SK282427B6 - Solid pharmaceutical composition with controlled release - Google Patents

Abstract

Controlled-release, solid, pharmaceutical compositions adapted for oral administration comprises: (a) at least one basic drug with a water solubility of less than 1 part per 30 parts water; (b) a water-soluble alginate salt; (c) a complex salt of alginic acid; and (d) an organic carboxylic acid to facilitate dissolution of the basic drug. An Independent claim is also included for a controlled release solid pharmaceutical composition (I) adapted for oral administration of a once-a-day dosage regimen and comprising (in mg): clarithromycin (500), sodium-calcium alginate (75-400) and citric acid (128).

Description

Technical field

The invention relates to an oral slow release oral dosage form for at least one poorly soluble basic drug useful for reducing the daily dosage regimen. More specifically, the invention relates to a single daily dose formulation for clarithromycin.

BACKGROUND OF THE INVENTION

The discovery of controlled release dosage forms has been of benefit to the pharmaceutical industry. Controlled-release formulations have made it possible to reduce the dosage regimen of drugs, particularly those administered orally to outpatients.

The benefits of a reduced dosing regimen for outpatient patients are convenience and, more importantly, better assurance of compliance. For example, reducing the dosing regimen from four times a day to three times a day allows the patient to take the medicine while awake. Reducing the dosing regimen to twice a day allows the patient to take the medicine in the morning and evening, providing more comfort, e.g. the patient does not need to take the next dose of the medicine while away from home. Of course, once-daily dosing regimen is the most preferred form of use. Unfortunately, the pharmacokinetic properties (e.g., absorption, elimination and metabolism) of most drugs do not allow their easy preparation, even as a single oral dose, to achieve controlled effective drug release over a 24 hour period with reproducible bioavailability.

One way to improve controlled-release solid formulations is to develop formulations containing an alginate gel. Typically, a water-soluble alginate, such as e.g. sodium alginate and calcium ions in the form of a calcium salt react together to cross-link the alginate and convert it to an insoluble calcium alginate gel. By adding a strong acid to the mixture of sodium alginate and calcium salt, the calcium salt is slowly ionized to form sludge, ion ions. The calcium ions then react with the soluble alginate to form an insoluble calcium alginate gel. The gelling is continued by sequential ionization of the calcium salt. In these formulations, the controlled release properties of the alginate gel vary depending on the different molecular weight of the alginate, the alginate concentration, the type of polyvalent crosslinking cation, or the cation concentration.

European Patent 188040-B1 and U.S. Pat. U.S. Patent 4,842,866 discloses an improved gel type alginate composition that is slowly soluble in body fluids, such as the gastrointestinal ("GI") tract, comprising a therapeutically effective amount of at least one therapeutically active ingredient that is sustained released during hydration of the alginate, The composition according to claim 1, wherein the water-soluble alginate, in particular sodium alginate, and the complex salt of alginic acid, in particular calcium alginate, have one cation which itself provides a soluble alginate salt and another cation which itself provides an insoluble alginate salt. Description of the US Analog, U.S. Pat. No. 4,842,866, which is incorporated by reference in its entirety.

However, the use of the technology developed in the aforementioned patents was not applicable to poorly water-soluble drugs. For example, drug release in an in vitro study from an alginate formulation of clarithromycin has been shown to be too slow. Similarly, for erythromycin, in vivo animal studies have shown that reproducible bioavailable controlled release formulations were not possible using alginates or any other monolithic hydrogel tablets. It has been concluded that macrolides, such as erythromycin, in a simple monolithic hydrogel tablet will not form a suitable controlled release dosage form due to problems of acid instability, poor drug solubility and gastrointestinal (GI) tract variability.

An oral formulation comprising 6-O-methylerythromycin A and citric acid with improved bioavailability is disclosed in Japanese Kokai Patent Application No. 163823/1985, as disclosed in Abstract WPI Acc.No. 85-247033 / 40th

SUMMARY OF THE INVENTION

It is an object of the present invention to reduce the daily dosage regimen of a poorly soluble basic drug with a controlled release formulation. The present invention solves the problems of slow release and potentially poor or variable absorption of poorly soluble basic drugs by combining the organic acid and drug into an alginate formulation.

The present invention provides a reduced daily dosage of poorly soluble basic drugs by applying an alginate matrix with incorporation of an organic acid. The solubility of the basic drug decreases as it progresses distal to the colon (pH 8.0) and is soluble in the stomach and upper or proximal small intestine. This will result in a lower availability of the drug for absorption in the lower or distal part of the intestine with poorly soluble basic drug. The incorporation of organic acid into the formulation overcomes this problem. Without wishing to be bound by any particular theory, it is contemplated that the organic acid formulation creates a low pH microenvironment to increase the solubility of the drug in dosage form during its passage through the GI tract.

Accordingly, the present invention includes a solid controlled-release pharmaceutical composition adapted for oral administration comprising:

a therapeutically effective amount of at least one basic drug having a water solubility of less than 1 part to 30 parts water;

a water-soluble alginate salt; a complex salt of alginic acid; and an effective amount of an organic carboxylic acid to facilitate dissolution of the basic drug.

A particular aspect of the present invention is the preparation of a once daily dosing regimen for clarithromycin, which is currently administered twice daily as a 250 mg or 500 mg tablet depending on the type of bacterial infection being treated.

The exact site of clarithromycin absorption in vivo is unclear. However, it is known that clarithromycin is very soluble in the stomach (pH 1.2) and quite soluble in the upper small intestine (pH 5.0), where absorption is most likely to occur. Since the solubility of the drug decreases in the lower parts of the intestine (pH 6-8), this results in less drug being available for absorption. The present invention provides a method of solving this problem by using an alginate formulation with an organic acid, particularly, for example, citric acid.

According to a second aspect of the present invention, the solid controlled-release pharmaceutical composition is adapted for oral administration in a once-daily dosing regimen comprising:

about 500 mg clarithromycin;

from about 75 to 400 mg of sodium alginate;

from about 10 to 400 mg of sodium calcium alginate and about 128 mg of citric acid,

DETAILED DESCRIPTION OF A PREFERRED EMBODIMENT OF THE INVENTION

It is an object of the present invention to provide a controlled release pharmaceutical composition wherein the poorly soluble basic drug can be continuously released from the dosage form during transit through the GI tract.

Thus, the present invention provides a single daily dosage regimen for at least one poorly soluble drug by administering a solid controlled release pharmaceutical composition adapted for oral administration to a patient in need thereof. The preferred composition is in tablet form.

A poorly soluble or poorly water-soluble basic drug is a drug having a solubility of less than 1 part in 30 parts of water. The present invention is also applicable even to less soluble drugs, for example to a solubility of 1 part in 10,000 parts water.

By way of example, poorly soluble basic drugs may include antibiotics such as sulfamethoxazole with a solubility of 1 in 3,400 (parts water); tetracycline, 1 in 2500; metronidazole and cimetidine (a histamine H2 receptor antagonist for the treatment of ulcers), both about 1 in 100 to 1 in 1000; indapamide (antihypertensive / diuretic), 1 in more than 10,000; atenolol (antihypertensive), about 1 in 30 to 1 in 100; diazepam (tranquilizer), ranging from 1 in 1000 to 1 in 10,000.

As a preferred basic medicament, the present invention includes macrolides which are also poorly soluble. Examples of macrolides are erythromycin with a solubility of 1 part in 1000 parts of water; dirithromycin, with similar solubility properties to erythromycin, josamycin, midecamycin, kitasamycin, all three very sparingly soluble in water, ranging from about 1 in 1,000 to 1 in 10,000; and tylosin, which is used for veterinary purposes only and has a solubility ranging from about 1 in 100 to 1 in 1000. Other macrolides that may be included are, for example, roxithromycin, rocitamycin, oleandomycin, miocamycin, flurithromycin, rosaramicin, azithromycin, and azithromycin. compounds designated ABT-229 or ABT-269. The most preferred macrolide for the present invention is clarithromycin with a solubility of about 1 part in 1000 parts water.

The pharmaceutical composition of the present invention may comprise other drugs in combination with a sparingly soluble basic drug wherever a known combination of therapy is desired or beneficial.

Thus, for example, for macrolides, erythromycin or clarithromycin may be formulated, in combination with a standard treatment for gastritis, ulcers or gastroesophageal reflux disease (GERD), such as those containing antiulcerous and antigastritic drugs; for example, selected from compounds inhibiting gastric secretion such as omeprazole, cimetidine, ranitidine, lanzoprazole, pantoprazole, sucralfate, famotidine or nizatidine, or an antacid such as magnesium hydroxide, aluminum hydroxide, sodium carbonate, sodium bicarbonate, simethicone or magnesium hydroxide monohydrate (magnesium hydroxide) known as magaldrate).

In another macrolide, particularly erythromycin or clarithromycin, the pharmaceutical composition of the present invention may be adapted for administration in combination with a composition comprising bismuth salts such as bismuth subcitrate, bismuth subalicylate, bismuth subcarbonate, bismuth subnitrate, and bismuth subnitrate.

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

The release rate of the formulation is controlled using a matrix based on a water-soluble alginate salt and a complex salt of alginic acid.

While sodium alginate is commonly used in the practice of this invention, the sodium cation may be replaced by another cation; e.g. potassium or other alkali metal, magnesium or ammonium cation to obtain a soluble alginate salt. Thus, the alginate may also be, for example, potassium or ammonium alginate.

The alginic acid complex salt is a soda-calcium alginic acid complex salt in which the amount of calcium is precisely controlled and which is self-gelling without the need to react with stomach acid or other calcium ions. Although sodium-calcium alginate is commonly used in the practice of this invention, the sodium cation may be replaced by another cation that provides a soluble alginate salt; e.g. potassium or other alkali metal, magnesium or ammonium cation and the calcium cation may also be replaced by another polyvalent cation (except magnesium) which forms an insoluble alginate salt; e.g. strontium, iron or barium. Most preferred formulations described herein typically comprise sodium alginate, such as that manufactured and sold by Alginate Industries, Ltd., England under the trademark "Manucol", and sodium calcium alginate, manufactured and sold by Kelco of Merck and Co., Inc., San Diego, Califomia, USA, under the trademark "Kelse ¹ .

The weight ratio of the soluble alginate salt to the alginic acid complex salt may vary from about 16: 1 to 1: 1, preferably from about 8: 1 to 2: 1. The same ratio of course applies to the ratio of sodium alginate to sodium calcium alginate. The combination of soluble alginate and complex salt to form an insoluble salt has been described in the specification of European Patent 188040 as mentioned to provide controlled release formulations.

The organic acid required for the controlled release formulation of the present invention is the amount of acid effective to produce a low pH microenvironment, less than 7.0, in close proximity to the hydrated dosage form. In another aspect, an effective amount of an organic acid is an amount that facilitates the dissolution of the basic drug in the GI tract. The exact amount may vary depending on the acid used and the choice of basic drug, as known to those skilled in the art. The ratio is the molar ratio and can vary from about 0.2: 1 to 5: 1 acid to drug. Preferably the molar ratio of acid to drug is 1: 1.

The organic acid for the purposes of the present invention includes any organic carboxylic acid, preferably an aliphatic organic carboxylic acid having anywhere between C ₃ -C ₂ carbon atoms. For example, tartaric, malic, succinic, glutaric, glutamic, maleic, mandelic and citric acids are preferred. Most preferred is citric acid.

A particular and preferred embodiment of the present invention is a solid controlled-release pharmaceutical composition adapted for oral administration in a single daily dosage regimen comprising:

about 500 mg clarithromycin;

from about 75 to 400 mg of sodium alginate;

from about 10 to 400 mg of sodium calcium alginate and about 128 mg of citric acid.

Preferably, the composition comprises from about 80 to 200 mg of sodium alginate and from about 10 to 40 mg of sodium calcium alginate.

Most preferably, the composition comprises about 120 mg sodium alginate and about 15 mg sodium calcium alginate.

The composition is also preferred in the form of a tablet, but may also be in the form of a capsule or in pellet / granular form.

Other ingredients commonly used in the preparation of the composition of the invention may include pharmaceutically acceptable excipients such as preservatives, solvents; e.g. starch or microcrystalline cellulose; binders such as starch, polyvinyl pyrrolidone (povidone) and sodium carboxymethylcellulose; glidants or lubricants such as talc and magnesium stearate; bulking agents such as lactose; and approved dyes. The dosage form may also be coated with agents not specifically designed to control or modify the release of the drug.

The formulation may be formulated into tablets, suppositories, or used as a capsule fill. The composition may also be coated as desired, for example, to cover an otherwise hot-tasting composition.

According to an example of the present invention, bioavailability studies on a representative formulation of the present invention containing clarithromycin, 500 mg, formulations met the acceptance criteria for a successful single dose once daily dosage formulation. This means that they have reached the area under the AUC ₀ curve. ₂ 4, at least equal to the dosing scheme of 250 mg twice daily (BID), and clarithromycin plasma concentrations at 24 hours were similar to the dose of 250 mg twice daily (BID).

DETAILED DESCRIPTION OF THE INVENTION

Example 1: Tablet production details. (A) Controlled release granulation

All tablet formulations used the following general manufacturing process. The active drug, polymer, binder and other excipients were sieved through a 850 µm sieve to remove any larger agglomerates. The screened material was then dry blended using a planetary mixer at the lowest speed for 5 minutes. The blended material was granulated by adding a 50/50 (v / v) solution of alcohol and water in small amounts until a suitable granulated mass was obtained. The wet mass was passed through a 4.0 mm orifice screen lined with paper and was dried in a hot air dryer at 50 ° C until the granules contained less than weight% moisture (determined using Sartoriuos IR balance. Model: YTC01L. Conditions: 98 ° C during 15 minutes). Finally, the dried granules were passed through a 850 µm mesh screen and blended with the tablet lubricant for minutes using a planetary mixer at the lowest speed.

.b) Compression

The tablets were compressed using a rotary tabletting machine equipped with ovaloid punches. The individual formulations A, B and C were compressed into tablets by a compression force which produced tablets of suitable thickness and friability. The composition of the tablets is given in Table 1.

Table 1

statement A B C Ingredients mg / tabl Me / table »» / T «bl Klari tromycin 500 500 500 Anhydrous citric acid USP 128 128 128 Sodium alginal 80 120 180 Sodium-calcium alginate 10 15 22.5 Lactose 300 mesh 100 100 100 Povidone K (29-33) 30 30 30 Talc, purified, powder 30 30 30 Stearic acid 21 21 21 Magnesium stearate 10 10 10

Example 2: Bioavailability study

2.a) Materials and supplies

The study compared the plasma concentration profiles of the three 500 mg single daily dose (QD) formulations A, B and C - mentioned, with the commercially available BIAXIN (R) 250 mg tablet with a twice daily dosing regimen as a control (ie 250 mg BID, referred to herein as D) at equilibrium. The input criteria for a successful QD formulation were:

- AUC ₀ . ₂₄ at least equivalent to a 250 mg twice daily (BID) dosing regimen,

- plasma concentrations of clarithromycin at 24 hours equivalent to a 250 mg BID dosing regimen.

2.b) Study design and results

The study was conducted as a Phase I, multi-dose, open-label, randomized, four-period study with balanced crossover. Patients with a complete history, physical examination and laboratory profile were selected, including haematological, renal and hepatic parameters.

Eight healthy male volunteers aged 18-50 received doses in the morning on Days 1, 2, and 3 for each of the four study periods. Formulation D (BIAXIN® clarithromycin 250 mg) was also dosed in the evening on days 1, 2, and 3 in each study period. Each subject received all formulations by the completion of the study.

Blood samples were taken prior to dosing at day 3 (hour 0) and 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours after dosing. All samples were transferred to heparinized tubes and centrifuged. The separated plasma was made up to equal volumes and transferred to suitably labeled tubes and frozen immediately. Plasma samples were stored frozen until analysis.

Plasma samples were analyzed using a large plate bioassay. This method measured total antibiotic activity and the results were expressed in clarithromycin in pg / ml.

2.c) Data and statistical analysis

The bioequivalence of three once daily formulations with standard tablets was determined by two unilateral t-tests. 90% confidence intervals were calculated from natural log analysis

SK 282427 Β6

AUC, and 24-hour concentrations. These were achieved by exposing the endpoints to 90% confidence intervals as opposed to the mean logarithms. Bioequivalence between formulations is when these limits lie in the range of 0.80 to 1.25. In addition, 90% confidence intervals for mean ratios were obtained from analyzes of untransformed AUC and 24-hour concentrations. The results of this analysis are summarized in Tables 3, 4 and 5. Pharmacokinetic data are shown in Table 2.

Table 2: Pharmacokinetic data

parameter Formula D (250mg BID) Formula A Formula B Formula C AUC ". _M (range) 32.16 · (25.66-42.70) 31.44 (21.16-38.50) 32 32 (24,65-40.78) 28.69 (24.61-32.74) C> pg / ml (ronili) 2.28 (1.49-3.34) 2.42 (1.53-3.26) 2.41 (1.81-3.07) 2.00 (1.62-2.40) T ". h. (range) 2 (1-4) 6 (4 «) 6 (3-8) 6 (5-10) Concentration pg / ml in 24b (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)

since the plasma sampling schedule does not monitor the full second standard tablet, the AUCq.24 was calculated by multiplying the AUC ₀ i 2 by two

Table 3: Results of AUC statistical analysis

formula AUC _e . _t * pg.h / ml Relative bioavailability (90¼ confidence intervals) Untransformed data Ln transformed data A 31.44 0.98 (0.86-1.10) 0.98 (0.84-1.14) B 32.32 1.01 (0.88 - 1.14) 1.01 (0.88 -1.16) C 28.69 0.89 (0.80-0.98) 0.90 (0.80-1.02)

Table 4: Results of statistical analysis C ^

formula C.M gg / mi Relative bioavailability (90% confidence intervals) Untransformed data Ln transformed data A 2.42 1.06 (0.86-1.26) 1.07 (0.87 to 1.32) B 2:41 1.06 (0.86-1.26) 1.08 (0.90-1.31) C 2.00 0.88 (0.75-1.01) 0.90 (0.76-1.06)

Table 5: Results of statistical analysis of 24-hour concentration

formula C .. G / ml Relative bioavailability (90% confidence intervals) Untransformed data Ln transformed data A 0.57 0.79 (.62-.99) 0.79 (0.63 to 0.99) B 0.65 0.90 (0.79-1.01) 0.89 (0.68-1.15) C 0.66 0.92 (0.76-1.08) 0.90 (0.71-1.15)

2.d) Discussion

Mean AUC ratios at 90% confidence limits indicate that formulations A, B, and C are bioequivalent to the standard dosing regimen. All three formulations had therapeutic levels at C ₂₄ hours. C _MX limits (untransformed) are acceptable for most formulations. All three single daily dosage formulations demonstrated prolonged absorption of clarithromycin compared to the standard formulation.

Formulations A and B, despite varying amounts of alginates, produce similar profiles in vivo. However, previous studies have shown that the reproducibility of release profiles is improved by increasing the amount of alginate. Therefore, formulation B showed the best overall results.

Said specifications, examples and data provide a complete description of the manufacture and use of the composition of the invention. Since many embodiments of the invention may be practiced without departing from the spirit and scope of the invention, the invention is based on the appended claims.

Claims (17)

PATENT CLAIMS Controlled release solid pharmaceutical composition adapted for oral administration, characterized in that it comprises: at least one basic drug having a water solubility of less than 1 part to 30 parts water; a water-soluble alginate salt; an alginic acid complex salt, wherein the weight ratio of the soluble alginate salt to the alginic acid complex salt is 16: 1 to 1: 1 and the organic carboxylic acid to facilitate dissolution of the basic drug, wherein the molar ratio of organic acid to basic drug is 0.2: 1 to 5 : 1. Composition according to claim 1, characterized in that it is in tablet form. 3. The composition of claim 1, wherein the composition is in the form of a once daily dosing regimen. 4. The composition of claim 1 wherein the basic drug is macrolide. The composition of claim 4, wherein the macrolide is clarithromycin. The composition of claim 1, wherein the water-soluble alginate salt is sodium alginate. 7. The composition of claim 1 wherein the alginic acid complex salt is sodium calcium alginate. 8. The composition of claim 1 wherein the organic carboxylic acid is selected from the group consisting of tartaric, malic, succinic, glutaric, glutamic, maleic, almond, and citric acids. 9. The composition of claim 8, wherein the organic carboxylic acid is citric acid. The composition of claim 1, wherein the weight ratio of sodium alginate to sodium calcium alginate is 16: 1 to 1: 1. The composition of claim 10, wherein the weight ratio of sodium alginate to sodium calcium alginate is 8: 1 to 2: 1. The composition of claim 1, wherein the molar ratio of organic acid to basic drug is 1: 1. The composition of claim 1, wherein the basic drug is selected from the group consisting of sulfamethoxazole, metronidazole, cimetidine, indapamide, atenolol, and diazepam. The composition of claim 4, wherein the macrolide is selected from the group consisting of erythromycin, dirithromycin, azithromycin, roxithromycin, and ABT-229. 15. The composition of claim 3, comprising: 500 mg clarithromycin; from 75 to 400 mg of sodium alginate; from 10 to 400 mg of sodium calcium alginate and 128 mg of citric acid. 16. The composition of claim 15, comprising: from 80 to 200 mg of sodium alginate and from 10 to 40 mg of sodium calcium alginate. A composition according to claim 16, comprising: 120 mg sodium alginate and 15 mg sodium calcium alginate.