MXPA97006031A - A controlled release formulation for basic pharmacy deficiently solub - Google Patents

Abstract

The present invention relates to a controlled release solid pharmaceutical composition adapted for oral administration comprising: a therapeutically effective amount of at least one basic drug having a solubility in water of less than 1 part per 30 parts of water; of water-soluble alginate, a complex salt of alginic acid, and an effective amount of an organic carboxylic acid to facilitate the dissolution of the basic drug.

Description

A CONTROLLED RELEASE FORMULATION FOR DEFICIENTLY SOLUBLE BASIC DRUGS Field of the Invention The invention relates to a controlled slow-release oral dosage form, for at least one sparingly soluble basic drug, useful for reducing the daily dose regimen. More particularly, the invention relates to a once-a-day formulation of clarithromycin.

Background of the Invention The advent of controlled release dosage forms has provided a benefit to the pharmaceutical industry. The controlled release formulations have allowed the possibility of reducing the dose regimens for drugs, especially those that are administered orally to outpatients. The advantages of reduced dose regimens for the outpatient are convenience and, more importantly, better assurance of compliance. For example, the reduction of a dose regime four times a day (q.i.d.) to three times a day (t.i.d.), allows the patient to take the prescribed drug during sailing hours. A reduction of a twice-daily dose regimen (b.i.d.) allows the patient to take the prescribed drug in the morning and in the afternoon, which provides greater convenience; for example, the patient is not required to take an extra dose when he is away from home. Of course, the most convenient dosage form is a once-a-day regimen. Unfortunately, the pharmacokinetic properties (eg, absorption, elimination, and metabolism) of most drugs do not allow them to be easily prepared in a single oral dosage form, and provide efficient controlled release of the drug throughout a period of 24 hours, with reproducible bioavailability. One method for improving solid preparations of controlled slow release has been the development of preparations containing an alginate gel. Typically, a water soluble alginate such as sodium alginate and calcium ions are reacted in the form of a calcium salt, to crosslink the alginate into an insoluble calcium alginate gel. In the addition of a strong acid to the mixture of sodium alginate and calcium salt, the calcium salt slowly ionizes to produce calcium ions. Then, the calcium ions react with the soluble alginate to form an insoluble calcium alginate gel. The gelation is carried out through the gradual ionization of the calcium salt. With these formulations, the controlled release properties of the alginate gel have been changed, by varying the molecular weight of the alginate, the concentration of alginate, the type of polyvalent cation crosslinking agent, or the concentration of the cation. European Patent 188040-B1 and its counterpart, US Pat. No. 4,842,866, describe an improved gel-like alginate composition that is slowly soluble in body fluids, such as from the gastrointestinal tract ("GI"), which contains a therapeutically effective amount of at least one therapeutically active agent that is released gradually such as alginate hydrates, characterized in that they are present in the preparation of both a water-soluble alginate, especially sodium alginate, and a complex salt of alginic acid , especially sodium-calcium alginate, which have a cation that only produces a soluble alginate salt, and another cation that only produces an insoluble alginate salt. The description of the counterpart of the United States of North America, the Patent of the United States of North America Number 4,842,866, is incorporated for reference in its entirety. However, it was found that the use of the technology developed in the patents mentioned above could not be applied with drugs poorly soluble in water. For example, in one study it was observed that the release of an in vitro drug from a clarithromycin alginate formulation is slow. In a similar way, with erythromycin, in vivo animal studies showed that controlled release formulations were bioavailable in a reproducible manner using alginates or any other monolithic hydrogel tablets. It was concluded that macrolides such as erythromycin in a simple monolithic hydrogel tablet would not produce an adequate controlled release dosage form, due to the problems of acid instability, poor drug solubility, and variable gastrointestinal transit. In Japanese Ko ai 163823/1985, as summarized in WPI Account Number 85-247033 / 40, an oral formulation containing 6-O-methylerythromycin A and citric acid with improved bioavailability has been reported. It is an object of the present invention to reduce the daily dose regimen of a basic drug poorly soluble in water, with a controlled release formulation. The present invention overcomes the problems of slow release and potentially deficient or variable absorption, with poorly soluble basic drugs, by combining an organic acid and the drug within the alginate formulation.

Compendium of the Invention. The present invention allows a reduced daily dosage of poorly soluble basic drugs, by applying the alginate matrix, with the incorporation of an organic acid. The solubility of a basic drug decreases as it passes distally into the large intestine (pH 8.0), while it is soluble in the stomach and the upper or proximal region of the small intestine. Therefore, a poorly soluble basic drug will cause less drug to be available for absorption in the lower or distal bowel. The inclusion of the organic acid within the formulation has overcome this problem. Although not intended to be found by any particular theory, it is believed that the formulation with the organic acid creates a low pH microenvironment to improve the solubility of the drug within the dosage form, as it moves down the gastrointestinal tract . Accordingly, the present 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 solubility in water of less than 1 part per 30 parts of water; a water-soluble alginate salt, - a complex salt of alginic acid; and an effective amount of an organic carboxylic acid to facilitate the dissolution of the basic drug.

A particular aspect of the present invention is the preparation of a once-a-day dose regimen for clarithromycin, which is currently administered twice a day as a 250-milligram or 500-milligram tablet, depending on the type of bacterial infection that is going to be treated. The precise site of clarithromycin absorption in vivo is uncertain. However, it is known that clarithromycin is very soluble in the stomach (pH 1.2) and slightly soluble in the upper region of the small intestine (pH 5.0), where absorption is more likely to occur. Because the solubility of the drug decreases in the lower intestine (pH 6 to 8), this causes less drug to be available for absorption. The present invention provides a way to overcome this problem, by using the alginate formulation with an organic acid, particularly, for example, citric acid. In accordance with the foregoing, a second aspect of the present invention is a solid controlled release pharmaceutical composition adapted for oral administration of a once-a-day dose regimen comprising: approximately 500 milligrams of clarithromycin; from about 75 to 400 milligrams of sodium alginate; from about 10 to 400 milligrams of sodium-calcium alginate, and approximately 128 milligrams of citric acid.

Detailed Description of the Preferred Modality The object of the present invention is to provide a controlled release pharmaceutical composition, wherein a basic drug poorly soluble from the dosage form can be continuously released as it passes through the gastrointestinal tract. The present invention thus allows a once-a-day daily dose regimen for at least one poorly soluble basic drug, by administration of a controlled release solid pharmaceutical composition, adapted for oral administration to a patient in need. Of the same. A preferred composition is in the form of a tablet. A basic drug poorly soluble or sparingly soluble in water is a drug that has a solubility of less than 1 part in 30 parts of water. The present invention can also be applied to still less soluble drugs, for example, with a solubility of up to one part in 10,000 parts of water. By way of example, sparingly soluble basic drugs may include antibiotics such as, for example, sulfamethoxazole, with a solubility of 1 in 3,400 (parts of water); tetracycline, 1 in 2,500; metronidazole and cimetidine (a H2 receptor antagonist of histamine to treat ulcers), both at approximately 1 in 100 to 1 in 1,000; indapamide (an antihypertensive / diuretic), 1 in more than 10,000; atenolol (an antihypertensive agent), approximately 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 that are also poorly soluble. Examples of macrolides are erythromycin with a solubility of one part in 1,000 parts of water; dirithromycin, with solubility properties similar to erythromycin; josamycin, midecamycin, quitasamycin, all three being 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 purposes, and with a solubility ranging from about 1 in 100 to 1 in 1,000. Other macrolides that may be included are, for example, roxithromycin, little icina, oleandomycin, mycocamycin, fluritromycin, rosaramycin, azithromycin, and the compounds designated ABT-229 or ABT-269. The most preferred macrolide for the present invention is clarithromycin having a solubility of about one part in 1,000 parts of water. The pharmaceutical composition of the present invention may include other drugs in combination with a poorly soluble basic drug wherein the known combination therapy is required or beneficial. Thus, for example, the macrolides, erythromycin or clarithromycin, may be formulated in combination with a preparation for standard therapy of gastritis, ulcers, or gastroesophageal reflux disease (GERD), such as preparations containing anti-ulcer or anti-gastritis drugs; for example, 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 hydrogencarbonate. , simethicone or aluminum-magnesium hydroxide or hydrates thereof (such as the monohydrate, known as magaldrate). Another macrolide, particularly erythromycin or clarithromycin, the pharmaceutical composition of the present invention, can be adopted to be administered in combination with a preparation containing bismuth salts such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, subnitrate. of bismuth or the bismuth subgalato. The amount of the drug or drugs in the pharmaceutical composition can vary from about 40 to 75 percent of the total composition or tablet. For clarithromycin, the amount may preferably vary over 50 percent and up to 75 percent of the weight of the total composition or tablet. The rate of release 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 employed in the practice of this invention, the sodium cation may be replaced by another cation, for example, potassium or other alkali metal, magnesium, or ammonium to yield a soluble alginate salt. In this way, the alginate could be, for example, potassium alginate or ammonium alginate. The complex salt of alginic acid is a complex sodium-calcium salt of alginic acid in which the amount of calcium is precisely controlled, and which is self-gelling without the need to react with stomach acid or calcium ions additional While sodium-calcium alginate is normally employed in the practice of this invention, the sodium cation may be replaced by another cation which yields a soluble alginate salt; for example, potassium or other alkali metal, magnesium, or ammonium, and the calcium cation can also be replaced by another polyvalent cation (except magnesium) that yields an insoluble alginate salt; for example, strontium, iron, or barium.

More preferred preparations described herein typically include sodium alginate, for example those manufactured and sold by Alginate Industries, Ltd., England, under the registered trademark "Manucol", and sodium-calcium alginate manufactured and sold by Kelco Division, of Merck and Co., Inc., San Diego, California, United States of America, under the registered trademark "Kelset". The weight ratio of the soluble alginate salt to the complex salt of alginic acid can vary from about 16: 1 to 1: 1, preferably from about 8: 1 to 2: 1. The same proportion applies of course to the ratio of sodium alginate to sodium-calcium alginate. The combination of the soluble alginate and the complex salt has been described to form an insoluble salt in the art of European Patent 188040, as mentioned above, to provide controlled release formulations. The organic acid that is required in the control release formulation of the present invention is an effective amount of acid to create a low pH microenvironment, less than 7.0, in the vicinity of the moisturizing dosage form. Seen differently, an effective amount of organic acid is the amount that facilitates the dissolution of the basic drug through the gastrointestinal tract. The precise amount may vary depending on the acid used and the choice of the basic drug as will be known to one skilled in the art. The ratio is a molar ratio and can vary from about 0.2: 1 to 5: 1 of acid to drug. Preferably, a molar ratio of 1: 1 of 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 of 3 to 20 carbon atoms. Preferred are, for example, tartaric acid, malic acid, succinic acid, glutaric acid, glutamic acid, maleic acid, mandelic acid and citric acid. The most preferred acid is citric acid. A particular and preferred embodiment of the present invention is a solid controlled, controlled release pharmaceutical composition adapted for oral administration of a once-a-day dosing regimen comprising: approximately 500 milligrams of clarithromycin; from about 75 to 400 milligrams of sodium alginate; from about 10 to 400 milligrams of sodium-calcium alginate, and about 128 milligrams of citric acid. Preferably, the composition contains from about 80 to 200 milligrams of sodium alginate and from about 10 to 40 milligrams of sodium-calcium alginate. Most preferably, the composition contains approximately 120 milligrams of sodium mal-glate and approximately 15 milligrams of sodium-calcium alginate. The composition is also preferably in the form of a tablet but may also be in the form of a pill / granule. Other ingredients usually used in a preparation according to the invention may include pharmaceutically acceptable excipients, diluents; for example, starch or microcrystalline cellulose; binders such as starch, polyvinyl pyrrolidone (providone) and sodium carboxymethyl cellulose; glidants or lubricants, such as talc and magnesium stearate, bulking agents such as lactose; and approved coloring agents. The dosage form is also coated with materials not specifically designated for the control or modification of drug release. The preparation can be processed into tablets, suppositories or can be used to fill capsules. The preparation can also be coated when desired, for example, to cover a preparation that would otherwise be bitter. By way of example of the present invention, it was found that bioavailability studies in a representative formulation of the present invention containing clarithromycin, 500 milligrams, met the acceptance criteria for a once-a-day successful dose formulation. This means that it achieved an area under the curve AUCQ.24 at least equivalent to the dosing regimen of 250 milligrams twice a day (BID), and plasma concentrations of clarithromycin at 24 hours were similar to the dosing regimen of 250 BID milligrams Examples Example 1 Tablet Manufacturing Details the. Controlled release granulation All tablet formulations used the following general manufacturing method. The active drug, the polymer, the binder and the remaining excipients were screened through an 850 micron aperture screen to remove any large agglomerates, then the screening material was mixed dry using a planetary mixer set at the minimum speed for 5 minutes, the mixed material was granulated by the addition of 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 millimeter aperture screen on lined paper trays and dried in a hot air oven at 50 ° C until the granule had a moisture content of less than 4 percent p / p (determined using the Sartorious IR scale Model: YTC01L Conditions: 98 ° C for 5 minutes). Finally, the dried granule was passed through an 850 micron aperture screen and mixed with the tablet lubricants for 5 minutes, using the planetary mixer placed at the minimum speed.

Ib. Compression The tablets were compressed using a rotary tablet machine, fitted with oval punches. The individual formulations A, B and C were compressed to a tablet compression strength which produced tablets of suitable thickness and friability. Tablet compositions are given in Table 1.

Table 1 Formulation: A B C Ingredients ma / tablet ma / tablet m / tablet Clarithromycin 500 500 500 Acid Anhydrous 128 128 128 Citrus USP Sodium alginate 80 120 180 Sodium alginate 10 15 22.5 Calcium Lactose mesh 300 100 100 100 Povidone K (29-32) 30 30 30 Talc, purified, 30 30 30 in powder Stearic acid 21 21 21 Stearate 10 10 10 magnesium Example 2 Eioavailability study 2a. Materials and Supplies One study compared the plasma concentration profiles of the three formulations of once daily (QD) A, B and C of 500 milligrams above, with a twice daily dosing regimen of the BIAXIN 250 tablet milligrams commercially available as a control (ie, 250 milligrams BID, referred to herein as Formulation D) in a stable state. The acceptance criteria for a successful QD formulation were: • AUCQ.24 at least equivalent to the dosing regimen of 250 milligrams twice a day (BID). • Plasma concentrations of clarithromycin at 24 hours equivalent to the BID dosing regimen of 250 milligrams. 2b. Study Design and Results The study was conducted as a balanced, four-period, randomized, open-label multi-dose, Phase I crossing study. Appropriate patients were examined with a physical examination, full history and laboratory profile, uding an assessment of hematological, renal and liver parameters. Eight male volunteers were given a dose between the ages of 18 and 50 on the morning of days 1, 2 and 3 in each of the four study periods. Formulation D (clarithromycin of 250 milligrams BIAXIN) was also administered in the afternoons of days 1, 2, and 3 in each of the periods of the study. Each subject received all the formulations upon completion of the study. Blood samples were collected before administering the dose on day 3 (hour 0) 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 centrifuged. The separated plasma was divided into equal volumes and transferred. in appropriately labeled tubes and immediately frozen. The plasma samples were kept frozen until they were tested. Plasma samples were subjected to the assay using a large platelet bioassay. This method measured the total antibiotic activity, and expressed the results in terms of clarithromycin, mcg / milliliter. 2 C. Data and Statistical Analysis The bioequivalence of the three formulations was assessed once a day by a one-sided, two-sided t-test procedure. 90 percent of the safety intervals were calculated from the analysis of the natural logarithms of AUC, Cn? Ax and concentration at 24 hours. These were obtained by exponentiating the extreme points of 90 percent of the safety intervals for the difference in mean logarithms. The bioequivalence between the formulations is deduced if these limits fall within the range of 0.80 to 1.25. In addition, 90 percent of the safety intervals for the media proportions were obtained from the analysis of the untransformed AUC and the concentration at 24 hours. Tables 3, 4 and 5 summarize the results of this analysis. Table 2 shows the pharmacokinetic data.

Table 2 Pharmacokinetic Data Since the plasma sampling program did not completely inspect the second standard tablet, the AUC0_24 value was calculated by multiplying the value AUC0. | 2 by 2. Table 3 Statistical Analysis / AUC Results Table 4 Statistical Analysis Results / Cmmax Table 5 Results of the Statistical Analysis / Concentration at 24 Hours 2d. Discussion The average AUC ratio, at 90 percent safety limits, showed that Formulations A, B and C are bioequivalent with the standard dosage regimen. All three formulations showed therapeutic levels at C24 hours. The limits C? Nax (untransformed) are acceptable for most formulations. The three once-daily formulations demonstrated extended absorption of clarithromycin when compared with the standard formulation. Formulations A and B, although containing different amounts of alginates, produced similar in vivo profiles. However, previous studies have shown that the reproducibility of the release profiles is improved by increasing the amount of alginate. Therefore, formulation B showed better overall results. The above specification, examples and data provide a complete description of the manufacture and use of the composition of the invention. Since many embodiments of the invention can be made without departing from the spirit and scope of the invention, the invention resides in the following claims appended hereto.

Claims (19)

1. A controlled release solid pharmaceutical composition, adapted for oral administration, comprising: a therapeutically effective amount of at least one basic drug having a solubility in water - of less than 1 part per 30 parts of water; a water soluble alginate salt; a complex salt of alginic acid; and an effective amount of an organic carboxylic acid to facilitate the dissolution of the basic drug.

2. The composition of claim 1, in the form of a tablet.

3. The composition of claim 1, in the form of a once-a-day dose regimen.

4. The composition of claim 1, wherein the basic drug is a 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. The composition of claim 1, wherein the complex salt of alginic acid is sodium-calcium alginate. The composition of claim 1, wherein the organic carboxylic acid is selected from the group consisting of tartaric, malic, succinic, glutaric, glutamic, maleic, mandelic, and citric acid. 9. The composition of claim 8, wherein the organic carbsylic acid is citric acid. The composition of claim 1, wherein the weight ratio of the salt of soluble alginate to the complex salt of alginic acid is from about 16: 1 to 1: 1. The composition of claim 10, wherein the weight ratio of sodium alginate to sodium alginate-calcium is from about 16: 1 to 1: 1. The composition of claim 11, wherein the weight ratio of sodium alginate to sodium-calcium alginate is from about 8: 1 to 2: 1. The composition of claim 1, wherein the molar ratio of the organic acid to the basic drug is from about 0.2: 1 to 5: 1. The composition of claim 1, wherein the molar ratio of the organic acid to the basic drug is about 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. 16. The composition of claim 4, wherein the macromolecule is selected from the group consisting of erythromycin, dirithomycin, azithromycin, roxithromycin and ABT-229. 17. A controlled release solid pharmaceutical composition adapted for oral administration of a once-a-day dose regimen comprising: approximately 500 milligrams of clarithromycin; from approximately 75 to 400 milligrams of sodium-calcium alginate, and approximately 128 milligrams of citric acid. The composition of claim 17, comprising: from about 80 to 200 milligrams of sodium alginate, and from about 10 to 40 milligrams of sodium-calcium alginate. The composition of claim 18, comprising: about 120 milligrams of sodium alginate, and about 15 milligrams of sodium-calcium alginate.