Tamper-resistant dosage form with immediate release and resistance against solvent extraction

• US 9,855,263 B2
• Filed: 06/01/2016
• Issued: 01/02/2018
• Est. Priority Date: 04/24/2015
• Status: Expired due to Fees

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: Wening, Klaus, Geiler, Anja, Denker, Jana, Barnscheid, Lutz
• Primary Examiner(s): Arnold, Ernst V
• Application Number:
  US15/169,778
• Publication Number:
  US 20160310487A1
• Time in Patent Office: 580 Days
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1658 Proteins, e.g. albumin, gelatin
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/50 Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals A61K9/2081 takes precedence; particles with a single coating comprising drug A61K9/167
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/26 Psychostimulants, e.g. nicotine, cocaine
• CPC Class Codes: A61P 25/36 Opioid-abuse

Abstract

A tamper-resistant pharmaceutical dosage form comprising a multitude of particles which comprise a pharmacologically active compound, a polyalkylene oxide, and a disintegrant; wherein the pharmacologically active compound is dispersed in a matrix comprising the polyalkylene oxide and the disintegrant; wherein the content of the disintegrant is more than 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles; wherein the content of the polyalkylene oxide is at least 25 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles; and wherein the dosage form provides under in vitro conditions immediate release of the pharmacologically active compound in accordance with Ph. Eur.

Claims

1. A tamper-resistant pharmaceutical dosage form comprising a multitude of particles which comprise a pharmacologically active compound, a polyalkylene oxide, and a disintegrant;

wherein the pharmacologically active compound is a stimulant selected from the group consisting of phenylethylamine derivatives;

wherein the pharmacologically active compound is dispersed in a matrix comprising the polyalkylene oxide and the disintegrant;

wherein the disintegrant is selected from the group consisting of croscarmellose sodium, partially pre-gelatinized starch, carboxylmethyl starch, and mixtures thereof;

wherein the content of the disintegrant is 15±

5.5 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles;

wherein the content of the polyalkylene oxide is at least 25 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles;

wherein the dosage form provides under in vitro conditions immediate release of the pharmacologically active compound in accordance with Ph. Eur;

wherein the particles exhibit an increased resistance against solvent extraction compared to comparison particles that are otherwise identical to said particles except the comparison particles lack any content of any disintegrant; and

wherein the increased resistance against solvent extraction is determined by (a) dispensing the particles or the comparison particles in 5 ml of boiling water to form a liquid, (b) after five minutes drawing the liquid up into a syringe needle 21G equipped with a cigarette filter, and (c) determining the amount of the pharmacologically active ingredient in the liquid in the syringe by high performance liquid chromatography, wherein the increased resistance against solvent extraction compared to the comparison particles is proven by a lower amount of the pharmacologically active ingredient in the syringe in the case of the particles compared to the amount of the pharmacologically active ingredient in the syringe in the case of the comparison particles.

2. The pharmaceutical dosage form according to claim 1, wherein the stimulant is selected from the group consisting of methylphenidate, dexmethylphenidate, and the physiologically acceptable salts thereof.

3. The pharmaceutical dosage form according to claim 1, wherein the stimulant is selected from the group consisting of pseudoephedrine, and the physiologically acceptable salts thereof.

4. The pharmaceutical dosage form according to claim 1, which has a breaking strength of at least 300 N.

5. The pharmaceutical dosage form according to claim 1, which exhibits resistance against solvent extraction such that when

(i) dispensing the pharmaceutical dosage form that is either intact or has been manually comminuted by means of two spoons in 5 ml of purified water,

(ii) heating the liquid up to its boiling point,

(iii) boiling the liquid in a covered vessel for 5 min without the addition of further purified water,

(iv) drawing up the hot liquid into a syringe, and

(v) determining the amount of the pharmacologically active compound contained in the liquid within the syringe,

the liquid part of the formulation that can be separated from the remainder by means of the syringe is not more than 10 wt.-% of the pharmacologically active compound originally contained in the dosage form.

6. The pharmaceutical dosage form according to claim 1, wherein the disintegrant is partially pregelatinized starch.

7. The pharmaceutical dosage form according to claim 1, wherein the disintegrant is sodium carboxymethyl starch.

8. The pharmaceutical dosage form according to claim 1, wherein the disintegrant is croscarmellose sodium.

9. The pharmaceutical dosage form according to claim 1, wherein the content of the disintegrant is at least 10 wt.-%, based on the total weight of the particles.

10. The pharmaceutical dosage form according to claim 1, wherein the polyalkylene oxide has a weight average molecular weight of at least 500,000 g/mol.

11. The pharmaceutical dosage form according to claim 1, which provides a release profile such that under in vitro conditions in 600 ml 0.1 M HCl (pH 1) at 75 rpm after 30 min at least 90 wt.-% of the pharmacologically active ingredient that was originally contained in the dosage form have been released.

12. The pharmaceutical dosage form according to claim 1, which additionally comprises a gelling agent.

13. The pharmaceutical dosage form according to claim 12, wherein the gelling agent is a polysaccharide;

or the content of the gelling agent is at least 1.0 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles.

14. The pharmaceutical dosage form according to claim 1, wherein the stimulant is selected from the group consisting of amphetamine, dexamphetamine, methylenedioxymethamphetamine, lisdexamphetamine, methamphetamine, and the physiologically acceptable salts thereof.

15. The pharmaceutical dosage form according to claim 1, wherein the content of the pharmacologically active compound is at least 5.0 wt.-%, based on the total weight of the pharmaceutical dosage form and/or based on the total weight of the particles.

16. The pharmaceutical dosage form according to claim 1, wherein the particles are hot melt-extruded.

17. The pharmaceutical dosage form according to claim 1, wherein the particles are film coated.

18. The pharmaceutical dosage form according to claim 1, which is a tablet or capsule.

19. The pharmaceutical dosage form according to claim 1, wherein the content of the polyalkylene oxide is at least 40 wt.-%, based on the total weight of the particles.

20. The pharmaceutical dosage form according to claim 1, wherein all of the polyalkylene oxide that is contained in the pharmaceutical dosage form is contained in the particles.

21. The pharmaceutical dosage form according to claim 1, wherein the stimulant is the only active ingredient in the pharmaceutical dosage form.