Analgesic drug with sustained-releasing active substance

FIELD: medicine, pharmacy.

SUBSTANCE: invention proposes new tablets with size less 3 mm with sustained-releasing the opioid analgesic drug for 30 min in the amount above 75%. Invention provides opioid for oral intake with taking into account individual necessity of patient due to selection of required amount of mictotablets by dispenser.

EFFECT: valuable properties of tablet, expanded assortment of medicinal formulations of opioid analgesics.

19 cl, 4 tbl, 4 ex

 

The present invention relates to pharmaceutical compositions intended for the controlled release of her 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 is slow, gradual release of active substances, which consists of several presents in retardirovannah (helps to slow down) form, containing opioids substrates with particle diameters from 0.1 to 3 mm and which is intended for administration as a daily dose. Suitable for use in this preparation the substrates can be presented in the form of spheroids, beads, spherical granules or conventional granules. To obtain substrates of this type usually require technological operations associated with relatively high costs such as the preparation and application of coatings on spherical granules or extrusion, spheronization to obtain spheroids and giving them the appropriate form.

Besides, for a variety of purposes and methods of treatment still feels the need to contain analge the IKI medicines which can be appropriately dosed with regard to the individual characteristics of patients, as is the case when the intended use for oral liquid dosage forms in the form of droplets, and which is preferably made using traditional, simple ways, such as tableting.

Based on the foregoing, the present invention was used to develop intended for oral administration of the drug controlled release of at least one contained in its analgesic, which would allow precisely, taking into account individual patient dosing it is comparable to the dosage drops way, for example, from the respective cylinders, or would the distribution of a certain quantity of the active substance on easily and accurately controlled set of substrates and which can be manufactured using conventional, low-cost technologies.

According to the invention this task is solved by the proposed intended for oral administration of the drug controlled release of at least one analgesic from microtablets diameter less than 3 mm, Preferably such microtablets have a diameter of from 1 to 3 mm and particularly preferably from 1.5 to 3 mm.

In the operation analgesic active substances microtablets according to the invention contain preferably at least one opioid. As such opioid used preferably hydromorphone, oxycodone, morphine, Levorphanol, methadone, Dihydrocodeine, codeine, fentanyl, dihydromorphine, pethidine, piritramid, buprenorphine, Tilidine, tramadol, their corresponding salts, or mixtures thereof.

Most preferred as an analgesic tramadol, tramadol hydrochloride, morphine, morphine hydrochloride and/or morphine sulfate.

Along with the above opioid analgesics in the drug composition according to the invention may include and non-opioid properties analgesics, which in combination with the first, under certain conditions, exhibit a synergistic effect. Such non-analgesics include ibuprofen, Ketoprofen, flurbiprofen, paracetamol, naproxen, propifenazona, acemetacin, acetylsalicylic acid, Metamizole and/or their respective salts.

Proposed for use according to the invention microtablets different controlled release of analgesic. The term "controlled release" is meant not as slow, gradual its release, and retardirovannah, prolonged isolation. It is preferable retardirovannah release opioid active substances. This retardation can be achieved by embedding the active substance in retardiculous matrix this solution provides controlled, gradual release of the active substance within the required time period. It is advisable to provide this level of retardation of the active substance, so it was enough for two, preferably only a single use of the drug in the day.

As materials for the matrix are suitable pharmaceutically acceptable hydrophilic materials known to a person skilled in the art. Preferably as hydrophilic materials for the matrix to use polymers, such as simple or complex esters of cellulose or acrylic resin. Especially preferred as these materials ethylcellulose, hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acid and/or derivatives thereof, in particular their salts, amides or esters.

The matrix can be made from hydrophobic materials, such as hydrophobic polymers, waxes, fats, oils, long-chain fatty acids, fatty alcohols or corresponding esters or a mixture thereof. Preferably used as the hydrophobic materials are mono - or diglycerides With12-C30fatty acids and/or C12-C30fatty alcohols and/or waxes. As reagiruyushih material for the matrix you can use the ka is Oh or mixtures of the mentioned hydrophilic and hydrophobic materials.

In addition, the proposed invention microtablets can contain other ingredients commonly used pharmaceutical excipients, in particular fillers, such as lactose, microcrystalline cellulose or calcium phosphate, and oil, grease and regulators fluidity, as, for example, highly dispersed silicon dioxide, talc, magnesium stearate and/or stearic acid. Especially preferred as pharmaceutically acceptable material for the matrix is at least simple and/or complex cellulose ether, 2 wt.%-aqueous solution which is at 20°With a viscosity of from 3000 to 150,000 MPa·C, preferably from 10000 to 150000 MPa·C, optionally in combination with kinabuhayan in the aquatic environment filler, such as calcium phosphate, or insoluble, Nauheim in the aquatic environment filler, such as microcrystalline cellulose or soluble in water filler, such as lactose.

Share analgesic, preferably opioid analgesic is selected depending on the envisaged duration of its release and the released quantity. Preferably the active substance is from 10 to 85 wt.% and particularly preferably from 25 to 70 wt.%, accordingly, virescence on the total amount of the mixture. Specialist in the art will know the effect of opioid and non-analgesics, and, following this, he determines how the combined use of both types of analgesics to achieve the desired release of the active substances.

In the application proposed in the invention in the form of microtablets drugs controlled the allocation of these active substances can also be achieved by applying on a separate pill of at least one shell, providing such controlled, as a rule, retardirovannah (progressive) release of the active substance in the aquatic environment. For the specified reagiruya shell acceptable amongst the water-insoluble waxes or polymers, such as acrylic resin, preferably a poly(meth)acrylates, or water-insoluble cellulose, preferably ethylcellulose. These materials are known from the prior art, in particular from the publication Bauer, Lehmann, Osterwald, Rothgang "Uberzogene Arzneiformen", published by Wissenschaftliche Veriagsgesellschaft mbH, Stuttgart, 1998, p.69 and forth and described in this description by reference.

Along with water-insoluble polymers 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 in rastvorimye polymers, such as polyvinylpyrrolidone or water-soluble cellulose, preferably the hypromellose or hydroxypropylcellulose, and/or known plasticizers.

In addition reagiruya of the shell on microtablets according to the invention can also be applied and other coatings. Thus, in particular, a coating containing the active substance coating, from which this active substance is released without delay after oral administration of the drug. Such multilayer microtablets designed to provide after drug administration the allocation of the appropriate fast initial dose of analgesic to reduce pain, while the effectiveness of the analgesic in General can be maintained at the required level due to subsequent gradual release of the active substance.

According to another variant of microtablets along with reagiruya shell can have more and different floor, the solubility of which depends on pH. Thus, in particular, we can ensure that, for example, a certain number of microtablets passes through the gastrointestinal tract without dissolving, and their action they show only when entering the intestinal tract.

According to another preferred variant of the production of the preparations according to the invention provides that mikroC is blecki, having retardiculous shell and other optional coverage that already contain the active substance in the corresponding matrix, which provides a controlled, gradual release of the active substance, or that microtablets with reagiruya matrix are not contributing to the retardation of the shell, and have at least one of the above-mentioned coating providing the selection of the initial dose of the analgesic and/or depending on pH values.

The proposed microtablets produced by known methods described, for example, in application EP-A 0166315. This application is given in the present description by reference.

Preferably the process of making microtablets as follows: first, all the ingredients are passed preferably through a sieve with a mesh size of 0.6 mm, then mixed to achieve homogeneity. The mixture can be translated in the form of a granulate, and the operation of sifting expedient to carry out after granulation. In the case of granulation before tabletting, it is preferable to add lubrication and/or oil. Next, the homogeneous mixture is fed into the tablet press press, preferably a press with rotary table, where the pressed tablets with a diameter of 1-3 mm, preferably 1.5 to 3 mm, This method is preferably used for making tablets with RETA is drowsey matrix, in the case of hydrophobic materials for the matrix, fusible at temperatures above 100°C, is the preferred method in the melt granulation. This technology is well-known specialist in this field of technology.

Because the preparations according to the invention contain in their composition microtablets with coatings, the latter can be formed using conventional methods, such as drazhirovanie, plating solutions, dispersions or suspensions, drawing from the melt or spraying.

Intended for oral administration of the preparations according to the invention have, in addition, the significant advantage that without much effort and cost allow you to split the total desired dose of the analgesic to a certain number of single doses. This enables you to produce prescribed for oral intake of the drug taking into account the patient's individual needs. To implement such a feature can, for example, selecting the required number of microtablets of their total number by a measuring device, preferably "drive", in accordance with the foreseen in each case the duration of the release of microtablets analgesic and its allocated amount.

With regard to the foregoing, another object of izaberete the Oia are individually dosed, intended for oral administration of drugs, the number of microtablets which is determined in accordance with the desired in each case, the duration of release of the analgesic and its allocated amount.

Another object of the invention is proposed for oral assignments drugs in the form of capsules, each of which is provided by the presence of a certain amount of microtablets controlled release of the analgesic in accordance with the required in each case the duration of release of the analgesic and its allocated amount. It is preferable to choose the number of microtablets in one capsule, so that this dose was sufficient for a single or twice daily administration. In the case of such dosage forms appropriate to allocate the dose of the analgesic in the minimum required number of microtablets, thereby providing the patient an opportunity to select a simple way, without proper reference, provided in each capsule dose.

Along with this, intended for oral administration of the preparations according to the invention can be produced also in the form of so-called microtablets, i.e. tablets normal size in the manufacture of which it is proposed to provide each of them is definitely the number of microtablets in accordance with the required in each case the duration of release of the analgesic and its allocated amount, together with a conventional auxiliary substances and additives, used traditionally during pelletizing. In these cases it is also advisable to choose for each microtablet such number of microtablets, which would be enough for a single or double daily intake, while providing the desired duration of release of the analgesic and the amount.

Accordingly, another object of the present invention are also intended for oral administration of drugs controlled release of microtablets at least one analgesic, it is proposed in the manufacture of one microtablets should include the presence of a certain amount of microtablets in accordance with the desired duration of release of the analgesic and its allocated amount and at the same time be used in the pelletizing conventional auxiliary substances and additives.

Examples

Characteristic features of release of active substances from products manufactured in the following examples was determined as follows.

The composition was placed in 600 ml of artificial gastric juice (pH of 1.2), served as release medium at the temperature of 37°and pre-loaded into the apparatus with a rotating basket (according to the requirements of the European reference lekarstvennayaforma) (the rotation speed of the baskets was 100 min -1). After 120 min the pH value of the releasing medium due additives buffer solution of phosphate was increased to 7.2 and this pH value was maintained at this level until completion of the pilot study. Released at each time point the amount of active substance was determined by spectrophotometry.

Example 1

Composition:

 One pillOne capsule with 10 tablets
Components microtabletstramadol·Hcl10.0 mg100 mg
microcrystalline cellulose4.0 mg40 mg
Povidon® K300.8 mg8 mg
magnesium stearate0.2 mg2 mg
Only15 mg150 mg

Salt of tramadol and microcrystalline cellulose using an aqueous solution Povidon® K30 was granulated, dried, sieved, mixed with magnesium stearate, and then extruded tablets with a diameter of 3 mm and a height of about 2 mm and has encapsulated by placing in each capsule 10 microtablets.

It was found that after 15 min released more than 80% of activegeodiv.

Example 2

Composition:

 One pillOne capsule with 10 tablets
Components microtabletstramadol·Hcl10.0 mg100 mg
microcrystalline cellulose4.0 mg40 mg
Povidon® K300.8 mg8 mg
magnesium stearate0.2 mg2 mg
Shell componentsethylcellulose (Aqacoat®)0.8 mg8 mg
dibutylsebacate0.2 mg2 mg
Only16,0 mg160 mg

Salt of tramadol and microcrystalline cellulose using an aqueous solution Povidon® K30 was granulated, dried, sieved, mixed with magnesium stearate, and then extruded tablets with a diameter of 3 mm and by using aqueous dispersions of ethyl cellulose and dibutylsebacate in a quantitative ratio of 4:1 in the apparatus with fluidized bed covered with a shell by spraying the specified variance in simultaneous continuous drying, and then spent encapsulation, placing in each capsule 10 microtablets.

In CPE is it the following data were obtained for the release of the active substance:

AfterThe release of the active substance in % from its initial concentration
30 minutes1%
240 minutes18%
480 minutes29%

Example 3

Analogously to example 2 were made and covered with a sheath microtablets with a diameter of 2 mm and a height of approximately 2 mm, which had the following composition. Then spent encapsulation, placing in each capsule 20 microtablets.

 One pillOne capsule with 20 tablets
Components microtabletstramadol·Hcl5.0 mg100 mg
microcrystalline cellulose2.0 mg40 mg
Povidon® K300.4 mg8 mg
magnesium stearate0.1 mg2 mg
Shell componentsethylcellulose (Aqacoat®)0.4 mg8 mg
dibutylsebacate0.1 mg2 mg
Only8.0 mg160 mg

the example 4

For the manufacture of microtablets with reagiruya matrix tramadol hydrochloride (5 mg/tablet) and glycerinated (Compritol 880 ato®) (5 mg/tablet) was passed through a sieve with a mesh size of 0.6 mm, Then from a homogenized mixture using appropriate punches extruded microtablets with a diameter of 2 mm, These tablets are characterized by the following indicators for the release of the active substance:

AfterThe release of the active substance in % from its initial concentration
60 minutes40%
120 minutes60%
240 minutes75%
480 minutes85%

1. Intended for oral administration of the drug controlled release of at least one opioid as an analgesic from microtablets diameter less than 3 mm

2. The preparation according to claim 1, characterized in that microtablets have a diameter of 1-3 mm, preferably 1.5 to 3 mm.

3. The preparation according to claim 1, characterized in that as opioid use hydromorphone, oxycodone, morphine, Levorphanol, methadone, Dihydrocodeine, fentanyl, codeine, dihydromorphine, pethidine, piritramid, buprenorphine, Tilidine, tramadol, their corresponding salts, or mixtures thereof.

4. The preparation according to claim 3, characterized the eat, as opioid use tramadol, tramadol hydrochloride, morphine, morphine hydrochloride and/or morphine sulfate.

5. Preparation according to one of claims 1 to 4, characterized in that microtablets contain opioid, evenly distributed in reagiruya matrix.

6. The preparation according to claim 5, characterized in that the matrix material using at least a polymer, a wax, fat, oil, fatty acid, fatty alcohol or the corresponding ester.

7. The preparation according to claim 6, characterized in that the polymer used as a simple cellulose ether, an ester of cellulose and/or acrylic resin.

8. The drug according to any one of pp.5-7, characterized in that as the material for the matrix using ethylcellulose, hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, mono - and/or diglycerides With12-C30fatty acids and/or C12-C30fatty alcohols.

9. The drug according to any one of claims 1 to 4, characterized in that microtablets have at least one shell.

10. The preparation according to claim 9, characterized in that the shell is used for retardation (prolongation).

11. The preparation according to claim 9 or 10, characterized in that the membrane formed on the basis of the water-insoluble polymer or wax.

12. The drug in claim 11, characterized in that the acrylic polymer used smo is from or derived cellulose, preferably alkylaryl.

13. The drug is indicated in paragraph 12, characterized in that as the material for the shell use ethylcellulose and/or poly (meth) acrylate.

14. The drug according to any one of claims 1 to 13, characterized in that microtablets presented in encapsulated form.

15. The drug 14, characterized in that each capsule contains a certain number of microtablets in accordance with the required individually extended release opioid and its allocated amount.

16. The drug is indicated in paragraph 15, characterized in that the number of microtablets in one capsule designed for once or twice daily administration.

17. The drug according to any one of claims 1 to 13, characterized in that the required number of microtablets can be selected using the appropriate dosing of their total number in accordance with the desired duration of release of the opioid and its allocated amount.

18. The drug according to any one of claims 1 to 13, characterized in that a certain number of microtablets provided individually for the required duration of release of the opioid and its allocated quantity, used in conjunction with conventional auxiliary substances and additives for the manufacture of a tablet.

19. The drug according to any one of claims 1 to 4, characterized in that the opioid is svoboditsa for 30 min more than 75%.



 

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