HRP970325A2 - Controlled release formulation for poorly soluble basic drugs - Google Patents

Description

Field of invention

The invention relates to a controlled 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 once-daily formulation of clarithromycin.

State of the art

The advent of controlled release dosage forms advanced the pharmaceutical industry. Controlled-release formulations have allowed reductions in drug dosage regimens, especially those administered orally to outpatients.

The benefits of a reduced dosage regimen for outpatients are convenience, and more importantly, better assurance of uptake. For example, reducing the dose regimen from four times daily (q.i.d.) to three times daily (t.i.d.) allows the patient to take the prescribed medication during office hours. Reducing the dose regimen to twice a day (b.i.d.) allows the patient to take the prescribed medication in the morning and in the evening, which provides greater convenience; for example, the patient does not have to pay extra attention when he is away from home. Of course, the best form of dosage is a regimen of one dose per day. Unfortunately, the pharmacokinetic properties (eg, absorption, elimination, and metabolism) of most drugs do not allow an easy way to prepare a single oral dosage form and do not allow a controlled efficient release of the drug over a 24-hour period with reproducible bioavailability.

One method of improving the controlled slow release of solid formulations has been developed for formulations containing alginate gel. Typically, water-soluble alginate, such as sodium alginate or calcium ions in the form of a calcium salt, react with the cross-linked alginate structure to form an insoluble calcium alginate gel. By adding a strong acid to a mixture of sodium alginate and calcium salt, the calcium salt is slowly ionized to give calcium ions. Then the calcium ions react with the soluble alginate to give an insoluble calcium alginate gel. Gelation takes place during the gradual ionization of the calcium salt. With these formulations, the controlled release properties of the alginate gel varied with a change in alginate molecular weight, alginate concentration, type of crosslinker polyvalent cation, or cation concentration.

In accepted European patent 188040-B1 and its amendment, U.S. No. 4,842,866 discloses an improved alginate gel-type composition, which is poorly soluble in body fluids, such as fluids in the gastrointestinal ("GI") tract, which composition contains a therapeutically effective amount of at least one therapeutically active agent that is gradually released as alginate hydrate , and it is indicated that both alginates are present in the preparation, a water-soluble one, especially sodium alginate, and a complex salt of alginic acid, especially sodium-calcium alginate, which has a cation that alone makes the alginate salt soluble, and another cation that alone makes the alginate salt insoluble . Published by the U.S. publication, 4,842,866 is incorporated by reference throughout this document.

However, the application of the technological development in the above-mentioned patents did not prove possible with poorly water-soluble drugs. For example, an in vitro drug release study from an alginate formulation of clarithromycin observed too slow a release. Similarly, in vivo animal studies with erythromycin showed that reproducible bioavailability of controlled release formulations could not be achieved using alginate or other monolithic hydrogel tablets. It was concluded that macrolides, such as erythromycin, in a single monolithic hydrogel tablet will not provide a suitable dosage form for controlled release due to the problems of instability in acid, poor solubility of the drug and variable passage through the GI tract.

An oral formulation containing 6-O-methylerythromycin A and citric acid with improved bioavailability is disclosed in Japanese Kokai 163823/1985, and as an abstract in WPI Acc. no. 85-247033/40.

The aim of the proposed invention is to reduce the daily dose regimen of a poorly water soluble base drug with a controlled release formulation.

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

Brief description of the invention

The proposed invention ensures a reduced daily dosage of poorly soluble basic drugs using an alginate matrix with the inclusion of an organic acid. The solubility of basic drugs decreases as they progress distally towards the colon (pH 8), while they are soluble in the stomach and above or in the proximal region of the small intestine. Therefore, a poorly soluble basic drug will result in less drug available for absorption in the lower or distal intestine. This problem is overcome by including an organic acid in the formulation. Not wishing to be bound by a particular theory, it is believed that as the drug travels down the GI tract, the organic acid formulation creates a low pH microenvironment that promotes drug solubility within the dosage form.

Accordingly, the proposed invention includes a solid pharmaceutical composition for controlled release, adapted for oral administration, which contains:

- a therapeutically effective amount of at least one basic drug that has a solubility in water of less than 1 part per 30 parts of water,

- water-soluble alginate salt,

- complex salt of alginic acid, i

- an effective amount of organic carboxylic acid to facilitate the dissolution of the basic drug.

A particular aspect of the proposed invention is the provision of a once-daily dosing regimen for clarithromycin, which is now administered twice daily as a 250 mg or 500 mg tablet, depending on the type of bacterial infection being treated. The exact side of the in vivo absorption of clarithromycin is unreliable. However, clarithromycin is known to be highly soluble in the stomach (pH 1.2) and less soluble in the upper small intestine (pH 5.0), where absorption most likely occurs. Due to the increased solubility of the drug in the lower intestine (pH 6 to 8), this results in less drug being available for absorption. The proposed invention provides a way to overcome this problem by using an alginate formulation with an organic acid, in particular, for example, citric acid.

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

approximately 500 mg of clarithromycin,

from approx. 75 to 400 mg of sodium alginate,

from approx. 10 to 400 mg of sodium-calcium alginate, i

approx. 128 mg citric acid.

Description of the preferred performance in detail

The object of the present invention is to provide a controlled release pharmaceutical composition in which a poorly soluble base drug can be released continuously from the dosage form as it progresses through the GI tract.

The present invention therefore provides a once-a-day daily dosing regimen for at least one poorly soluble basic drug by providing a controlled-release solid pharmaceutical composition adapted for oral administration to a patient in need thereof. The preferred composition is in the form of a tablet.

A sparingly soluble or basic drug of moderate water solubility is one that has a solubility of less than 1 part in 30 parts of water. The proposed invention can also be applied to even less soluble drugs, for example up to a solubility of one part in 10,000 parts of water.

For example, basic drugs of moderate solubility may include antibiotics, such as, for example, sulfamethoxazole with a solubility of 1 in 3400 (parts of water); tetracycline, 1 in 2500; metronidazole and cimetidine (histamine H2 receptor antagonist for the treatment of ulcers), both of which have a solubility of approx. 1 in 100 to 1 in 1000; indapamide (antihypertensive/diuretic), 1 in more than 10,000; atenolol (antihypertensive), approx. 1 in 30 to 1 in 100; diazepam (tranquilizer), ranging from 1 in 1,000 to 1 in 10,000.

As preferred basic drugs, the proposed invention includes macrolides that are also poorly soluble. Examples of macrolides are erythromycin with a solubility of 1 part in 1000 parts of water; dirithromycin of similar solubility to erythromycin; josamycin, midekamycin, kitasamycin, all three of which are very poorly soluble in water, in the range of approx. 1 in 1000 to 1 in 10000; and tylosin, which is used only in veterinary medicine, with a solubility in the range of approx. 1 in 100 to 1 in 1000. Other macrolides that may be included are, for example, roxithromycin, rokitamycin, oleandomycin, myocamycin, flurithromycin, rosaramycin, azithromycin, and compounds designated as ABT-229 or ABT-269. The macrolide most preferred for the proposed invention is clarithromycin, which has a solubility of approx. one part in 1000 parts of water.

The pharmaceutical composition of the present invention may include other drugs in combination with a poorly soluble base drug where combination therapy is known to be necessary or useful.

Thus, for example, in combination with macrolides, erythromycin or clarithromycin, preparations can be formulated for the standard therapy of gastritis, ulcers or gastroesophageal reflux disease (GERD), such as preparations containing anti-ulcer or anti-gastric drugs; eg selected from compounds that inhibit gastric secretion 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 their hydrate (such as the monohydrate known as magaldrate).

Other macrolides, especially erythromycin or clarithromycin, of the pharmaceutical composition of the present invention can be adapted for administration in combination with a composition containing bismuth salts, such as bismuth subcitrate, bismuth subsalicylate, bismuth subcarbonate, bismuth subnitrate or bismuth subgallate.

The amount of the drug or drugs in the pharmaceutical composition can vary from approx. 40 to 75% of the total composition or tablet. For clarithromycin, the amount can primarily vary from 50% to 75% of the weight of the total composition or tablet.

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

While sodium alginate is normally used in the particles of this invention, the sodium cation may be replaced with another cation; eg with potassium or other alkali metal, magnesium or ammonium, so that a soluble alginate salt is obtained. Thus alginate can also be, for example, potassium alginate or ammonium alginate.

The complex salt of alginic acid can be a sodium-calcium complex salt of alginic acid, in which the amount of calcium is precisely controlled, and which is self-gelling without the necessary reaction with gastric acid or additional calcium ions. While sodium-calcium alginate is normally used in the practice of this invention, the sodium cation can be replaced with another cation, so that a soluble alginate salt is obtained; eg with potassium or other alkali metal, magnesium or ammonium, and the calcium cation can also be replaced by another polyvalent cation (other than magnesium) giving an insoluble alginate salt; eg with strontium, iron or barium. The compositions described herein, which are most preferred, typically include sodium alginate, manufactured and sold, for example, by Alginate Industries, Ltd., England, under the trade name “Manucol”, and sodium calcium alginate, manufactured and sold by Kelco Division of Merck and Co., Inc., San Diego, California, USA, under the trade name “Kelset”.

The weight ratio of the soluble alginate salt to the complex salt of alginic acid can range from about 16:1 to 1:1, preferably from about 8:1 to 2:1. The same ratio naturally applies to the ratio of sodium alginate to sodium-calcium alginate. As already mentioned here, to obtain a controlled release formulation, European patent 188040 describes the combination of soluble alginates and a complex salt to form an insoluble salt.

The organic acid required in the controlled release formulation of the proposed invention is one of the acids that can create a low pH microenvironment, lower than 7.0, in the vicinity of the hydrating dosage form. Given the differences between the acids, the effective amount of the organic acid is the amount that facilitates the dissolution of the basic drug through the GI tract. The precise amount may vary depending on the acid used and the choice of base agent, as is known to those skilled in the art. The ratio refers to the molar ratio and can vary from approximately 0.2:1 to 5:1 acid to drug. The molar ratio of acid to drug of 1:1 is used first.

An organic acid for the purposes of the present invention includes any organic carboxylic acid, preferably an aliphatic organic carboxylic acid having anywhere from 3 to 20 carbon atoms. These are primarily, for example, tartaric acid, malic acid, succinic acid, glutaric acid, glutamic acid, maleic acid, mandelic acid and citric acid. The greatest preference is given to citric acid.

A particular and preferred embodiment of the proposed invention is a controlled release solid pharmaceutical composition adapted for oral administration for a once-daily dosing regimen comprising:

approximately 500 mg of clarithromycin;

from approx. 75 to 400 mg of sodium alginate;

from approx. 10 to 400 mg of sodium-calcium alginate, i

approx. 128 mg citric acid.

First of all, the composition contains approx. 80 to 200 mg of sodium alginate and from approx. 10 to 40 mg of sodium-calcium alginate. It is best if the composition contains approx. 120 sodium alginate and approx. 15 mg sodium-calcium alginate.

The composition is primarily in the form of a tablet, but it can also be in the form of a capsule or pill or granulate.

Other ingredients, which are commonly used in the compositions according to the invention, may include pharmaceutically acceptable auxiliaries, such as preservatives, diluents, for example starch or microcrystalline cellulose, binders, such as starch, polyvinyl pyrrolidone (Povidone) and sodium carboxymethylcellulose, slip agents or lubricants, such as talc and magnesium stearate, bulking agents, such as lactose, and approved coloring agents. The dosage form may also be coated with a material not specifically designed to control or modify drug release.

The preparation can be processed into tablets, suppositories or can be used to fill capsules. The preparation may also be coated, if desired, for example, to mask the otherwise bitter taste of the preparation.

By studying the bioavailability on the example of a typical formulation of the proposed invention containing 500 mg of clarithromycin, the acceptance criterion for a successful once-daily dosage formulation was met. This means that the area under the AUC0-24 curve achieved is at least equivalent to the 250 mg twice daily (BID) dosing regimen, the 250 mg dosing regimen, and that 24-hour plasma concentrations of clarithromycin are at least equivalent to those of the 250 mg BID regimen .

Examples

Example 1

Details of making the tablet

1a. Granules for controlled release

The following general manufacturing method was used for all tablet formulations. To remove any larger aggregates, the active drug, polymer, binding agent and remaining excipients are sieved through a sieve with a mesh size of 850 μm. The dry sieved material is then mixed for 5 minutes in a planetary mixer set to the lowest speed. The mixed material is granulated with the addition of 50/50 vol./vol. solution of alcohol and water in small quantities until a suitable granulated mass is obtained. The wet mass is sieved through a 4.0 mm mesh sieve on a paper-covered base and dried in a hot air oven at 50oC to a moisture content of less than 4 wt. % (determined using a Sartorius IR scale, Model YTC01L, measurement conditions: 98oC/15 minutes). Finally, the dried granulate is passed through an 850 μm mesh screen and mixed for 5 minutes with tablet lubricants in a planetary mixer set to the lowest speed.

1b. Pressing

Tablets are pressed on a rotary tablet press with oval stamps. Individual formulations A, B and C were pressed into tablets under pressure sufficient to obtain tablets of suitable thickness and crushability. Tablet compositions are listed in Table 1.

Table 1.

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Example 2

Study of bioavailability

2a. Materials and suppliers

The plasma concentration profiles of the above three once-daily (QD) 500 mg formulations A, B and C were compared with the twice-daily dosing regimen of commercially available BIAXIN® 250 mg tablets (ie, 250 mg BID, referred to herein as formulation D ) in the solid state. The acceptance criterion for a successful QD formulation was:

• AUC0-24 equivalent to at least a 250 mg twice daily (BID) dosing regimen,

• plasma concentrations of clarithromycin during 24 hours equivalent to a dosage regimen of 250 mg BID.

2b. Method of study and results

The study was conducted as a phase I, multi-dose, open-label, randomized, four-period, balanced crossover study. Appropriate patients were examined for a complete history, physical examinations were performed, and laboratory profiles were determined, including hematological, renal, and liver parameter evaluations.

Eight healthy male volunteers between 18 and 50 years of age were dosed in the morning on days 1, 2 and 3 of 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. At the end of the study, each person received all formulations.

Blood samples were collected before dosing on the third day (0 hours) and 1, 2, 3, 4, 6, 8, 10, 12, 16 and 24 hours after dosing. All samples were transferred in heparinized collection tubes and centrifuged. The separated plasma was divided into equal volumes and transferred into appropriately labeled tubes and immediately frozen. Plasma samples were frozen until assayed.

Plasma samples were tested using a large bioassay plate. This method measures the total antibiotic activity, and the result is expressed as mcg of clatithromycin in ml.

2c. Data and statistical analysis

The bioequivalence of the three once-daily formulations with standard tablets was examined using a two-tailed, one-tailed t-test. 90% confidence intervals were calculated from natural logarithm analysis for AUC, Cmax and concentration after 24 hours. This is obtained by the exponent of the endpoint of the 90% confidence interval for the magnitude of the difference in mean logarithms. Biological equivalence between formulations exists if these limits lie within the range of 0.80 to 1.25. Additionally, 90% confidence intervals for mean ratios were obtained from analysis of unchanged AUC and 24-hour concentrations. The results of these analyzes are summarized in Tables 3, 4 and 5. Pharmacokinetic data are presented in Table 2.

Table 2: Pharmacokinetic data

[image] *As the second standard tablet was not fully observed by the plasma sampling program, the AUC0-24 value was calculated by multiplying the AUC0-24 value by 2.

Table 3: Results of statistical analysis for AUC.

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Table 4: Results of statistical analysis for Cmakc.

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Table 5: Results of statistical analysis of concentration after 24 hours.

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Discussion

The average AUC ratio within 90% confidence limits indicates that formulations A, B and C are biologically equivalent to the standard dosing regimen. All three formulations show therapeutic levels at C24 hours. Cmax limits (unchanged) are acceptable for most formulations. Compared to the standard formulation, all three once-daily formulations showed prolonged absorption of clarithromycin.

Formulations A and B, despite containing different amounts of alginate, give similar in vivo profiles. However, previous studies have shown that the reproducibility of the release profile is improved with increasing amounts of alginate. Therefore, formulation B showed the best overall results.

The above specification, examples and data provide a complete description of the manufacture and use of the compositions of the invention. Since many embodiments of the invention are possible without departing from the spirit and purpose of the invention, the invention is supported by the appended claims.

Claims (19)

1. Solid pharmaceutical preparation for controlled release adapted for oral administration, characterized in that it contains: - a therapeutically effective amount of at least one basic drug that has a solubility in water of less than 1 part per 30 parts of water, - water-soluble alginate salt, - complex salt of alginic acid i - an effective amount of organic carboxylic acid to facilitate the dissolution of the basic drug. 2. The composition according to claim 1, characterized in that it is in the form of a tablet. 3. The composition according to claim 1, characterized in that it is in the form of a dosage regimen that is given once a day. 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 agglutinate salt is sodium alginate. 7. Composition according to claim 4, 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, malic, succinic, glutaric, glutamic, maleic, mandelic and citric acids. 9. Composition according to claim 8, characterized in that the organic carboxylic acid is citric acid. 10. The composition according to claim 1, characterized in that the mass ratio of the soluble alginate salt to the complex salt of the alginic acid salt is approximately 16:1 to 1:1. 11. Composition according to claim 10, characterized in that the mass ratio of sodium alginate to sodium-calcium alginate is approximately 16:1 to 1:1. 12. The composition according to claim 11, characterized in that the mass ratio of sodium alginate to sodium-calcium alginate is approximately 8:1 to 2:1. 13. Composition according to claim 1, characterized in that the molar ratio of organic acid to basic drug is approximately 0.2:1 to 5:1. 14. The composition according to claim 1, characterized in that the molar ratio of the organic acid to the basic drug is approximately 1:1. 15. 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. 16. The composition according to claim 4, characterized in that the macrolide is selected from the group consisting of erythromycin, dirithromycin, azithromycin, roxithromycin and ABT-229. 17. A solid pharmaceutical composition for controlled release, adapted for oral administration in a once-daily dosing regimen, characterized in that it contains: approximately 500 mg of clarithromycin; from approx. 75 to 400 mg of sodium-calcium alginate, i approx. 128 mg citric acid. 18. Composition according to claim 17, characterized in that it contains: from approx. 80 to 200 mg of sodium alginate, i from approx. 10 to 40 mg of sodium-calcium alginate. 19. Composition according to claim 18, characterized in that it contains: approx. 120 mg sodium alginate, i approx. 15 mg sodium-calcium alginate.