NO310095B1 - A controlled release formulation for heavily soluble basic drugs - Google Patents

Abstract

A controlled release, oral, solid, pharmaceutical composition for a reduced daily dosage regimen is described in which the therapeutic ingredient is a sparingly soluble basic drug. The formulation comprises the use of a water-soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid in addition to the therapeutic drug. A special embodiment comprising a once daily dosage form of clarithromycin is also described.

Description

The field of the invention

This invention relates, as stated in the preamble of claim 1, to a controlled slow-release oral dosage form for at least one heavily soluble basic drug useful for reducing the daily dosage regimen. More particularly, the invention comprises a once daily formulation of clarithromycin.

Background for the invention

The advent of controlled release dosage forms has provided an advantage to the pharmaceutical industry. Controlled release formulations have allowed the possibility of reducing the dosage regimen of drugs, especially those administered orally to outpatients.

The advantages of reduced dosage regimens for outpatients are convenience and, more importantly, better assurance of compliance. E.g. the reduction of a dosage regimen from four times daily (q.i.d.) to three times daily (t.i.d.) allows the patient to take the prescribed drug during waking hours. A reduction of a dosing regimen to twice daily (b.i.d.) allows the patient to take the prescribed drug in the morning and evening, which provides greater convenience; i.e. the patient does not need to carry a supplement when away from home. Of course, the most convenient dosage form is a once-daily dosage regimen. Unfortunately, the pharmacokinetic properties (ie, absorption, elimination, and metabolism) of most drugs do not allow them to be easily formulated in a simple oral dosage form and provide controlled, efficient release of the drug over a 24-hour period with reproducible bioavailability.

One method of improving controlled slow release solid formulations has been the development of formulations containing an alginate gel. Typically, a water-soluble alginate such as sodium alginate and calcium ions in the form of a calcium salt are reacted to crosslink the alginate by converting it to an insoluble calcium alginate gel. By adding a strong acid to the mixture of sodium alginate and calcium salt, the calcium salt slowly ionizes to give calcium ions. The calcium ions then react with the soluble alginate to form an insoluble calcium alginate gel. Gelation proceeds through gradual ionization of the calcium salt. With these formulations, the controlled release properties of the alginate gel have been varied by varying the molecular weight of the alginate, the alginate concentration, the type of polyvalent cation crosslinking agent or the concentration of the cation.

Granted European Patent 188040-B1 and its counterpart, U.S. patent 4,842,866, describes an improved gel-type alginate composition which is slowly soluble in body fluids, such as of the gastrointestinal ("GI") tract, containing a therapeutically effective amount of at least one therapeutically active agent which is gradually released as the alginate is hydrated, characterized by that it is present in the production of both a water-soluble alginate, especially sodium alginate, and a complex salt of alginic acid, especially sodium-calcium alginate, which has one cation which alone gives a soluble alginate salt and another cation which alone gives an insoluble alginate salt. The statement of the U.S. counterparty, the U.S. 4,842,866, is incorporated by reference in its entirety.

The application of the technology developed in the above-mentioned patents, on the other hand, was not found to be applicable to poorly water-soluble drugs. E.g. an in vitro drug release study from an alginate formulation of clarithromycin was observed to be too slow. Similarly, with erythromycin, in vivo animal studies showed that reproducible bioavailable controlled release formulations were not possible using alginates or some other monolithic hyrogel tablets. It was concluded that macrolides such as erythromycin in a simple monolithic hyrogel tablet would not produce a suitable controlled release dosage form due to the problems of acid instability, poor drug solubility and variable GI transit.

An oral formulation containing 6-O-methylerythromycin A and citric acid with improved bioavailability has been reported in Japanese Kokai 163823/1985, as referenced in WPI Acc. No. 85-247003/40.

It is an object of the invention to reduce the daily dosage regimen of a heavy water-soluble basic drug with a controlled release formulation.

The present invention overcomes the problems of slow release and potentially poor or variable absorption with soluble basic drugs by combining an organic acid and the drug into an alginate formulation.

Summary of the invention

The present invention provides for a reduced daily dosage of poorly soluble basic drugs by using the alginate matrix with the incorporation of an organic acid. The solubility of a basic drug decreases as it proceeds from the colon (pH 8.0) while it is soluble in the stomach and the upper or proximal region of the small intestine. Thereby, a poorly soluble basic drug will lead to less drug being available for absorption in the lower or remote intestine. The inclusion of the organic acid within the formulation has overcome this problem. Without intending to be bound by any particular theory, it is believed that the formulation with the organic acid creates a low pH microenvironment to promote the solubility of the drug within the dosage form as it moves down the GI tract.

Accordingly, the invention includes a controlled release solid 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 per 30 parts water;

a water-soluble alginate salt;

a complex salt of alginic acid, wherein the cation providing an insoluble salt is selected from the group consisting of calcium, strontium, iron, and barium; and

an organic carboxylic acid to facilitate dissolution of the basic drug, wherein the weight ratio of the water-soluble salt to the complex salt of alginic acid varies from 16:1 to 1:1, and the molar ratio of carboxylic acid to drug varies from 0.2: 1 to 5:1.

A particular aspect of the invention is the preparation of a once daily dosing regimen for clarithromycin which is now dosed twice daily as a 250 mg or 500 mg tablet depending on the type of bacterial infection to be treated. The exact site of clarithromyci absorption in vitro is uncertain. In contrast, clarithromycin is known to be very soluble in the stomach (pH 1.2) and quite soluble in the upper part of the small intestine (pH 5.0) where absorption is most likely to occur. Because drug solubility decreases in the lower intestine (pH 6 to 8), this results in less drug being available for absorption. The invention provides a way to overcome this problem by using alginate formulations with an organic acid, in particular, e.g. si-tr onic acid .

Accordingly, the second aspect of the invention is a controlled release solid pharmaceutical composition adapted for oral administration of a once daily dosage regimen comprising: about 500 mg clarithromycin;

from 75 to 400 mg of alginate;

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

Detailed description of preferred designs

The purpose of the present invention is to provide a controlled release pharmaceutical composition where a poorly soluble basic drug can be continuously released from the dosage form as it continues through the GI tract.

The invention thereby provides a once-daily dosing regimen for at least one sparingly soluble basic drug by administering a controlled-release, solid pharmaceutical composition adapted for oral administration to a patient in need thereof. A preferred composition is in tablet form.

A poorly soluble or poorly soluble basic drug is a drug that has a solubility of less than 1 part in 30 parts of water. The invention can also be used for less soluble drugs, e.g. up to a solubility of one part in 10,000 parts of water.

For example, sparingly soluble basic drugs may include antibiotics such as, e.g. sulfamethoxazole with a solubility of 1 in 3,400 (parts water); tetracycline, 1 in 2,500; metronidazole and cimetidine (a histamine H2 receptor antagonist for treating peptic ulcers), both about 1 in 100 to 1 in 1,000; indapamide (an antihypertensive/diuretic), 1 in more than 10,000; atenolol (an antihypertensive), about 1 in 30 to 1 in 100; diazepam (tranquilizer), varying from 1 in 1,000 to 1 in 10,000.

As a preferred basic drug, the present invention includes macrolides which are also sparingly soluble. Examples of macrolides are erythromycin with a solubility of one part in 1,000 parts of water; dirithromycin, with similar solubility properties to erythromycin; josamycin, midecamycin, kitasamycin, all three are very slightly soluble in water, varying from about 1 in 1,000 to 1 in 10,000; and tylosin which is used only for veterinary tar targets with a solubility varying from about 1 in 100 to 1 in 1,000. Other macrolides that may be included are, e.g. roxithromycin, rokithamycin, oleandomycin, myocamycin, flurithromycin, rosaramicin, azithromycin, and compounds named ABT-229 or ABT-269. The most preferred macrolide of the invention is clarithromycin with a solubility of about one part in 1,000 parts of water.

The pharmaceutical composition of the invention may include other drugs in combination with a heavily soluble basic drug where known combination therapy is required or beneficial.

Thereby, e.g. with macrolides, erythromycin or clarithromycin may be formulated in combination with a preparation for standard therapy of peptic ulcer, peptic ulcer, or gastroesophageal reflux disease (GERD), such as preparations containing anti-peptic ulcer or anti-peptic ulcer drugs; i.e. selected from gastric secretion inhibiting compounds such as omeprazole, cimetidine, ranitidine, lansoprazole, pantoprazole, sucralfate, famotidine, or nizatidine, or antacids such as magnesium hydroxide, aluminum hydroxide, sodium carbonate, sodium hydrogen carbonate, simethicone or aluminum magnesium hydroxide or hydrate thereof (such as the monohydrate known as magaldrat).

Another macrolide, especially erythormycin or clarithromycin, pharmaceutical composition of the invention can be adapted to be administered in combination with a preparation containing bismuth salts such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgallate.

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 can preferably vary from 50% and up to 75% of the 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 normally 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 to give a soluble alginate salt. Thereby, the alginate can also be, e.g. potassium alginate or ammonium alginate.

The complex salt of alginic acid is a sodium-calcium complex salt of alginate where the amount of calcium is precisely controlled, and which is self-gelling without the need to react with stomach acid or additional calcium ions. While sodium-calcium alginate is normally used in the practice of this invention, the sodium cation can be replaced by another cation which gives a soluble alginate salt; e.g. potassium or other alkali metal, magnesium, or ammonium, and the calcium cation can also be replaced by another polyvalent cation (except magnesium) which gives an insoluble alginate salt; e.g. strontium, iron, or barium. The most preferred formulations described herein typically include sodium alginate, e.g. it manufactured and sold by Alginate Industries, Ltd., England, under the trade mark "Manucol", and sodium-calcium alginate manufactured and sold by Kelco Division of Merck and Co., Inc., San Diego, California, U.S.A., under the trade mark " Kelset".

The weight ratio of soluble alginate salt to complex salt of alginic acid may vary from 16:1 to 1:1, preferably from 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 technique of European Patent 188040, as mentioned above, to provide controlled release formulations.

The organic acid required in the controlled release formulation of the invention is an amount of acid effective to form a low pH microenvironment, less than 7.0, in the vicinity of the hydrated dosage form. Put differently, an effective amount of organic acid is the amount that enables dissolution of the basic drug through the GI system. The exact amount may vary depending on the acid used and the choice of basic drug which will be known to one skilled in the art. The ratio is a molar ratio that can vary from about 0.2:1 to 5:1 of acid to drug. A molar ratio of 1:1 of acid to drug is preferably used.

The organic acid includes for the purposes of the invention any organic carboxylic acid, preferably an aliphatic organic carboxylic acid having anywhere from C3-C20 carbon atoms. Preferred is, e.g. tartaric acid, malic acid, succinic acid, glutaric acid, glutamic acid, malic acid, mandelic acid and citric acid. The most preferred acid is citric acid.

A particular and preferred embodiment of the invention is a controlled-release, solid pharmaceutical composition adapted for oral administration of a once-daily dosage regimen comprising: about 500 mg clarithromycin;

from 75 to 400 mg of sodium alginate;

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

Preferably, the composition contains from 80 to 200 mg of sodium alginate and from 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.

The composition is also preferred in tablet form, but can also be in capsule or pellet/particle form.

Other ingredients commonly used in a preparation according to the invention may include pharmaceutically acceptable excipients, such as preservatives, diluents; e.g. starch or microcrystalline cellulose; binders such as starch, polyvinyl pyrrolidone

(povidone) and sodium carboxymethyl cellulose; glidants or lubricants, such as talc and magnesium stearate; bulking agents such as lactose; and approved dyes. The dosage form can also be coated with materials not in particular

designed for control or modification of drug release.

The preparation can be processed into tablets, suppositories or used to fill capsules. The production can also be coated if desired, e.g. to mask an otherwise bitter-tasting preparation.

Using examples of the invention, it was found that bioavailability studies on a representative formulation of the invention containing clarithromycin, 500 mg, meet the acceptance requirements for a successful once daily dosage formulation. This means that it reached an area under the curve AUC0_24 at least equivalent to the 250 mg twice daily (BID) dosing regimen, and clarithromycin plasma concentrations at 24 hours were similar to the 250 mg BID dosing regimen.

Examples

Example 1: Tablet manufacturing details

let. Controlled release granulation

All tablet formulations used the following general production method. The active drug, polymer, binder and remaining excipients were sieved through an 850 µm apparatus sieve to remove any large agglomerates. The sieved material was then mixed dry using a planetary mixer set to the lowest speed for 5 minutes. The mixed material was granulated by adding a 50/50 volume/volume solution of alcohol and water in small amounts until a suitable granulate mass was obtained. The wet mass was passed through a 4.0 mm apparatus sieve onto paper-lined trays and dried in a hot air oven at 50°C until the granulate had a moisture content of less than 4% w/w (determined using Sartorious IR wt.Model: YTCL.Condition: 98°C for 15 minutes) . Finally, the dried granules were passed through an 850 µm apparatus sieve and mixed with tablet lubricants for 5 minutes, using a planetary mixer set at the lowest speed.

lb. Compression

The tablets were compressed using a rotary tablet machine, equipped with oval punches. Individual formulations/recipes A, B and C were pressed to a tablet-crushing strength which produced tablets of suitable thickness and friability. The tablet compositions are given in Table 1.

Example 2: Bioavailability study

2a. Materials and supplies

One study compared the plasma concentration profiles of the three 500 mg once-daily (QD) formulations A, B and C, above, with the twice-daily dosing regimen of the commercially available 250 mg BIAXIN® tablet as a control (ie, 250 mg BID, here referred to formulation D) in steady state. The acceptance criteria for a successful QD formulation were: • AUC0_24 at least equivalent to the 250 mg twice daily (BID) dosing regimen. • Clarithromycin plasma concentrations at 24 hours equivalent to the 250 mg BID dosing regimen.

2b. Study of design and results

The study was conducted as a phase I, multi-dose, open-label, randomized, four-period, balanced crossover study. Suitable patients were sorted with a complete history, physical examination and laboratory profile, including determination of haematological, renal and liver parameters.

Eight healthy male volunteers between 18-50 years of age were dosed on the morning of days 1, 2 and 3 of each of the four study periods. Formulation D (BIAXIN® clarithromycin 250 mg) was also dosed in the evening of days 1, 2, and 3 in each of the study periods. Each subject received all formulations after study completion.

Blood samples were collected before dosing on day 3 (0 hour) and at 1, 2, 3, 4, 6, 8, 10, 12, 16, and 24 hours after dosing. All samples were transferred to heparinized collection tubes and late-centrifuged. The separated plasma was separated into equal volumes and transferred to appropriate labeled tubes and frozen at once. The plasma samples were kept frozen until analyzed. The plasma samples were analyzed in the large plate bioassay. This method measured total antibiotic activity, and expresses the results in terms of clarithromycin, mcg/ml.

2c. Data and statistical analyses

The bioequivalence of the three once-daily formulations with the standard tablet was analyzed by a two, one-tailed t-test procedure. 90% confidence intervals were calculated from analyzes of the natural logarithms of AUC, and concentration at 24 hours. These were obtained by exponentiating the endpoints of the 90% confidence intervals from the difference in mean logarithms. Bioequivalence between formulations is established if these limits lie within the range of 0.80 to 1.25. In addition, 90% confidence intervals for the ratios of means were obtained from analyzes of untransformed AUC and concentration at 24 hours. The results of this analysis are summarized in Tables 3, 4, and 5. The pharmacokinetic data are shown in Table 2.

2d. Discussion

The average AUC ratio, at 90% confidence limits, shows that formulations A, B and C are bioequivalent to the standard dosing regimen. All three formulations show therapeutic levels at C24 hours. C,,,^ limits (untransformed) are acceptable for most formulations. All three once-daily formulations demonstrate enhanced absorption of clarithromycin when compared to the standard formulation.

Formulations A and B, despite containing different amounts of alginates, produce similar in vivo profils. In contrast, previous studies have shown that reproducibility of release profiles is improved by increasing the amount of alginate. Formulation B therefore showed the best overall result.

The above specifications, examples and data provide a complete description of the production and use of the composition of the invention. Because many embodiments of the invention can be made without departing from the spirit and scope of the invention, the invention is stated in the claims hereafter attached.

Claims (17)

1. A controlled-release, solid pharmaceutical composition suitable for oral administration, characterized in that it comprises: a therapeutically effective amount of at least one basic drug which has a water solubility of less than 1 part per 30 parts water; a water-soluble alginate salt; a complex salt of alginic acid, wherein the cation providing an insoluble salt is selected from the group consisting of calcium, strontium, iron, and barium; and an organic carboxylic acid to facilitate dissolution of the basic drug, wherein the weight ratio of the water-soluble salt to the complex salt of alginic acid ranges from 16:1 to 1:1, and the molar ratio of carboxylic acid to drug ranges from 0.2:1 to 5:1. 2. Composition according to claim 1, characterized in that it is in tablet form. 3. Composition according to claim 1, characterized in that it is in the form of a once-daily dosing regimen. 4. Composition according to claim 1, characterized in that the basic drug is a macrolide. 5. Composition according to claim 4, characterized in that the macrolide is clarithromycin. 6. Composition according to claim 1, characterized in that the water-soluble alginate salt is sodium alginate. 7. Composition according to claim 1, characterized in that the complex salt of alginic acid is sodium-calcium alginate. 8. Composition according to claim 1, characterized in that the organic carboxylic acid is selected from the group consisting of tartaric acid, malic acid, succinic acid, glutaric acid, glutamic acid, maleic acid, mandelic acid and citric acid. 9. Composition according to claim 8, characterized in that the organic carboxylic acid is citric acid. 10. Composition according to claim 1, characterized in that the weight ratio of sodium alginate to sodium-calcium alginate is 16:1 to 1:1. 11. Composition according to claim 1, characterized in that the weight ratio of sodium alginate to sodium-calcium alginate is 8:1 to 2:1. 12. Composition according to claim 1, characterized in that the molar ratio of organic acid to basic drug is approximately 1:1. 13. Composition according to claim 1, characterized in that the basic drug is selected from the group consisting of sulfamethoxazole, metronidazole, cimetidine, indapamide, atenolol and diazepam. 14. Composition according to claim 4, characterized in that the macrolide is selected from the group consisting of erythromycin, dirithromycin, azithromycin, roxithromycin and ABT-229. 15. A controlled release solid pharmaceutical composition adapted for oral administration of a once daily dosage regimen, characterized in that it comprises: about 500 mg of clarithromycin; from 75 to 400 mg of sodium alginate, from 10 to 400 mg of sodium-calcium alginate, and about 128 mg of citric acid. 16. Composition according to claim 14, characterized in that it comprises: from 80 to 200 mg of sodium alginate, and from 10 to 40 mg of sodium-calcium alginate. 17. Composition according to claim 15, characterized in that it comprises: approximately 120 mg of sodium alginate, and approximately 15 mg of sodium-calcium alginate.