HK1029749B - Opioid analgesics with controlled release - Google Patents

Description

The present invention relates to an oral formulation of a medicinal product from which the opioid analgesic agent is released in a controlled manner.

The state of the art has given rise to a large number of analgesic formulations which ensure a controlled release of the active substance.

For example, EP-A-0647448 already describes a delayed-release analgesic preparation consisting of a variety of opioid substrates, present in a delayed form, with a diameter of 0.1 to 3 mm, as a single daily dose. Suitable substrates may be in the form of spheroids, microbeads, pellets or granules.

On the other hand, many opioid active substances are produced in crystalline form, so that there is a need to use them directly, i.e. without the above-mentioned complex formulation techniques, in the manufacture of medicinal products.

From the Journal of Controlled Release 7 (1988), pages 69-78, subdermal microcapsules are known to contain the active substance L-methadone in crystalline form.

The present invention was therefore intended to provide an orally administered preparation with a controlled release of at least one opioid active substance, in which the crystals obtained in the manufacture of the active substance can be used immediately, i.e. without complex formulation steps.

According to the invention, this task is solved by providing an orally administered preparation with a controlled release of an opioid analgesic in the form of crystals with a particle size of 10 μm to 3 mm, which have at least a retardant coating.

Preferably, the crystals have a particle size of 50 μm to 1 mm. The active substance of the analgesic preparations of the invention contains at least one opioid in crystalline form. The opioids may be hydromorphone, oxycodone, morphine, levorphanol, methadone, dihydrocodeine, codeine, dihydromorphine, pethidine, fentanyl, pyritramide, buprenorphine, tilidin, tramadol, their respective salts or mixtures.

Tramadol, tramadol hydrochloride, morphine, morphine hydrochloride and/ or morphine sulphate are particularly preferred as analgesics.

The active substance crystals of the preparations of the invention may be single crystals or have a polycrystalline structure.

In addition to the opioid analgesics mentioned above, the product of the invention may contain non-opioid analgesics which may exhibit synergistic effects with the opioid analgesics, such as ibuprofen, ketoprofen, flurbiprofen, propyphenazone, paracetamol, naproxen, acemetacin, acetylsalicylic acid, metamizole and their salts, preferably in crystalline form.

The preparations of the invention are characterised by a controlled, preferably delayed, release of the analgesic.

This is achieved by coating the active substance crystals with at least a retardant coating, which ensures that the release of the active substance is delayed in a controlled manner over the desired period, thus allowing a targeted control of the duration of action compared with conventional dosage forms, i.e. those without a retardant coating, and preferably by adjusting the release of the active substance to a maximum of two doses, preferably once a day.

The coating materials are all pharmaceutically safe coating materials known to the professional. Preferably, natural, modified or synthetic polymers are used as coating materials. These are polymers, such as cellulose ether or acrylic resins. Especially preferred are water-insoluble or water-soluble cellulose derivatives, such as alkyl cellulose, preferably ethyl cellulose, or water-insoluble acrylic resins, such as poly (meth) acrylic acid and/or their derivatives, their salts, amides or esters.

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In addition to the water-insoluble polymers and waxes, preferably up to 30% by weight of non-retardant, preferably water-soluble polymers, such as polyvinylpyrrolidone or water-soluble cellulose derivatives, such as hydroxyethylcellulose, hydroxypropylmethylcellulose or hydroxypropylcellulose, and/or known plasticizers, may be used to adjust the rate of release of the active substance, where appropriate.

In addition to the retarded coating, the active substance crystals can be equipped with additional coatings, such as a coating of a material different from the material of the retarding coating, which can be applied as a non-retarding separation layer on the crystal surface.

The coating materials for this separation layer are cellulose ether, polyvidone, polyacrylates or polymeric natural materials.

It is also possible to make the additional coating, preferably via the delayed coating, from the active substance of the crystals or from one of these different preferably opioid analgesics, from which this active substance is released unlatentably after oral administration. This multi-layer coating allows an initial dose of analgesic to be provided very quickly after the preparation is administered for initial pain relief, maintaining the level of analgesic by the subsequent delayed delivery of the active substance.

In addition to the retarder coating, the crystals may also have coatings that dissolve depending on pH, for example, at least part of the crystals of a preparation can be obtained to pass through the gastrointestinal tract undissolved and only be released into the intestinal tract.

A further preferred embodiment of the preparations of the invention is that they contain, in addition to the active substance crystals equipped with a retarder and, where appropriate, additional coatings, which guarantee a controlled release of the active substance, also unretarded active substance crystals, but with one or more of the non-tretard coatings mentioned.

The production of the opioid crystals is known, and they are produced directly during the purification of the active substance.

The crystals of the active substance obtained immediately after manufacture, preferably after recrystallization, are coated by usual known methods, such as spraying solutions, dispersions and/or emulsions or by powder-making.

Preferably, a separation layer is first applied over the individual crystals by coating the active substance crystals after the final cleaning step, crystallization and drying, by spraying a lacquer solution or preferably an aqueous coating dispersion.

If further coatings are applied, they shall preferably be obtained by the same method.

The present invention is also intended to provide oral preparations in the form of capsules, in which the active substance crystals are present with a controlled release of the opioid analgesic according to the individual release duration and the amount of analgesic to be released. Preferably, the amount of active substance crystals in a capsule is chosen so that the dose is sufficient for one application twice, preferably once a day. This delayed formulation in capsules is also done without the necessary formulation technology, since the excess active substance lubricants are only available in capsules. The active substance crystals can be used in a bottle or a filling or, if necessary, in a dosage bottle or a filling or a volume additive.

In addition, the oral preparations of the invention may also be presented in the form of a tablet, to which the overlapping crystals of the active substance may be added to a tablet, with or without the addition of usual analgesics and excipients, according to the individual release duration and the amount of opioid analgesic to be released.

Preferably, tablets with a high content of excipients are manufactured to preserve the individual crystals of the active substance in the coated tablets.

It is also possible to produce tablets with a low content of excipients, whereby the coated crystals of the active substance can aggregate together during compression to form an additional retard matrix, and such tablets no longer decompose spontaneously, so that the retardation is more pronounced than in individually coated crystals.

Preferably, the preparations of the invention have a total concentration of tramadol calculated as hydrochloride salt of 10 to 1000 mg, preferably 50 to 800 mg.

Examples Example 1

Tramadol hydrochloride crystals with a polycrystalline structure in a particle size of 250 to 500 μm have been used after manufacture and purification without further formulation.

The composition:

Kristalle aus	Tramadol HCl	1,000 kg
Überzug aus	Ethylcellulose (Aquacoat®)	0,200 kg
	Dibutylsebacat	0,050 kg
Total		1,250 kg

These tramadol hydrochloride crystals were moved in a spinning coating device by heated air, the aqueous ethyl cellulose suspension in which dibutyl sebacate had been previously stirred was slowly sprayed onto the crystals by means of a two-component nozzle, and the crystals were dried after application.

Example 2

The coated crystals in Example 1 were processed into capsules.

The coated crystals were mixed in a cube mixer with the excipients listed above and filled in hard gelatine capsules of size 2 by means of a capsule machine.

The composition:

Kapselfüllung	pro Kapsel	pro Ansatz
Tramadol HCl Kristalle, überzogen gemäß Beispiel 1	125 mg	1,25 kg
Mikrokristalline Cellulose	75 mg	0,75 kg
Natriumcarboxymethylstärke, Typ A	45 mg	0,45 kg
Magnesiumstearat	5 mg	0,05 kg
Total	250 mg	2,50 kg

Example 3

250 g of the coated crystals as described in example 1 were mixed with 344 g of microcrystalline cellulose and 6 g of magnesium stearate and placed in rapidly decomposing tablets of 10 mm diameter and 300 mg weight .

Example 4

Tramadol hydrochloride crystals with a polycrystalline structure with a particle size of 250 to 500 μm after manufacture and purification have been used.

The tramadol hydrochloride crystals were moved in a vortex layering device by heated air and the aqueous dispersion was first sprayed and dried to form the intermediate layer, then the aqueous ethyl cellulose suspension into which dibutyl sebacate had been previously stirred was slowly sprayed onto the crystals by a two-component nozzle and the crystals were dried after application of the suspension.

The composition:

Kristalle aus	Tramadol HCl	1,000 kg
Zwischenschicht	Macrogol 6000	0,025 kg
	Talkum	0,040 kg
	Hydroxypropylmethylcellulose Typ 2910, 6 mPas	0,100 kg
Überzug aus	Ethylcellulose (Aquacoat®)	0,200 kg
	Dibutylsebacat	0,050 kg

Claims (16)

1. A preparation to be administered orally with a controlled release of an opioid analgesic in the form of crystals with a particle size of 10 µm to 3 mm which have at least one action-sustaining coating based on polymers, wherein acrylic resins and/or cellulose derivatives and/or waxes are present as the polymers.
2. Preparation according to claim 1, characterized in that the particle size is 50 µm to 1 mm.
3. Preparation according to claim 1 or 2, characterized in that the crystals are monocrystals or have a polycrystalline structure.
4. Preparation according to one of claims 1 to 3, characterized in that the action-sustaining coating comprises up to 30 wt.% of a polymer which is not action-sustaining.
5. Preparation according to one of claims 1 to 4, characterized in that alkylcellulose is employed as the cellulose derivative.
6. Preparation according to one of claims 3 to 5, characterized in that ethylcellulose and/or poly(meth)acrylic acid and/or derivatives thereof and optionally up to 30 wt.% hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose or polyvidone are employed as the polymer.
7. Preparation according to one of claims 1 to 6, characterized in that hydromorphone, oxycodone, morphine, levorphanol, methadone, dihydrocodeine, codeine, dihydromorphine, pethidine, piritramide, fentanyl, tilidine, buprenorphine, tramadol, their particular salts or mixtures thereof are employed as the opioid analgesic.
8. Preparation according to claim 7, characterized in that the opioid analgesic is tramadol, tramadol hydrochloride and/or morphine, morphine hydrochloride and/or morphine sulfate.
9. Preparation according to one of claims 1 to 8, characterized in that in addition to the action-sustaining coating, the crystals have at least one more further coating.
10. Preparation according to claim 9, characterized in that as a further coating a coating of a material which differs from the action-sustaining coating is applied directly to the crystal surface as a separating layer which is not action-sustaining.
11. Preparation according to claim 9 or 10, characterized in that a coating which is resistant to gastric juice is present as a further coating.
12. Preparation according to one of claims 9 to 11, characterized in that a coating comprising the same opioid analgesic as or one which differs from the analgesic of the crystals or another pharmaceutical active compound is present as a further coating.
13. Preparation according to claims 1 to 12, characterized in that the crystals are present in a capsule, a sachet, a bottle, a dispenser, preferably a dosed dispenser.
14. Preparation according to claims 1 to 12, characterized in that the crystals are pressed to tablets with conventional auxiliary substances and additives.
15. Preparation according to claims 1 to 12, characterized in that the crystals are pressed to tablets optionally with pharmaceutical active compounds which are not sustained-action, without auxiliary substances and additives.
16. Preparation according to one of claims 1 to 15, characterized in that the total concentration of the tramadol, calculated as the hydrochloride salt, is 10 to 1,000 mg.