Opioid analgesics controlled release of active substances

 

(57) Abstract:

Proposed new intended for oral administration of the drug controlled-release opioid analgesic in the form of crystals with a particle size of from 10 μm to 3 mm, preferably from 50 μm to 1 mm, having at least one retardiculous shell. The invention expands the Arsenal of oral dosage forms of opioid analgesics with delayed release of active ingredient. 15 C.p. f-crystals, 3 tables.

The present invention relates to introduce oral pharmaceutical composition intended for the controlled release of her opioid analgesic action of the active substance.

The prior art a number containing analgesic means compositions that provide controlled release of the active substance. Thus, in particular, in the application EP-A 0647448 already described analgesic effect of the drug with a slow, gradual release of active substances, which consists of several presents in retardirovannah form containing an opioid substrates with a diameter of 0.1 to 3 mm, and which is intended for administration as a daily Sharikov, spherical pellets and conventional granules. To obtain substrates of this type are required, usually associated with relatively high costs of technological operations, such as preparation and application of coatings on spherical granules or extrusion, spheronization to obtain spheroids and give them the appropriate form.

On the other hand, many opioid active substances in their production process are formed in the form of crystals, and this in turn creates the problem of the possibility of their direct, i.e. without performing these costly manufacturing operations, use in the manufacture of medicines.

With regard to the foregoing, the present invention was used to develop intended for oral administration of the drug controlled release of at least one opioid active substances, which could be directly, i.e. without holding associated with high costs of technological operations, to use the crystals formed in the process of obtaining active substances.

According to the invention this problem is solved by creating prednaznachennogo with a particle size of from 10 μm to 3 mm, having at least one retardiculous (contributing an anemic selection) shell. Preferably the size of the crystalline particles is from 50 μm to 1 mm

As analgesic active substance preparations according to the invention contain at least one opioid in crystalline form. As opioids can be used hydromorphone, oxycodone, morphine, Levorphanol, methadone, Dihydrocodeine, codeine, dihydromorphine, pethidine, fentanyl, piritramid, buprenorphine, Tilidine, tramadol, their corresponding salts, or mixtures thereof. The most preferred analgesics include tramadol, tramadolhydrochlorid, morphine, morphinehydrochloride1 and/or martinslife.

The active substance in the preparations according to the invention may be a single crystal or have a polycrystalline structure.

Along with the above opioid analgesics in the drug composition according to the invention can include non-analgesic means that under certain conditions exhibit together with opioid analgesics synergistic effect. Among such non-analgesics include, among other things, ibuprofen, ketoprofene, all preferably in the form of crystals.

Proposed for use according to the invention the products are controlled, preferably gradual allocation contained in their composition analgesics. This effect is achieved by the deposition of the crystals of the active substance at least one reagiruya shell. This shell provides controlled, slow, prolonged release of the active substance within a certain period of time. Thus it is possible to purposefully control the duration of action proposed in the invention of drugs in contrast to conventional dosage forms, i.e. forms that do not have specified reagiruyushih coverage. This is provided that for the selection of the active substance of the drug is enough to enter a maximum of two times per day, preferably even only once.

As coating materials, i.e. materials for the shell, you can use all pharmaceutically acceptable for purposes such materials known to a person skilled in the art. It is preferable to use natural, and under certain conditions, modified or sinteticheskimi preferred water-insoluble or vodosnabzhenie derivatives of cellulose, such as alkylaryl, preferably ethylcellulose, or water-insoluble acrylic resin such as poly(meth)acrylic acid and/or its derivatives, in particular its salts, amides or esters. As a coating material suitable water-insoluble waxes. All these materials are known from the prior art, for example from the publication of C. Bauer, Lehmann, Osterwald, Rothgang "Ueberzogene Arzneiformen", published by Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998, pages 69 and forth, and is incorporated into this description by reference.

In addition to water-insoluble polymers and waxes, for regulating the rate of release of the active substance, if necessary, can also be used in an amount up to 30 wt.% and not having reagiruya ability, preferably water-soluble polymers, such as polyvinylpyrrolidone or water-soluble cellulose derivatives such as hydroxyethylcellulose, hypromellose or hydroxypropylcellulose, and/or known plasticizers.

In addition reagiruya coating on the crystals of the active substance can also be applied and other coatings. Such coverage at the same time, made for example from a material different from reagiruya shell, may be deposited on the surface is acceptable separation layer is preferably a simple cellulose ether, polyvidone, polyacrylates, as well as polymeric natural substances.

Another possibility, an alternative to the above, is that on the shell, preferably retardiculous, put another coating of crystalline active substance or from another, different from the last, preferably opioid analgesic that is released from this additional coverage without delay, immediately after oral administration of the drug. Such multilayer coating should ensure that after the introduction of appropriate drug fast initial dose of analgesic to reduce pain, while the effectiveness of the analgesic in General is provided by the subsequent gradual allocation of the active substance. As coating materials for these purposes can be used pharmaceutically acceptable materials in combination with the initial active substance, such as, for example, a simple cellulose ether, polyvidone or polyacrylates. In neretardnye the floor as additives to crystalline active substance either instead of, or instead of different from another, preferably the opioid, analgesic may provide different pharmaceutical is yuusei shell may have other coverage, solubility depends on pH. Thus, in particular, we can ensure that at least a part of crystals of the drug passes through the gastrointestinal tract in undissolved form and is released only when the flow in the intestinal tract.

In another preferred variant provides that proposed in the invention of drugs along with having retardiculous shell and optional additional coverage crystals of the active substance, providing a controlled release of the active substance, also contain crystals of the active substance coated with one or several neredediryeni coatings from the number above.

The technology of obtaining crystals of opioid active substances known. When the crystals obtained directly in the process required for these purposes cleanup.

On the formed directly in their production process, preferably after recrystallization, the crystals of the active substance is applied coating by the usual known methods, for example by spraying solutions, dispersions and/or emulsions, or by atomization. Acceptable method koatservatsii. Preferably in this case, first who report on the completion of the last stage of cleaning crystallization and drying by spraying a lacquer solution, or preferably the aqueous coating dispersion. Then this separation layer is also coated coating dispersion and then drying the applied retardiculous shell. The thickness of this shell can be varied depending on the desired duration of excretion of the active substance. If you provide more coverage, they should preferably be applied also using the above described method.

The object of the present invention is further intended for oral administration of drugs in the form of capsules, which contain crystals of the active substance controlled-release opioid analgesic in accordance with the desired in each case, the duration of such release and provided the amount of analgesic.

The number of crystals of the active substance in one capsule is selected when it is preferable, therefore, to provide a dose adequate for a double, preferably a single dose. Manufacturing technology this reagiruya composition does not require significant costs, as already coated with crystals Norte uniform dosage in bottles or sachets or implement volumetric dosing with the appropriate dispenser. It does not exclude the addition of conventional excipients, such as fillers, lubricants or substances that contribute to the decomposition of the coating.

Intended for oral administration of the preparations according to the invention can be produced also in the form of tablets, while the crystals of the active substance tabletirujut in accordance with stipulated for specific cases, the duration of release and the allocated amount of opioid analgesic using conventional auxiliary substances and additives or without them. In these cases, the number of crystals of the active substance from which the pressed tablets, preferably be chosen in such a way as to provide the desired duration of release and the amount of analgesic sufficient to twice, preferably once daily administration. It is preferable to produce tablets with a high proportion of auxiliary substances in order to keep the active substance for a particular purpose. With the rapid disintegration of tablets crystals, of which there is then a gradual release of the active substance, are highlighted. In case of a split tablets into parts such prolonged matrial low content of auxiliary substances. In the process of tabletting can be covered aggregation of crystals of the active substance between them, so that there is additional retardery matrix. Such pills not break up spontaneously and, thus, prolonged action is manifested more clearly in comparison with crystals, with coverage in each case.

Preferably the total concentration of tramadol in the preparations according to the invention in terms of cleaners containing hydrochloride salt is from 10 to 1000 mg, preferably from 50 to 800 mg

Examples

Example 1

In this example, the crystals tramadolhydrochloride with polycrystalline structure and a particle size of 250-500 μm was used after receiving them and cleaning without conducting the subsequent stage of the preparation of the composition. Data regarding the number of applications is specified in terms of dry weight after application of the aqueous dispersion.

These crystals tramadolhydrochloride moved into the apparatus with fluidized bed by means of heated air and on the crystals using a nozzle for two-component materials slowly deposited aqueous suspension of ethyl cellulose, in the cat the Gali drying.

Example 2

From covered in example 1, the crystals produced capsules. With this purpose, the coated crystals were mixed in a cubic mixer with the above-mentioned auxiliary substances and using kapsuljatora formed capsules with terrorisation shell size 2.

Example 3

250 g of crystals coated according to example 1, coating was mixed with 344 g of microcrystalline cellulose and 6 g of magnesium stearate and the mixture extruded rapidly disintegrating tablets with a diameter of 10 mm and a weight of 300 mg.

Example 4

In this example, upon completion of the process for their preparation and purification of used crystals tramadolhydrochloride polycrystalline structure with a particle size of 250-500 μm. Data about the intermediate layer, as well as reagiruya shell, specified in terms of dry weight after application of the aqueous dispersion.

These crystals tramadolhydrochloride moved into the apparatus with fluidized bed by means of heated air and first for the formation of an intermediate layer deposited on them the aqueous dispersion, and then were dried. Then on the crystals using a nozzle for two-component materials slowly is at. After application of the suspension crystals were dried.

1. Intended for oral administration of the drug controlled-release opioid analgesic in the form of crystals with a particle size of from 10 μm to 3 mm, preferably from 50 μm to 1 mm, having at least one retardiculous shell.

2. The drug under item 1, characterized in that the crystals are single crystals or have a polycrystalline structure.

3. The drug under item 1 or 2, characterized in that retardery shell is made on the basis of the polymer.

4. The drug under item 3, characterized in that retardery shell contains up to 30 wt.% not having prolonging properties of the polymer.

5. The drug under item 3 or 4, characterized in that the polymers are used as the acrylic resin and/or cellulose derivatives, preferably alkylaryl.

6. The drug according to any one of paragraphs.3-5, characterized in that the polymers are used as ethylcellulose, and/or poly(meth)acrylic acid and/or its derivatives and the optional hydroxypropylcellulose, hydroxyethylcellulose, hypromellose or polyvidone in an amount up to 30 wt.%.

8. The drug under item 7, wherein the opioid analgesic is a tramadol, tramadolhydrochlorid and/or morphine, morphinehydrochloride1 and/or martinslife.

9. The drug according to any one of paragraphs.1-8, characterized in that the crystals along with reagiruya shell have at least one more floor.

10. The drug under item 9, characterized in that the second coating directly on the surface of the crystals are coated in the form of not having prolonging properties intermediate (separation) layer of a material different from reagiruya shell.

11. The drug under item 9 or 10, characterized in that the second coating is a coating resistant to the action of gastric juice.

12. The drug according to any one of paragraphs.9-11, characterized in that the second coating is a coating containing the same opioid analgesic that and crystals, or other than itself, or any other pharmaceutically active substance.

14. The drug according to any one of paragraphs.1-12, characterized in that the crystals are presented in the form of tablets, pressed together with a conventional auxiliary substances and additives.

15. The drug according to any one of paragraphs.1-12, characterized in that the crystals are presented in the form of tablets, compressed if necessary, together with not possessing prolonging properties of pharmaceutically active substances without auxiliary substances and additives.

16. The drug according to any one of paragraphs.1-15, characterized in that the total quantity of tramadol in terms of cleaners containing hydrochloride salt is 10-1000 mg



 

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