Sustained release tablet formulations comprising clarithromycin
WO 2001049246 A2

This invention covers the sustained release tablets that contains hydroxypropylmethylcellulose as matrix material and clarithromycin as active component. Clarithromycin is released from sustained release tablet having a rate expressed through the equation Mt/M =ktn. Within this equation n may be the exponent from the release kinetics and n value determines the kind of release mechanism. When n value is between .89 to at least one, release rate matches zero-order kinetic which is independent from time.

Патентная формула (13)

1. Sustained release clarithromycin tablets characterised for the reason that it has hydroxyalkylcellulose like a hydrophilic matrix material, pharmaceutically recognized excipients and lubricants.

2. Sustained release clarithromycin tablets based on claim 1 characterised for the reason that the discharge in the tablet for a price expressed as Mt/Moo = k t n where n may be the exponent from the release kinetics.

3. Sustained release clarithromycin tablets based on claims 1 and a pair of characterised for the reason that n is all about .89 to at least one.00 these types of this criteria the discharge mechanism is led to zero-order release kinetics.

4. Sustained release clarithromycin tablets based on claims 1 ,2 and three, characterised for the reason that a minimum of 60 % clarithromycin is released in 14 hrs.

5. Sustained release clarithromycin tablets based on claims 1 ,2,3 and 4 characterised for the reason that maximum 65 % clarithromycin is released as much as 8 hrs.

6. Sustained release clarithromycin tablets based on claims 1 ,2,3,4 and 5 characterised for the reason that the discharge of clarithromycin in the tablet as much as 12 hrs with zero-order kinetic.

7. Sustained release clarithromycin tablet based on claims 1 ,2,3,4,5 and 6 characterised for the reason that the hydroxyalkylcellulose polymers are hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose and mixtures of those polymers.

8. Sustained release clarithromycin tablets based on claims 1 ,2,3,4,5,6 and seven characterised for the reason that weight percent of clarithromycin as a whole tablet weight is 25 to 90.

9. Sustained release clarithromycin tablets based on claims 1 ,2,3,4,5,6,7 and eight characterised for the reason that weight percent of hydroxyalkylcelluloses or their mixtures as a whole tablet weight is 3 to 40.

10. Sustained release clarithromycin tablets based on claims 1 ,2,3,4,5,6,7,8 and 9 characterised for the reason that citric acidity, lactose and microcrystalline cellulose are utilized as pharmaceutically recognized excipients.

11. Sustained release clarithromycin tablets based on claims 1 ,2,3,4,5,6,7,8,9 and 10 characterised for the reason that weight percent of lactose as a whole tablet weight is 5 to 50.

12. Sustained release clarithromycin tablets based on claims 1 ,2,3,4,5,6,7,8,9,10 and 11 characterised for the reason that weight percent of microcrystalline cellulose as a whole tablet weight is 5 to 50.

13. Sustained release clarithromycin tablet based on claims 1 ,2,3,4,5,6,7,8,9,10,11 and 12 characterised for the reason that the lubricants are talc, magnesium stearate, stearic acidity or mixtures of these.

SUSTAINED RELEASE TABLET FORMULATIONS COMPRISING

The current invention is worried having a sustained release pharmaceutical formulation that contains clarithromycin because the active component for dental administration.

Clarithromycin is really a semi-synthetic macrolid antibiotic. Chemically, it’s 6-O- methylerythromycin. The molecular formula of clarithromycin is C38 H69 NO3 and also the molecular weight is 747.96. J.P.Pat.No. 163,823/1985 signifies elevated bioavailability of 6-O-methylerythromycin with citric acidity.

Various sorts of sustained release dental dosage forms happen to be developed, but each one has some disadvantages which effect its appropriateness to particular drug and therapeutic objective. Hydrophilic polymers, especially celluloses, are very popular in managing the discharge rate of medication from solid dosage forms. Their easy compression, capability to accomodate considerable amounts from the drug, the minimum influence exerted through the processing variables around the release rate and comparatively inexpensive would be the primary causes of their advantages.

Hydroxypropylmethylcellulose (HPMC) is most broadly utilized in matrix tablets and other kinds of sustained-release dosage forms due to its characteristics, namely, non-toxic nature of polymer, its ability to incorporate ingredients, output of tablets by direct compression or wet granulation and pH independence.

An ideal way to lessen the fluctuation of plasma bloodstream levels would be to provide the drug inside a dosage form which leads to zero order absorption kinetics. Presuming the release rates are the speed-restricting step for drug arrival in the systemic circulation, the kinetics from the release process ought to be zero order.

Korsmeyer et. al. used an easy equation to explain drug release conduct from sustained release polymer matrices. Mt / Moo = k t or log Mt / Moo = log k + n log t Where Mt / Moo may be the fraction from the released drug, k represents a continuing incorporating structural and geometric characteristics from the release device, and n may be the diffusional exponent for that released drug. The need for n gives a sign from the release mechanism. When n value is between .89 and 1. the discharge rates are separate from time which is an appealing mechanism in dental sustained drug delivery systems (U.S. Pat. No. 5,945,125)

U.S. Pat. Nos. 4,601 ,894 and 4,657,757 have disclosed controlled-release matrix dosage forms that contains acetaminophen, dextrobrompheniramine maleate in one homogenous combination of of hydroxypropylmethylcellulose and ethers along with other cellulose and cellulose ether derivatives.

U.S.Pat.No.4,571 ,333 have disclosed using hydroxypropylmethylcellulose because the carrier base for sustained release pharmaceutical tablets. Within this study is forwarded to preparation of daily controlled release tablets incorporating naproxen or naproxen sodium and 4 to nine percent hydroxypropylmethylcellulose as a whole tablet weight.

Sustained release indapamide tablets happen to be made by using hydroxypropylmethylcellulose in U.S.Pat. No. 5,334,392. Within this study 50 % of the quantity of indapamide is released linearly in additional than eight hrs between your duration of 5 and 14 hrs. U.S. Pat. No. 5,705,190 have disclosed controlled-release dosage forms that contains drug and organic acidity in alginat formulation. Within this invention controlled release clarithromycin tablets happen to be made by using alginate.

The current invention is worried using the preparation of sustained release tablet formulations that contains clarithromycin for dental administration and discharge of active component in the tablet between and 12 hrs by zero-order kinetic.

DESCRIPTION From The Sketches

Fig. 1 Dissolution profiles of the immediate release clarithromycin tablet and SRC I and SRC II coded tablets prepared based on the example 1.

Fig. 2 Dissolution profiles of the immediate release clarithromycin tablet and SRC III coded tablets prepared based on the example 2. DESCRIPTION From The INVENTION

Methylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, carboxymethylcellulose and carboxyethylcellulose or mixtures of these or mixtures of those polymers with hydroxypropylmethylcellulose are utilized as swellable polymer within the sustained release dosage forms.

Particularly HPMC USP 2910 and USP 2208 polymers that are pointed out in USP are utilized extensively. Of these polymers Methocel K100M, Methocel E4M, E15M are created through the Dow jones Chemical Co. using these trade names. Here the designation ‘ describes USP 2910 and also the designation ‘K’ describes USP 2208 in which the amount designations make reference to the viscosity from the polymer inside a 2% aqueous solution (e.g. 4M designates a viscosity of 4000 cps) and average molecular weight (E4M has molecular weight of 86,000, E15M has molecular weight of 120,000, K100M has molecular weight of 246,000).

The sustained-release clarithromycin tablets (SRC I an SRC II) were prepared based on the formula succumbed Table 1. The dissolution profiles of those tablets were tested and evaluated by utilizing rotated paddle method succumbed USP test 711 in 900 mL pH 4 phosphate buffer at 37 °C and 50 revoltions per minute paddle rate. Table 1 displays the most well-liked levels of ingredients is going to be employed for a sustained release clarithromycin tablet that is coded in this invention.

Table. Unit Formula from the SRC I and SRC II Tablets

Composition Unit formula Unit formula SRC I SRC II

Clarithromycin 500 500

Citric acidity 130 130

Hydroxypropylmethylcellulose * 70 80

Lactose 150 220

Stearic acidity 20 20

Magnesium stearate 10 10

* Any high-viscosity hydroxypropylmethylcellulose can be used, preferably getting a viscosity between 1 ,000 and 20,000 cps. Within this example the main one getting a viscosity 15,000 cps was utilized.

Preparation from the Tablet:

1. Clarithromycin, lactose, citric acidity and hydroxypropylmethylcellulose are blended inside a appropriate blending equipment. 2. The blended material acquired in stage 1 is granulated by utilizing purified water.

The granulated mass is undergone a suitable screen.

3. The granulated materials are dried until getting moisture content of under 4% by utilizing moisture balance.

4. The dried granulated materials are undergone screen getting appropriate apertures.

5. The blended material acquired in stage 4 is lubricated by utilizing talc, stearic acidity and magnesium stearate.

6. The blended materials are tabletted by utilizing appropriate tablet machine.

The sustained-release clarithromycin tablets (SRC III) were prepared based on the formula succumbed Table 2. The dissolution profiles of those tablets were evaluated as described in Example 1. Table 2 displays the most well-liked levels of ingredients is going to be employed for a sustained release clarithromycin tablet that is coded in this invention.

Unit Formula from the SRC III Tablets

Composition Unit formula

Citric acidity 130

Microcrystalline cellulose 120

Stearic acidity 20

Magnesium stearate 10

* Any high-viscosity hydroxypropylmethylcellulose can be used, preferably getting a viscosity between 1 ,000 and 20,000 cps. Within this example the main one getting a viscosity 15,000 cps was utilized.

Preparation from the Tablet:

Clarithromycin, Microcrystalline cellulose, citric acidity and hydroxypropylmethyl cellulose are blended inside a appropriate blending equipment. Starting with the 2nd stage, production method is equivalent to using the method succumbed Example 1.

Sustained release clarithromycin tablets coded in this invention could be created by others with a few additions or changes to achieve exactly the same leads to different mixing ratios, If however these additions or changes are associated using the components and knowledges of the description, they’re evaluated within the content of the invention as varied applying this invention.