Directly compressible matrix for controlled release once-daily doses of clarithromycin

 

Oral solid dosage form for controlled release once-daily doses of clarithromycin is used in the treatment and prevention of bacterial infections. Dosage form contains clarithromycin and new combined matrix of a mixture of fatty and hydrophilic components. The content of the oily component is 10-36% by weight of the tablet. The content of the hydrophilic component is 5-18% by weight of the tablet. Dosage form may further comprise a surfactant and a pH modulator. A simple, efficient and pH-independent ready form macrolide antibiotic clarithromycin. The form provides reproducible release of clarithromycin for 24 hours to minimize the subjective impact on each individual patient. 3 N. and 11 C.p. f-crystals, 2 Il.

The present invention relates to the field of pharmaceutical technology and considers the macrolide antibiotic clarithromycin and its derivatives.

In a narrow sense, the present invention relates to a new oral pharmaceutical finished form of clarithromycin or its derivatives with controlled-release based the added surfactant and a pH modulator optionally have an additional effect on the release profile of the active substance.

Background of invention

Clarithromycin is a slightly alkaline, practically water-insoluble and kislotoustojchivy macrolide antibiotic. Its solubility decreases with increasing temperature and increasing pH. A daily dose component 500 mg, it is necessary to introduce a relatively small matrix, because the tablet should not be too large to swallow, leaving a relatively narrow space for optimization of biopharmaceutical and physico-technological properties of the form of the drug. Therefore, when receiving 24-hour tablets are faced with the problem of high doses of slightly soluble active substances and at the same time, the need to ensure reproducible and pH-independent release profile of clarithromycin in accordance with specifically selected the optimal time mode.

Commercially available oral ready form of clarithromycin extended release contains alginate matrix, which is known for its high dependence of the release of the active substance from pH and production technology which includes including time-consuming and expensive processes wet granulirovanniye parties and the decrease in solubility due to aging.

Thus, the present invention is based on the need to find simple, effective, and pH-independent ready-made form of medicines, which would provide a reproducible release of clarithromycin for 24 hours, while minimizing the subjective impact on each individual patient. The release rate should provide optimal concentration of active substance in the blood in order to provide a therapeutic effect over an extended period of time.

Background of invention

Clarithromycin is a semisynthetic antibiotic produced by methylation of erythromycin on the lactone in position C6. Synthesis it is described in the U.S. patents 4331803 and 4672109. It acts on gram-positive bacteria and is used in clinical practice due to the wide range of its antimicrobial activity. It is on the market in the form of glazed tablets, suspensions and tablets slow release.

The following patent literature describes various oral forms of compositions with clarithromycin.

In the patent JP 85/163823 describes an oral composition containing clarithromycin and citric acid, Genty.

Revoked the patent application EP No. 227042 describes an oral pharmaceutical composition with improved taste, which has a coating of special polymers (especially polyvinyltrimethylsilane-AEA), soluble in gastric juice, and the average particle diameter of less than 60 microns.

In U.S. patent 4808411 describes the form of the composition with erythromycin or its derivatives and Carbonera not necessarily in the form of particles of an ionic complex, coated with polymer, in which these particles can be suspended in the liquid carrier.

In the patent JP 89/42625 describes the preparation of microgranules drugs with continued release coated film, which in addition to erythromycin also contains AEA and water.

Revoked the patent application EP No. 302370 and patent application WO No. 90/08537 describe improved oral form (oily solution, suspension, emulsion) erythromycin and its derivatives for filling soft gelatin capsules N-organic.

Patent EP 420992 describes a method of obtaining oral forms with masked taste, including the spraying of a suspension of a drug in a cold aqueous solution of AEA.

U.S. patent 5017383 describes a method of obtaining tongaporutu other means and the coating in the form of fine powder adhering to the surface of the particles.

In U.S. patent 5599556 and 5609909 describes how to disguise the taste of the encapsulated particles clarithromycin prelaminate surfaces before preparing the suspension.

Patent application WO No. 96/34628 describes the shape of the composition with masked taste for oral administration (especially dry syrup) containing medicinal product with an unpleasant taste, polymer with high solubility in the stomach (preferably AEA or Eudragit E (Eudragit E)) and monoglyceride with a low melting point (preferably, glycerylmonostearate) stablecrystal form (the transition from meta-stable-forms with shaking at elevated temperature) and the method of masking the taste.

Patent application WO No. 97/16174 describes how water granulation macrolide antibiotic with Carbonara (acrylic polymer).

U.S. patent 5705190 describes solid oral pharmaceutical form with controlled release formulation containing the drug is poorly soluble in water, water-soluble alginate salt, a complex salt of alginic acid with a metal cation and an organic carboxylic acid, to facilitate the dissolution of the drug.

U.S. patent 5707646 about the unpleasant taste, functional polymer (preferably AEA and/or Eudragit E (Eudragit E) substance with a melting point of 40-120With, sugar alcohols (e.g. sorbitol), and the primary oxide (preferably MgO).

Patent application WO No. 98/46239 describes pharmaceutical form prolonged action, containing eritromicina derivative and a hydrophilic water-soluble polymer, which when administered orally demonstrates a superior taste profile and reduced gastrointestinal side effects compared to conventional form, as well as the technology of production, which includes, among others, how wet granulation, drying, sieving and grinding.

Thus, in the patent and other literature in this area you can find many publications describing the drug and various ready-made forms with clarithromycin, however, there is no literature that can be described as simple way to obtain the final form of clarithromycin with adjustable release, enabling choice and obtain pH-independent release profile of the active substance within 24 hours.

Description new solution examples

The object of izobreteny which contains a mixture of water-insoluble fatty component, representing the main media to maintain prolonged release, and a hydrophilic component, which in the aquatic environment swells and forms a gel or thickens and thus forms a viscous layer, through which diffuses solubilization dissolved active substance, thus affecting the structure and consistency of the whole matrix.

This basic matrix can be added wetting agent, surfactant, which softens the matrix and binds together both types of components and contributes to a more simple solubilization of the active substance. The result is a matrix system, which through a mixed mechanism of erosion of the tablet and diffusion releases solubilization and/or dissolved active substance through the viscous layer.

To provide additional effect on the release profile of the active substance to the matrix can be optionally added to the pH modulator, which represents an alkaline substance, for example phosphate buffer, affecting the amount of the released active substance in the stomach in relation to the bowel or reduce the impact of existing acidity levels in any part of the digestive tract.

In h which are triglycerides of higher saturated fatty acids, such as palmitic acid, stearic acid and Baganova acid, preferably glycerinated, hydrogenated oils (e.g. vegetable oil or castor oil), Carnauba wax and similar tools. The content of the oily component in the matrix reaches approximately 10-36% by weight of the tablet.

Glycerinated is a lipid substance that is most often used as a lubricating agent with more favorable characteristics, manifested in the fact that at high concentrations it supports the release of active substances. Chemically it is a mixture of glycerolipid esters of beganovi/docosanoic acid (C22with low content of monoparental and melting point 69-74C.

As the hydrophilic component, choose substances which increase the viscosity of microarray environment capable of suspendibility, stabilize existing viscous layer and may also have the ability to soften the fatty components of the matrix. Suitable agents are the alkyl substituted cellulose ethers, preferably hypromellose (receiver array), more preferably a receiver array with a low viscosity, fatty alcohols (e.g. cetyl, p is Amed), adsorbents with a large specific surface (for example, MD-Al-silicates) and other Content of the hydrophilic component in the matrix is about 5-18% by weight of the tablet.

A receiver array is a simple cellulose ether is commonly used to increase the viscosity of the environment, but it also influences the rate of release of active substances. Use the receiver array types with low viscosity, the viscosity of which (nominally 2% aqueous solution at 20(C) up to about 40 SP, and the value of Mnapproximately 20,000 (defined according to the method of measurement of osmotic pressure).

It was found that when combining glycerinate and receiver array are exclusively efficient matrix for extension and regulation of release of the active substance, as by contact with an aqueous medium (in the stomach), it swells and thus loses lipid (glycerinate) structure, which makes possible the release of clarithromycin due to the diffusion through the viscous layer with simultaneous erosion of the matrix, i.e., tablets. The ratio between the lipophilic and hydrophilic components may be between 2:1 and 10:1.

Among the surfactants can espressomachine surfactant comprises about 0.5-3% by weight of the tablet.

The sodium docusinate is an anionic surfactant, which in this combination contributes to a more uniform wetting of the lipid structure and thus facilitates the hydration and swelling of the matrix and makes it possible to repeat the diffusion of clarithromycin from the matrix.

Tablet of clarithromycin can also be covered with glaze, for example by suspension from a mixture of a receiver array and hydroxypropylcellulose (LDCs), in accordance with the traditional method or the release profile of clarithromycin is modulated by the application of acid-resistant coating, such as a receiver array phthalates.

Excellent property ready form of the composition according to the present invention in comparison with the level of equipment is a simple production technology, since all the ingredients are simply homogeneous mixed with each other at room temperature, sieved and directly pressed into tablets, so no need for water or any other solvents.

An important technological advantage of the finished form of the composition according to the present invention is that no additional lubricating agents, because glycerinated itself, as is the orenia clarithromycin in vitro of two matrix samples with controlled release within 24 hours measured at 37 With in the first hour at pH 3.0 and in the next 23 hours at pH 6.8. The results obtained are shown in Fig.1 and 2.

The invention is illustrated and is in no way limited to the following examples.

Example 1

Composition one tablet:

clarithromycin 500 mg

glycerinated (Compritol 888) 350 mg

A receiver array (E50-LV R) 150 mg

Lactose 150 mg

The test for dissolution:

The dissolution profile shown in Fig.1.

Example 2

The composition has the same composition as in example 1, except that instead of 34.5 g of lactose using the same number of Na-docusinate.

Example 3

Composition one tablet:

clarithromycin 500 mg

glycerinated (Compritol 888) 350 mg

A receiver array (E50-LV R) 150 mg

Lactose 131,905 mg

Pan2RHO449,538 mg

Na2HPO42,607 mg

Na-docusinate 5,95 mg

The test for dissolution:

The dissolution profile shown in Fig.2.

Example 4

Composition one tablet:

clarithromycin 500 mg

glycerinated (Compritol 888) 350 mg

A receiver array (E15 motorway-LV P) 150 mg

polyvinylpyrrolidone (25) 60 mg

microcrystalline cellulose 40 mg

stearic acid 15 mg

SiO2(Aerosil 200) 5 mg

Talc 5 mg

CA-stearate 25 mg

Example 5

Composition one tablet:

clarithromycin 500 mg

glycerinated (Compritol 888) 350 mg

A receiver array (E50-LV P) 150 mg

polyvinylpyrrolidone (2

CA-stearate 25 mg

Example 6

The composition of the tablets is the same as in examples 1-5, except that the tablet also has an acid-resistant coating of the following composition:

A receiver array phthalate 28,75 mg

Triethylcitrate 2,875 mg

Yellow pigment (Fe-oxide) 0,822 mg

TiO20,514 mg

Talc 4,039 mg

Claims

1. Oral solid dosage form for controlled release once-daily doses of clarithromycin in the treatment and prevention of bacterial infections containing clarithromycin and a mixture of fatty and hydrophilic components, and the content of the oily component is approximately 10-36% by weight of the tablet and the content of the hydrophilic component is about 5-18% by weight of the tablet.

2. Dosage form under item 1, characterized in that it contains a surfactant.

3. Dosage form under item 1, characterized in that it further comprises a modulator pH.

4. Dosage form under item 1, characterized in that it further comprises other pharmaceutically acceptable additives.

5. Dosage form under item 1, wherein the fatty component is glycerinated.

6. Dosage form under item 1, characterized in that the hydrophilic Coase fact, that has a viscosity hypromellose 15 CP.

8. Dosage form under item 2, characterized in that the surface-active agent is sodium docusinate.

9. Dosage form under item 3, characterized in that the modulator pH is a phosphate buffer.

10. Dosage form under item 1, characterized in that it is a tablet.

11. Dosage form under item 10, wherein the tablet is coated with glaze.

12. Dosage form under item 10, characterized in that the pill caused acid resistant coating.

13. The method of obtaining oral solid dosage form under item 1, characterized in that it includes a homogeneous mixing of these components, sieving and directly pressed into tablets without the use of solvents.

14. Oral solid dosage form for controlled release once-daily doses of clarithromycin in the treatment and prevention of bacterial infections, characterized in that it is manufactured according to the method of p. 13.

 

Same patents:

The invention relates to the field of pharmaceutical industry and relates to antimicrobial pharmaceutical composition for the treatment of pneumonia, infections of the respiratory tract, gastrointestinal tract, etc. containing as active ingredient co-trimoxazole and special additive: sodium carboxymethylcellulose, cellulose, sorbitol food, glycerin, parable, tween-80, food flavors and is made in the form of a suspension for oral administration

The invention relates to medicine, in particular to obstetrics and gynecology, and for the treatment of bacterial vaginosis

The invention relates to 1-(6-amino-3,5-differencein-2-yl)-8-bromo-7-(3-acylaminoalkyl-1-yl)-6-fluoro-4-oxo-1,4-dihyd-rhinolin-3-carboxylic acid or its salt, as well as to antimicrobial drug and compositions on the basis of this compound or its salt

The invention relates to the field of veterinary medicine, in particular to the means for treatment of animals

The invention relates to pharmaceutical preparations and their use in medicine and, in particular, relates to the use of lysostaphin in the treatment of staphylococcal infections in mammals, including man, as well as pharmaceutical preparations used in this way
The invention relates to medicine, specifically to Oncology, and can be used in clinical practice Oncology hospitals

The invention relates to a method of deriving 9 deoxo-9a-Aza-9a-homoerythromycin A formula 1A or its pharmaceutically acceptable salts, including the interaction of the monohydrate of the compound of formula 2 with n-Propylamine in isopropanol at a temperature of 50-s and atmospheric pressure

The invention relates to the field of medicine and relates to a pharmaceutical preparation for oral administration containing moxifloxacin or its salt and/or hydrate, at least one dry binder

The invention relates to pharmaceutical industry

The invention relates to film-coated tablets comprising as active compounds cyclophosphamide and containing core tablets cyclophosphamide, one or more fillers, one or more dehumidifiers-binding except for the swollen starch, regulator fluidity and sizing
The invention relates to medicine and pharmacology

The invention relates to the field of medicine and relates to a pharmaceutical preparation for oral administration containing moxifloxacin or its salt and/or hydrate, at least one dry binder

The invention relates to pharmacology

The invention relates to the pharmaceutical industry and relates to a mixture of primary fatty acids derived from sugar-cane wax
The invention relates to index chewing candy free sugar

The invention relates to pharmacology, and relates to pharmaceutical drug omeprazole
The invention relates to medicine, namely relates to a method of obtaining vitamin complex pills

The invention relates to novel oral pharmaceutical dosage forms, containing a proton pump inhibitor, that is an inhibitor of H+, K+-ATPase

The invention relates to confectionery and pharmaceutical industries and for the production of candies containing biologically active additives

The invention relates to medicine, specifically to antifungal medicinal preparation containing as active ingredient a therapeutically effective amount of clotrimazole and targeted supplements, which are used lactose, starch, MCC, citric acid, salt of stearic acid
Up!