIG. 5 (Examples 3 and 4) and FIG. 6 (Examples 5 and 6). Specifically, for Examples 3 and 4, in Table 5, oxycodone hydrochloride trihydrate, polyoxyethylene (POE), citric acid (CA), and vitamin E (VE) were mixed in a container mixer (form: PM100 type Boule container mixer (100 L container) was mixed by a container rotating type mixer (manufactured by Kotobuki Kogyo Co., Ltd.), and magnesium stearate (St-Mg) was further mixed by a container mixer. The rotation speed of the container mixer was 12 times / minute, and the mixing time was about 47 minutes. The mixed powder was compressed by a tableting machine (type: VIRGO 0512SS2AZ type tableting machine, manufactured by Kikusui Seisakusho Co., Ltd.) to produce a slag tablet. The slag tablets were pulverized with a granulator (type: WP120 × 40V type roller compactor, manufactured by Alexander Ewrk) to obtain granules (dry granulation). The obtained granules were mixed by a container mixer (model: PM100 type Boule container mixer (100L container) container rotating type mixer, manufactured by Kotobuki Kogyo Co., Ltd.), and the produced tablet granules were tableted (model: VIRGO 0512SS2AZ type punching). Uncoated tablets were made using a tablet machine (manufactured by Kikusui Seisakusho). This compressed uncoated tablet was put into a coating pan (model: AQC-80 type Aqua Coater, manufactured by Freund Corporation), and 25% of the total coating film amount was coated (primary coating). Thereafter, the tablets were cured by heating them to 63 ° C. or higher for about 180 minutes to cure the tablets. After curing, the remaining coating film (75%) was coated (secondary coating). The operating conditions for primary coating, curing and secondary coating are shown in Table 6. For Examples 5 and 6, from Examples 3 and 4, except for citric acid (CA) and vitamin E (VE), except for the step of dry granulation with slag tablets, the same as Examples 3 and 4 It is.
Comparative Example 4 is a preparation whose appearance was observed before and after curing. Comparative Example 5 is a preparation that was cured after coating the entire amount of the coating agent. The formulations of Comparative Examples 4 and 5 are shown in Table 5.


  The tablet surfaces of Examples 3 to 6 had no irregularities, and no cracks were observed in the coating (FIG. 7). On the other hand, after curing, the formulation of Comparative Example 4 which was coated with a coating agent had irregularities on the tablet surface (FIG. 8). Further, in Comparative Example 5 of the preparation coated with the coating agent after curing, the tablet itself expanded after the coating agent was coated, and the coating film surface was cracked (FIG. 9).

  As an opioid abuse-preventing preparation, a preparation with high uniformity of oxycodone hydrochloride trihydrate content could be produced. Moreover, when the coating agent was coated, it was possible to produce an opioid abuse-preventing preparation in which the tablet surface had no irregularities and the coating film did not crack.

Claims (16)

  1. A solid preparation containing a tablet powder prepared by mixing oxycodone hydrochloride trihydrate powder and polyoxyalkylene powder with high shear force, the tablet powder in a content uniformity test the relative standard deviation of content of oxycodone hydrochloride trihydrate is within 8.5%, solid preparation.
  2. A solid preparation containing tablet granules prepared by dry granulation of oxycodone hydrochloride trihydrate powder and polyoxyalkylene powder , wherein the tablet granules are oxycodone hydrochloride in a content uniformity test the relative standard deviation of content of salt trihydrate is within 8.5%, solid preparation.
  3.   The solid preparation according to claim 2, wherein the dry granulation is a slag tableting method.
  4.   The solid preparation according to any one of claims 1 to 3, wherein the relative standard deviation of the content of oxycodone hydrochloride trihydrate in the content uniformity test is within 5%.
  5. The solid preparation according to any one of claims 1 to 4, wherein the content of oxycodone hydrochloride trihydrate per solid preparation is 0.1 to 10% by weight.
  6. Furthermore, the solid formulation in any one of Claims 1-5 containing a free acid.
  7. The solid preparation according to claim 6, wherein the free acid is citric acid.
  8.   Furthermore, the solid formulation in any one of Claims 1-7 containing antioxidant.
  9.   The solid preparation according to claim 8, wherein the antioxidant is α-tocopherol.
  10.   The solid preparation according to any one of claims 1 to 9, which is a granule.
  11.   A solid preparation containing the granule according to claim 10.
  12. The solid preparation according to any one of claims 1 to 9, which is a tablet.
  13. Coated solid preparation produced by a production method comprising the following steps:
    (I) a step of coating the tablet of claim 12 with a coating agent;
    (Ii) a step of curing the tablet coated with the coating agent by the step (i), and (iii) a step of coating the tablet cured by the step (ii) with the coating agent.
  14.   The coated solid preparation according to claim 13, wherein the step (ii) is a step of exposing the tablet coated with the coating agent according to the step (i) to 55 to 90 ° C and then cooling to 45 to 55 ° C.
  15. Coated solid preparation produced by a production method comprising the following steps:
    (I) mixing oxycodone hydrochloride trihydrate powder and polyoxyalkylene powder and slugging the resulting mixed powder;
    (ii) a step of tableting the granule obtained by the step (i),
    (Iii) a step of coating the tablet obtained by the step (ii) with a coating agent;
    (Iv) a step of curing the tablet coated with the coating agent obtained by the step (iii), and (v) a step of coating the cured tablet obtained by the step (iv) with the coating agent.
  16. Contains oxycodone hydrochloride trihydrate and polyoxyalkylene, including any of the following steps, and the relative standard deviation of the content of oxycodone hydrochloride trihydrate in the content uniformity test is within 8.5% Manufacturing method of solid preparation:
    a) mixing oxycodone hydrochloride trihydrate powder and polyoxyalkylene powder with high shear force; or b) oxycodone hydrochloride trihydrate powder and polyoxyalkylene powder The process of granulating.
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