BG65116B1 - Medicamentous form with controlled release of poorly soluble basic medicamentous forms - Google Patents

Abstract

The solid pharmaceutical composition with controlled release is designed for peroral administration at reduced daily doses. The therapeutical ingredient is a poorly soluble basic medicamentous form. The medicamentous form contains water soluble alginate salt, complex salt of the alginic acid and organic carboxylic acid mixed with the therapeutical medicament. In particular an option of the invention containes a batched form of claritomycin for single daily administration.

Description

Technical field

The invention relates to a slow-release, single-release formulation of at least one readily soluble basic drug adapted for oral administration useful for reducing the daily dosage regimen. In particular, the invention relates to a dosage form for the administration of clarithromycin once daily in a daily dose.

BACKGROUND OF THE INVENTION

The advent of slow-release controlled-release single-dose forms has provided benefits to the pharmaceutical industry. Controlled-release dosage forms have provided the opportunity to reduce dosage regimens for medicines, especially for those for oral administration, in incoming patients.

The benefits of reduced dosage regimens in incoming patients are convenience, and more importantly, a better guarantee of consent. For example, reducing the dosage regimen from four times a day (q. I. D.) To three times a day (t. I. D.) Allows the patient to take the prescribed drug within hours of waking. Reducing the dosing regimen twice daily (b.i.d.) allows the patient to take the prescribed medication in the morning and evening, which provides greater convenience; for example, the patient does not have to take it extra when outside their home. Of course, the most convenient dosage form is the once-a-day dosing regimen. Unfortunately, the pharmacokinetic properties (e.g., absorption, elimination, and metabolism) of most drugs do not allow them to be facilitated in a single dosage form for oral administration and to provide controlled effective release of the drug for a prolonged period. for a period of 24 hours, with reproducible bioavailability.

One method of perfecting slow-release solid formulations was the development of compositions containing an alginic acid salt. Characteristically, water-soluble alginate, such as sodium alginate and calcium ions in the form of a calcium salt, interact to form a crosslinking in the alginate, making it an insoluble calcium alginate gel. After the addition of strong acid to the mixture of sodium alginate and the calcium salt, the calcium salt is slowly ionized to give calcium ions. The calcium ions are then reacted with the soluble alginate to give an insoluble calcium alginate gel. The gel formation process undergoes a gradual ionization of the calcium salt. In such dosage forms, the properties of the alginate gel for controlled release are altered by varying the molecular weight of the alginate, the concentration of the alginate, the type of the polyvalent cation as a cross-linking agent, or the concentration of the capillon.

EP 188040-B1 and its Compliance US 4,842,866 describe an improved type of gelatin-type alginate composition that is poorly soluble in body fluids, such as those of the gastrointestinal tract ("GI") containing a therapeutically effective amount of at least one active therapeutic agent, which is gradually released as alginate hydrates, characterized in that the composition contains both - and water-soluble alginate, in particular sodium alginate, and a complex salt of alginic acid, in particular sodium-calcium alginate , and mastic one cation that gives soluble alginate salt on its own, and another cation that independently produces insoluble alginate salt. The description of the corresponding US part, US 4,842,866, is included in its entirety for reference.

However, the use of the technology developed in the patents described above is not applicable to poorly water-soluble drugs. For example, in vitro studies of alginate drug release for clarithromycin administration have been found to be very slow. Similarly, in erythromycin, in vivo animal studies have shown that it is not possible to use alginates or any other monolithic hydrogel tablets in reproducible bioavailable controlled release formulations. This concludes that macrolides, such as erythromycin, in a conventional monolithic hydrogel tablet, do not produce a suitable controlled release dosage form due to problems arising from acid instability, poor drug solubility, and variable GI transition.

An oral drug containing 6-O-methylerythromycin A and citric acid with improved bioavailability is reported in Japanese Kokai 163823/1985, as abstracted in WPI Acc. No. 85-247033 / 40.

It is an object of the present invention to reduce the daily dosage regimen of a basic drug with poor solubility in water by means of a controlled release dosage form.

The present invention solves the problems of slow separation and the potentially weak or variable absorption of basic drugs with poor solubility by combining organic acid and the drug in an alginate dosage form.

SUMMARY OF THE INVENTION

The present invention provides a reduced daily dosage of poorly soluble basic drugs by the use of alginate to include organic acid. The solubility of the major drugs decreases when they pass to the large intestine (pH 8.0), until they are soluble in the stomach, and the upper or near part of the small intestine. In this way, basic drugs with poor solubility lead to a smaller drug that is able to be absorbed in the inferior or distal bowel. The inclusion of organic acid in the dosage form solves this problem. Insofar as it is not related to any specific theory, it is believed that the organic acid dosage form creates a low pH microenvironment that increases the solubility of the drug in the dosage form as it moves into the GI (gastrointestinal) tract.

Accordingly, the present invention includes a solid, controlled release pharmaceutical composition suitable for oral administration comprising a therapeutically effective amount of at least one drug, a water-soluble alginate salt and a complex alginic acid salt, characterized in that it contains:

a therapeutically effective amount of at least one drug, consisting of a basic drug, with a water solubility of less than 1 part to 30 parts water, selected from the group consisting of macrolide, sulfamethoxazole, metronidazole, simetidine, indapamide, atenolol and diazepam and an effective amount of an organic carboxylic acid selected from the group consisting of malic, tartaric, succinic, glutaric, maleic, almond and citric acid to facilitate dissolution of the parent drug.

A specific aspect of the present invention is the preparation of a single dosage unit for daily administration of clarithromycin, which is usually administered twice daily in the form of 250 mg or 500 mg tablets, depending on the type of bacterial infection required. to be treated. The exact site of absorption of clarithromycin in vivo is unclear. However, clarithromycin is known to be very soluble in the stomach (pH 1.2) and quite soluble in the upper area of the small intestine (pH 5.0), where absorption is most likely to occur. As the solubility of the drug decreases in the lower part of the intestine (pH 6 to 8), this results in a smaller drug that is able to be absorbed. The present invention provides a way of solving this problem by using an alginate dosage form for administration with an organic, in particular, for example, citric acid.

Accordingly, a second aspect of the present invention is a controlled release solid pharmaceutical composition suitable for oral administration in a single daily dosage regimen comprising:

500 mg clarithromycin;

from 75 to 400 mg of sodium alginate;

from 10 to 400 mg of sodium-calcium alginate and

128 mg citric acid.

Detailed description of preferred embodiments of the invention

It is an object of the present invention to provide a controlled release pharmaceutical composition in which a poorly soluble basic drug can be continuously withdrawn from the dosage form as it passes through the GI (gastrointestinal) tract.

Thus, the present invention provides a regimen of once daily dosing of at least one poorly soluble parent drug by administering a solid, controlled-release pharmaceutical composition suitable for oral administration to patients in need of such treatment. The preferred composition is in the form of tablets.

A poorly soluble or slowly water soluble basic drug is a drug that has a solubility of less than 1 part in 30 parts water. The present invention can also be applied to even less soluble drugs, for example, to a solubility of 1 part per 10,000 parts water.

Thus, for example, slowly soluble drugs can be: sulfamthoxazole with a solubility of 1 in 3,400 (parts of water); tetracycline, 1 in 2,500; metronidazole and cimetidine (histamine H2 receptor antagonist for ulcer treatment), both from about 1 in 100 to about 1 in 1,000; indapamide (antihypertensive / diuretic), 1 in 100; diazepam (tranquilizer), ranging from 1 in 1,00 to 1 in 10,000.

As a preferred basic drug, the present invention includes macrolides, which are also poorly soluble. Examples of macrolides are erythromycin, with a solubility of one part per 1,000 parts of water; dirithromycin, having similar solubility properties as erythromycin; ozamycin, midamycin, kitazamycin, all three are very slightly soluble in water, in the range of about 1 in 1,000 to 1 in 10,000; and tylosin, which is used for veterinary purposes only, and with a solubility in the range of about 1 in 100 to 1 in 1000. Other macrolides that may be included are, for example, roxithromycin, roquitamycin, oleandomycin, myocamycin, flurithromycin, rosaramycin, acitromycin and compounds designated ABT-229 or ABT269. The most preferred macrolide of the present invention is clarithromycin having a solubility of about one part per 1000 parts water.

The pharmaceutical composition of the present invention may include other drugs in combination with the poorly soluble parent drug when it is known that combination therapy is known or is advantageous.

For example, erythromycin or clarithromycin macrolides can be formulated for use in combination with standard gastritis, ulcer, or gastroesophageal disease (GERD) compositions, such as compositions containing ulcerative or anti-gastric drugs; for example, those selected from the group consisting of compounds that inhibit gastro-secretion, such as omeprazole, cimetidine, ranitidine, lansoprazole, pantoprazole, sucralfate, famotidine, or nizatidine, or antacids, such as magnesium hydroxide, aluminum hydroxide, aluminum hydroxide, sodium bicarbonate, cimeticone, or aluminum-magnesium hydroxide, or hydrates thereof (such as the monohydrate known as magaldrate).

Pharmaceutical compositions of the present invention with other macrolides, in particular erythromycin or clarithromycin, may be suitable for use in combination with compositions containing bismuth salts, such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subcarbonate, .

The amount of drug or drugs in the pharmaceutical composition may vary from 40 to 75% of the total composition or tablet. For clarithromycin, the amount may preferably vary over 50% and up to 75% by weight of the total composition or tablet.

The rate of release of the drug for administration was controlled using a matrix based on a water-soluble alginate salt and a complex salt of alginic acid.

Because sodium alginate is normally used in the practice of the present invention, the sodium cation may be replaced by another cation; for example, potassium or other alkali metal, magnesium, or ammonium cation yields a soluble alginate salt. For example, the alginate could also be potassium alginate or ammonium alginate.

The alginic acid complex salt is a sodium-calcium complex alginic acid salt in which the amount of calcium is precisely controlled and which itself forms a gel without having to interact with gastric juice or with additional calcium ions. Because sodium-calcium alginate is normally used in the practice of the present invention, the sodium cation may be replaced by another cation, which results in the formation of a soluble alginate salt; for example, potassium or other alkali metal, magnesium, or ammonium cation, and the calcium cation may also be replaced by another polyvalent cation (except for magnesium) which results in the insoluble alginate salt; for example, strontium, iron, or barium. The most preferred compositions described herein typically include sodium alginate, for example those obtained and marketed by Alginate Indutries, Ltd., England, under the trademark "Manucol" and sodium-calcium alginate, obtained and marketed by Kelco Divivsion of Merck and Co., Ins., San Diego, California, US A., under the trademark “Kelset”.

The weight ratio of the soluble alginate salt to the alginic acid complex salt can range from about 16: 1 to 1: 1, preferably from about 8: 1 to 2: 1. Of course, the same ratio applies to the ratio of sodium alginate to sodium calcium alginate. The combination of soluble alginate and complex salt for the preparation of insoluble salt is described in the prior art EP 18840 as mentioned above to provide a controlled release dosage form.

The organic acid required for the controlled release dosage form according to the present invention is an amount of acid that is effective in creating a low pH microenvironment of less than 7.0 adjacent to the hydrating dosage form. Given the differences, an effective amount of organic acid is the amount that facilitates dissolution of the parent drug as it passes through the GI (gastrointestinal) tract. The exact amount may vary depending on the acid used and the choice of the parent drug, as is known to those skilled in the art. The ratio is a molar ratio and can range from about 0.2: 1 to 5: 1 acid to drug. Preferably, a molar ratio of about 1: 1 acid to drug is used.

The organic acid for the purposes of the present invention includes any organic carboxylic acid, preferably an aliphatic organic carboxylic acid having anywhere from C3-C20 carbon atoms. For example, tartaric acid, malic acid, succinic acid, glutaric acid, maleic acid, amygdalic acid and citric acid are preferred. The most preferred acid is citric acid.

A more particular and preferred embodiment according to the present invention is a controlled release solid pharmaceutical composition adapted for oral administration in a once daily dosage regimen comprising:

500 mg clarithromycin;

from 75 to 400 mg of sodium alginate;

from 10 to 400 mg of sodium-calcium alginate, and

128 mg citric acid.

Preferably, the composition contains from about 80 to 200 mg of sodium alginate and from about 10 to 40 mg of sodium-calcium alginate. Most preferably, the composition contains about 120 mg of sodium alginate and about 15 mg of sodium-calcium alginate.

Also, the composition is in the form of tablets, but may also be in the form of capsules or pellets / granules.

Other constituents commonly used in the composition of the invention may include pharmaceutically acceptable excipients such as preservatives, diluents; for example, starch or microcellulose; adhesives such as starch, polyvinyl pyrrolidone (povidone) and sodium carboxymethylcellulose; lubricants such as talc and magnesium stearate; bulking agents such as lactose; and suitable coloring agents, single dosage forms may also have a coating of products not specifically designed to control or modify drug release.

The composition can be processed in the form of tablets, suppositories, or used for capsule filling. The composition may also have a coating where necessary, for example, to mask an otherwise bitter-tasting composition.

As an example of the present invention, in bioavailability studies of a representative dosage form for administration according to the present invention containing clarithromycin, 500 mg, it was found to meet the criterion of a successful single dose daily dosage form. This means that it fills an area under the AUC0-24 curve at least equivalent to a 250 mg twice daily dosing regimen (BID), and plasma clarithromycin concentrations at 24 h are similar to the 250 mg BID dosing regimen.

Examples of carrying out the invention

Example 1. Preparation of controlled release tablets 1a. Granulation

All dosage forms for use as tablets use the following general method of preparation. The active drug, polymer, adhesive and other fillers are screened through a 850 micrometer sieve to remove all large agglomerates. The sieved product was then adhered to dryness using a planetary mixer kit at the lowest speed for 5 min. The glued product is granulated by the addition of 50/50 vol./vol. a solution of alcohol and water in small quantities until an appropriately granulated mass is obtained. The wet mass is passed through a 4.0 mm mesh screen onto paper-coated plates and dried in hot air at 50 ° C until the moisture content of the granules is less than 4% w / w (determined using a balance Sartorius IR Model: YTC01L (Conditions: 98 ° C for 15 min). Finally, the dried granules were passed through a 850 micrometer sieve and soldered with a tablet lubricant for 5 min using a planetary mixer kit at the lowest speed.

lb. Pressing

The tablets are compressed using a rotary drum unit provided with oval openings. The individual dosage forms for Annexes A, B and C are compressed into tablets of reduced strength, yielding tablets of appropriate thickness and brittleness. The compositions of the tablets are given in Table 1.

Table 1

AekapcmBe A Application Form: _____

Ingredients mg / nozzles _______________ fly

Claritro- 500 mg / tab-mg / tablet _____ flyer

500 500 Mycin

Citric acid anhydrous USP 128 128 128 Sodium alginate SO 120 180 Sodium-calcium alginate 10 15 22.5 Lactose 300 mesh 100 100 100 Povidone K (29 * 30) 30 30 30 Talc, purified, powdered 30 30 30 Stearic acid 21 21 21 Magnesium stearate 10 10 10

~ Example 2: Bioavailability study 2a. Products and Application The study compares the plasma concentration profiles of the three dosage forms for Annexes A, B, and C given above with single dose 500 mg daily dose (QD) regimen with twice daily dose regimen , of commercially available 250 mg BIAXIN® tablets as a control (i.e., 250 mg BID, refer to dosage form for application D herein) at steady state. The criteria for a successful QD dosage form are:

- AUC0-24 at least equivalent to a 250 mg twice daily dose (BID) regimen.

- Plasma concentrations of clarithromycin at 24 hours are equivalent to a twice daily dose of 250 mg BID.

2b. Study description and results

The study was conducted as a phase 1, multi-dose, open-label, random, four-period, balanced cross-over study. Suitable patients with a competitive medical history, physical examination and laboratory profile including haematological analysis, and parameters of the kidney and liver are selected.

Eight healthy male volunteers between the ages of 18-50 years received the dose in the morning on days 1, 2 and 3 in each of the four study periods. The dosage form for application D (BIAXIN® clarithromycin 250 mg) was also taken in the evening on days 1,2 and 3 in each of the four study periods. Each individual is given all dosage forms to complete the study.

Blood samples were collected before dosing on day 3 (0 h) and on 1, 2, 3, 4, 6, 8, 10,12,16 and 24 hectare ice dose. All samples were transferred to heparinized collection tubes and centrifuged. The separated plasma is divided into equal volumes and transferred to appropriately labeled tubes and frozen immediately. Plasma samples are stored frozen for the duration of the assay. 10

Plasma samples are examined using large plates for bioassay. This method measures the total antibiotic activity, the results are expressed as clarithromycin, mcg / ml. 15

2s. Data and statistical analysis

The bioequivalence of the three single dose daily dosage forms with standard tablets was examined by two single-profile t-test procedures. 90% confidence intervals are calculated from the analysis of the natural logs of AUC, Cmax and the concentration at 24 h. They are obtained by exposing the end points of the 90% confidence intervals for the difference in the mean logs. The bioequivalence between the dosage forms is deduced if their limits lie within 6 ranges from 0.80 to 1.25. In addition, 90% confidence intervals for mean ratios were obtained from a study of unchanged AUC and concentration at 24 h. The results of these studies are summarized in Tables 3,4 and 5. Pharmacokinetic data are shown in Table 2.

Table 2: pharmacokinetic data

Parameter formula D (250 mg BID) formula A formula C formula C AUCo-24 mcg.h / ml (range) 32.16 * (25,66-42,70) 31,44 (21,16-38,50) 32,32 (24,65-0,78) 28,69 (24,65-2,74) Cmax mcg./ml (range) 2.28 (1,49-3,34) 2.42 (1,53-3,26) 2.41 (1.81-3.07) 2.00 (1,62-2,40) Ooh Hours 2 (1-4) 6 (3-8) 6 (3-8) 6 (4-10) Concentration mcg./ml at 24 hr (range) 0.72 (0.53-1.05) 0.57 (0,33-0,91) 0.65 (0,30-0,87) 0.66 (0,37-0,91)

As the plasma sample program has not been fully observed for the second standard tablet, the AUC0-24 value is calculated by multiplying the AUC0-24 value by 2.

Table 3: Results of the AUC statistical survey

formula AUCo-24 mcg.h / ml Relative bioavailability (90% trust, interval Unchanged data Ln changed data A 31,44 0.98 (0.86-1.10) 0.98 (0.84-1.14) IN 32,32 1.01 (0.88-1.14) 1.01 (0.88-1.16) P 28,69 0.89 (0.80-0.98) 0.90 (0.80-1.02)

Table 4: Results of the statistical survey With _tach

formula I found mcg / ml Relative bioavailability (90% confidence interval Unchanged data Ln changed data A 2.42 1.06 (0.86-1.26) 1.07 (0.87-1.32) IN 2.41 1.06 (0.86-1.26) 1.08 (0.90-1.31) P 2.00 0.88 (0.75-1.01) 0.90 (0.76-1.06)

Table 5: Results of a statistical study of the concentration at 24 hours

formula Stach mcg / ml Relative bioavailability (90% confidence interval Unchanged data Ln changed data A 0.57 0.79 (0.62-0.99) 0.79 (0.63-0.99) IN 0.65 0.90 (0.79-1.01) 0.89 (0.68-1.15) P 0.66 0.92 (0.76-1.08) 0.90 (0.71-1.15)

2d. Discussion

The mean AUC ratio at 90% confidence intervals indicates that the dosage forms for administration A, B, and C are bioequivalent to the standard dosing regimen. All three dosage forms show therapeutic levels at 24 hours. Cmax limits (unchanged) are acceptable for most dosage forms. All three single-dose daily dosage forms demonstrate absorption of clarithromycin when compared to a standard dosage form.

The dosage forms for Annexes A and B, although containing different amounts of alginates, produce similar profiles in vivo. However, preliminary studies show that the reproducibility of excretion profiles improves with increasing amount of alginate. Therefore, the dosage form for administration in the best results.

The foregoing description, examples and data provide a complete description of the preparation and use of the composition according to the invention. Because many embodiments of the invention can be made without departing from the spirit and description of the invention, the invention lies in the claims appended hereto.

Claims (16)

Claims A solid, controlled release pharmaceutical composition suitable for oral administration comprising a therapeutically effective amount of at least one drug, a water-soluble alginate salt and an alginic acid complex salt comprising - a therapeutically effective amount of at least one drug consisting of a basic drug with a water solubility of less than 1 part by 30 parts water selected from the group consisting of macrolide, sulfamethoxazole, metronidazole, simethidine , indapamide, atenolol and diazepam and - an effective amount of an organic carboxylic acid selected from the group consisting of malic, tartaric, succinic, glutaric, maleic, almond and citric acid to facilitate the dissolution of the parent drug. Composition according to claim 1, characterized in that it is in the form of tablets. Composition according to claim 1, characterized in that it is in the form of a single dose for a single daily dosage regimen. Composition according to claim 1, characterized in that the macrolide is clarithromycin. 5. The composition of claim 1, wherein the water-soluble alginate salt is sodium alginate. Composition according to claim 1, characterized in that the alginic acid complex salt is sodium-calcium alginate. Composition according to claim 1, characterized in that the organic carboxylic acid is citric acid. Composition according to claim 1, characterized in that the weight ratio of the soluble alginate salt to the alginic acid complex salt is approximately 16: 1 to 1: 1. Composition according to claim 8, characterized in that the weight ratio of sodium alginate to sodium-calcium alginate is approximately 16: 1 to 1: 1. Composition according to claim 9, characterized in that the weight ratio of sodium alginate to sodium-calcium alginate is approximately 8: 1 to 2: 1. Composition according to claim 1, characterized in that the molar ratio of the organic acid to the parent drug is approximately 0.2: 1 to 5: 1. A composition according to claim 1, characterized in that the molar ratio of the organic acid to the parent drug is approximately 1: 1. A composition according to claim 1, characterized in that the macrolide is selected from the group consisting of erythromycin, dirithromycin, azithromycin, roxithromycin and ABT229. 14. A controlled release pharmaceutical composition suitable for oral administration in a single daily dosage regimen comprising: 500 mg clarithromycin; from 75 to 400 mg of sodium-calcium alginate 5 and 128 mg citric acid. 15. Composition according to claim 14, characterized in that it contains: from 80 to 200 mg of sodium alginate and from 10 to 40 mg of sodium-calcium alginate. The composition according to claim 15, characterized in that it contains: 120 mg of sodium alginate and 15 mg of sodium-calcium alginate.