Background o the Invention There is an ever-present need in the pharmaceutical industry for improved pharmaceutical formulations that enhance the efficacy of poorly soluble therapeutic agents. There is especially a need for formulations that (1) enhance the absorption of poorly soluble therapeutic agents, and (2) extend the period of duration of effect of the therapeutic agents.

The aqueous solubility of drug substances plays an important role in the formulation of dosage forms. For the oral route of administration it is well experienced that, unless the substance has an aqueous solubility above 10mg/ml over the pH range 1-7, potential absorption problems may occur. Numerous active ingredients suffer from the disadvantage of being poorly soluble in an aqueous medium, thus having an insufficient dissolution profile and consequently, poor bioavailability following oral administration.

The therapeutic dose required to be administered must be increased in order to obviate this disadvantage. This necessitates the administration of active ingredients three or four times a day in order to achieve the desired effect.

For a drug that is administered in multiple doses, it is reported that the patient compliance is as high as 87% when administered once a day as when compared to 39% for a q. i. d. dosage regimen. An extended-release dosage form may improve the quality of therapy and the safety profile relative to a conventional dosage form. However, in order to be effective, these extended release formulations should completely release the drug within a predetermined period.

Erythromycin and its derivatives are useful in treating bacterial infections and are known as anti-bacterial agents useful against a number of organisms and are typically administered two to three times a day as immediate release compositions. In particular, 6-

0-methoxyerythromycin A (clarithromycin), which has been disclosed in US Patent No.

4,331, 803, has to be administered at least twice daily for optimal effect.

Surprisingly, the inventors have discovered that extended release tablets prepared using micronized clarithromycin, which has been processed with suitable wetting agents, results in an improved dissolution and absorption characteristics even when the tablets are administered in fasting conditions.

Use of wetting agent also helps in incorporating a very high content of the active, over 70% w/w in the tablets, while maintaining the tablet size that is acceptable and easy to swallow. Compositions with high drug content leave little room for excipients, especially where the size of the dosage form is an issue. In clarithromycin compositions, where more than 70% w/w of the active agent is to be incorporated without increasing the size of the dosage form, the high concentration of the hydrophobic active acts as a barrier for aqueous media. However, this problem can be overcome by treating clarithromycin with a small amount of a wetting agent and as a result, more than 70% w/w of the active agent may be incorporated into a single tablet without further increasing the size of the tablet.

Summary of the Invention In one general aspect there is provided a pharmaceutical composition which includes micronized clarithromycin and one or more wetting agents.

Embodiments of the pharmaceutical compositions may include one or more of the following features. For example, the clarithromycin may be present at more than 70% w/w of the tablet, or more particularly from about 70% w/w-90% w/w of the tablet. For example, the clarithromycin may make up approximately 1000 mg of the composition.

The clarithromycin may be micronized to have a particle size less than 50 microns, and more particularly to a particle size less than 35 microns. l The pharmaceutical composition may further include one or more wetting agents.

The wetting agents may be one or more of gelatin, casein, lecithin, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, polyethylene glycols, polyoxyethylene stearates, sodium dodecylsulfate, partial fatty acid esters of polyhydroxy ethylene sorbitan, such as polyethylene glycol sorbitan monolaurate, monopalmitate, monostearate and

monooleate; polyethylene glycol sorbitan tristearate and trioleate ; polyethylene glycol sorbitan monolaurate and monostearate; polyethylene glycol sorbitan monooleate, polyhydroxyethylene fatty alcohol ethers such as polyoxyethylene cetyl stearyl ether; corresponding lauryl ethers; polyoxyethylene fatty acid esters; ethylene oxide/propylene oxide block copolymers; sugar ethers and sugar esters; phospholipids and their derivatives; and ethoxylated triglycerides such as the derivatives of castor oil. For example, the wetting agent may be polyoxyethylene fatty acid ester, or it may be ethoxylated derivative of castor oil. The wetting agent may be present in an amount from about 0.025% to about 5% w/w of the tablet.

The pharmaceutical composition may further include one or more rate controlling polymers. The rate controlling polymers may be one or more of carbohydrate gums, polyuronic acid salts, cellulose ethers, and acrylic acid polymers.

The pharmaceutical composition may be a once a day formulation. The dosage form may be a tablet or a capsule.

In another general aspect there is provided process for preparing a pharmaceutical composition of clarithromycin. The process includes micronizing clarithromycin; processing the clarithromycin with one or more wetting agents; and compressing to form a tablet.

Embodiments of the process may include one or more of the following features.

For example, the process may further include blending the clarithromycin and wetting agents with one or more rate controlling polymers and pharmaceutically acceptable excipients; and granulating the blend.

The clarithromycin may make up approximately 1 000mg of the tablet.

The clarithromycin may be micronized to have a particle size less than 50 microns.

More particularly, the clarithromycin may be micronized to have a particle size less than 35 microns.

The wetting agents used in the process may include one or more of gelatin, casein, lecithin, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, polyethylene glycols, polyoxyethylene stearates, sodium dodecylsulfate, partial fatty acid esters of polyhydroxy ethylene sorbitan, such as polyethylene glycol sorbitan monolaurate, monopalmitate, monostearate and monooleate; polyethylene glycol sorbitan tristearate and

trioleate; polyethylene glycol sorbitan monolaurate and monostearate; polyethylene glycol sorbitan monooleate, polyhydroxyethylene fatty alcohol ethers such as polyoxyethylene cetyl stearyl ether; corresponding lauryl ethers; polyoxyethylene fatty acid esters; ethylene oxide/propylene oxide block copolymers; sugar ethers and sugar esters; phospholipids and their derivatives; and ethoxylated triglycerides such as the derivatives of castor oil. For example, the wetting agent may be polyoxyethylene fatty acid ester or it may be ethoxylated derivative of castor oil.

The rate controlling polymers may be or more of carbohydrate gums, polyuronic acid salts, cellulose ethers and acrylic acid polymers.

In another general aspect, there is provided a method of treating a bacterial infection in a mammal in need of treatment. The method includes administering a pharmaceutical composition which includes micronized clarithromycin, one or more pharmaceutically acceptable excipients, and one or more wetting agents.

Detailed Description of the Invention The process of developing pharmaceutical compositions of clarithromycin is challenging for the pharmaceutical formulator because of opposing solubility and stability constraints. In particular, clarithromycin has increased solubility but reduced stability at the acidic pH conditions in the stomach, and increased stability but reduced solubility at the alkaline pH of the lower portion of the intestine (pH 6.0 to 8.0). These constraints result in poor bioavailability of clarithromycin. In spite of these competing constraints, the inventors nonetheless realized the desirability of dosage forms of clarithromycin having improved dissolution and absorption characteristics that can be administered once per day, and conducted research and development activities for developing such a clarithromycin formulation. As a result of these efforts, the inventors have surprisingly found that the dissolution and absorption characteristics of clarithromycin, as well as its bioavailability, can be increased by micronizing the clarithromycin.

The term"micronization"used herein means any process or methods by which the size of the particles is reduced. As also used herein, clarithromycin particles with reduced size are referred to as"micronized particles of clarithromycin"or"micronized clarithromycin".

The clarithromycin used in the pharmaceutical compositions described herein can be prepared by any known method, such as, for example, using either of the procedures disclosed in U. S. Patent No. 4,331, 803 or U. S. Patent No. 4,672, 109. Both of these patents are incorporated herein in their entirety by reference.

The process of the invention for preparing a solid formulation of clarithromycin with improved dissolution and absorption characteristics includes the micronization of clarithromycin. Size reduction, or micronization, may be carried out using any of the conventionally known mills, such as a ball mill, colloid mill, grinding mill, air jet mill, roller mill, impact mill, etc. Air jet milling is particularly well suited for this application as it is a well proven technique that consistently produces particles of a size less than 35 microns. Primary advantages of air jet milling are that the predominant particle size reduction occurs through particle to particle collisions, there is limited particle size reduction that results from metal to product contact, and there is no generation of heat that can adversely affect the particles being micronized.

The process of air jet milling involves exposing the material to be micronized to streams of compressed air or gas. Particles in the fluidized bed created by the gas streams are accelerated towards the center of the mill and collide with the slower moving particles.

These collisions break the particles into smaller particles, thereby micronizing the particles. The air jet mills operate by applying opposing air flows and centrifugal forces.

By balancing the two forces, desired particle size and fines can be separated.

The reduction of the particle size of clarithromycin to a Dgo particle size of less than 50 microns, and more particularly less than 35 microns, results in improved bioavailability of clarithromycin pharmaceutical compositions as compared to clarithromycin pharmaceutical compositions that contain larger sized clarithromycin particles. Clarithromycin particles having a Dgo particle size of less than about 50 microns, and more particularly less than about 35 microns, are referred to herein as "micronized clarithromycin particles. "As used herein,"Dgo particle size"is the particle size of at least 90% of the particles of clarithromycin used in the composition.

When clarithromycin is micronized, the resulting particles can be difficult to process because highly micronized particles may possess poor flow properties and have a tendency to agglomerate during processing. To overcome these potential and actual

difficulties, the clarithromycin may be micronized in the presence of one or more pharmaceutically inert carrier (s) or mixed with inert carriers after micronization to neutralize the static charge.

In our co-pending patent application, we have described how extended release pharmaceutical compositions of clarithromycin could be prepared using micronized clarithromycin. These extended release compositions were found to possess improved dissolution and absorption characteristics and exhibited bioavailability comparable to two doses of immediate release formulations of clarithromycin. However, comparable results were obtained only in fed conditions.

The inventors nonetheless realized the desirability of dosage forms of clarithromycin having improved dissolution and absorption characteristics that can be administered once per day during the fasted state. Accordingly, they conducted research and development activities for developing such a clarithromycin formulation. As a result of these efforts, the inventors have surprisingly found that processing the micronized clarithromycin particles with a sufficient amount of a wetting agent can increase the dissolution and absorption characteristics of clarithromycin and its bioavailability.

Further, a large dose of the drug can be incorporated into a single tablet without increasing the size of the tablet.

As used herein, the term"pharmaceutically inert carrier"refers to a substance that is physiologically acceptable, compatible with the drug and other excipients in the formulation, and has a capacity to adsorb the drug on its surface. The pharmaceutically inert carriers prevent reagglomeration of drug particles and also help in wetting of the drug by uptake of water by capillary action and thereby enhancing drug dissolution further.

The pharmaceutically inert carrier may be selected from cellulose derivatives such as microcrystalline cellulose and carboxymethyl cellulose; silicate derivatives such as magnesium silicate, colloidal silicon dioxide, magnesium trisilicate, and magnesium aluminum silicate; and clays such as veegum, bentonite, etc.

The micronized clarithromycin, either with or without an inert carrier, then is processed with a suitable wetting agent. Suitable wetting agents include one or more of gelatin, casein, lecithin (phosphatides), glycerol monostearate, cetostearyl alcohol,

cetomacrogol emulsifying wax, polyethylene glycols, polyoxyethylene stearates, sodium dodecylsulfate, partial fatty acid esters of polyhydroxy ethylene sorbitan, such as, polyethylene glycol sorbitan monolaurate, monopalmitate, monostearate and monooleate; polyethylene glycol sorbitan tristearate and trioleate (available under the trade name Tween); polyethylene glycol sorbitan monolaurate and monostearate; polyethylene glycol sorbitan monooleate, polyhydroxyethylene fatty alcohol ethers; polyoxyethylene fatty acid esters; ethylene oxide/propylene oxide block copolymers (available under the trade name Pluronic); sugar ethers and sugar esters; phospholipids and their derivatives; and ethoxylated triglycerides, such as, the derivatives of castor oil (available under the trade name Cremophor).

The concentration of wetting agent in the aqueous or hydroalcoholic wetting solution is the amount sufficient for sufficient wetting and may be from about 0.025% to about 5.0% by weight of the clarithromycin. However, the concentration of wetting agent may vary depending on whether incremental or single shot wetting treatments are employed. In general, small incremental treatments require less wetting agent than a large single shot treatment.

The wetting agent should be applied over the micronized clarithromycin particles as a layer or film. Without being restricted to any particular theory, it is believed that the wetting agents form a layer or coat over clarithromycin particles, which bring about enhancement in wetting characteristics of clarithromycin. This layer or coat results in increased absorption and bioavailability of clarithromycin.

The micronized clarithromycin particles may be processed by using any of the processes known in the conventional art, which include one or more of granulation, particle coating and spray drying.

The wetted clarithromycin particles are dried using conventionally known methods of drying including spray drying or fluidized bed drying.

The dried particles are milled to break the agglomerates and finally processed to form a solid formulation (e. g. , tablet) that includes a rate-controlling polymer and one or more pharmaceutically acceptable excipients. The rate-controlling polymer provides sustained or extended release characteristics to the finished dosage form. For example, the amount of micronized clarithromycin in the finished dosage form can be present at

between approximately 100 mg and 1000 mg and the finished dosage form taken only once per day.

The rate-controlling polymers of the solid formulation and finished dosage form may be selected from the group that includes carbohydrate gum, polyuronic acid salts, cellulose ethers, acrylic acid polymers and mixtures, thereof. Carbohydrate gums may be selected from the group that includes xanthan gum, tragacanth gum, gum karaya, guar gum, acacia, gellan, locust bean gum and other carbohydrate gums having similar properties. Polyuronic acid salts include alkali metal salts of alginic acid or pectic acid and mixtures thereof. Examples of alkali metal salts of alginic acid that may be used include sodium alginate, potassium alginate, ammonium alginate and other suitable alkali metal salts of alginic acid. Cellulose ethers include hydroxypropyl methyl cellulose, hydroxypropyl cellulose and other suitable cellulose ethers. Any suitable polyacrylic acid polymer, such as is available under the brand name carbopol, may be used. Rate controlling polymers may contribute about 0.5-4. 5% w/w of the tablet.

The other pharmaceutically acceptable excipients include gas generating components, swelling agents, lubricants, binders, and fillers and diluents. Gas generating components include carbonates, such as calcium carbonate; bicarbonates such as sodium bicarbonate; sulfites such as sodium sulfite; and other suitable known gas generating components. Swelling agents include cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose sodium, sodium starch glycolat and other suitable, known swelling agents. Lubricants include talc, calcium stearate, magnesium stearate, polyethylene glycols, silicon dioxide, sodium lauryl sulphate, sodium stearyl fumarate, other suitable, known lubricants, and mixtures thereof. Binders include polyvinyl pyrrolidone (PVP) and other suitable, known binders. Fillers and diluents include lactose and other suitable, known fillers and diluents.

The following examples are provided to illustrate various implementations of the invention without being limiting. In general, the process includes the following steps: 1. micronization of clarithromycin, 2. processing the micronized clarithromycin with a solution of sufficient amount of wetting agent, 3. drying the mixture of step 2,

4. milling; 5. blending milled material with polymers and other excipients, 6. granulating; 7. drying the granules, lubricating and compressing to form tablets.

EXAMPLE 1 Preparation of Extended release Clarithromycin tablets Ingredients mg/tablet Clarithromycin 1000. 0 Polyethylene glycol 40.0 Polyoxyethylene sorbitan ester 20.0 Hydroxypropyl methylcellulose 52.5 Intragranular Lactose 90. 0 Polyvinyl pyrrolidone 25.0 Colloidal Silicon dioxide 2.0 Talc 10. 0 Extragranular Sodium stearyl fumarate 31. 5 Colloidal silicon dioxide 3.0 Magnesium stearate 1.0 Film coating 3S. 0

Process: Polyethylene glycol and polyoxyethylene sorbitan ester were dissolved in a mixture of isopropyl alcohol and purified water (25: 75). This solution was slowly added to micronized clarithromycin particles in a high shear mixer. The wet particles were dried in a fluidized bed dryer at 60°C and milled. The dried and milled clarithromycin particles, hydroxypropyl methylcellulose, polyvinyl pyrrolidone and lactose were sieved through a British Standard Sieve (BSS) 44 mesh sieve, blended together, and granulated with water.

The resulting granulate was dried in a fluid bed drier at 60°C for 20 minutes. The dried granules were sifted through a BSS 16 mesh sieve. The granules obtained were lubricated with the remaining ingredients and compressed to tablets.

EXAMPLE 2 Preparation of Extended release Clarithromycin tablets Ingredients mg/tablet Clarithromycin 1000. 0 Polyethylene glycol 40.0 Polyoxyl 40 hydrogenated castor oil 20.0 Hydroxypropyl methylcellulose 52.5 Intragranular Lactose 90. 0 Polyvinyl pyrrolidone 25.0 Colloidal Silicon dioxide 2. 0 Talc 10. 0 Extragranular Sodium stearyl fumarate 31.5 Colloidal silicon dioxide 3.0 Magnesium stearate 1.0 Film coating 38. 0

Process: As followed in Example 1.

The release profile of clarithromycin extended release tablets prepared with untreated clarithromycin particles and clarithromycin particles wetted with wetting agents is provided in Table 1.

Table 1. Release profile of tablets prepared without wetting agents and tablets prepared according to Examples 1 and 2 in pH 6.8 phosphate buffer/1000m1/USP Apparatus I/100 rpm Time Percent drug Percent drug release Percent drug release (hr) release from from tablets of from tablets of tablets without Example 1 (%) Example 2 (%) wetting agent (%) 1. 0 2 13 11 2. 0 3 20 19 4. 0 31 29 8. 0 10 46 45 10. 0 13 50 50

As can be seen from the data above, only 13% of the clarithromycin is released from a formulation that does not include a wetting agent whereas when the formulation is such that clarithromycin is wetted with a wetting agent, a clarithromycin release of about 50 % is obtained.

Pharmacokiszetic evaluation Extended release clarithromycin tablets (1000 mg) prepared without a wetting agent were subjected to pharmacokinetic investigation along with Biaxin XL, 2 x 500 mg tablets, currently marketed by Abbott, in normal healthy male subjects under fasting conditions.

Values for pharmacokinetic parameters, including observed Cmax, AUCo-t and AUCo «, were calculated using standard non-compartmental methods. The results as indicated by ratio of test to reference, are shown in Table 2.

Test (A): Clarithromycin XL tablets 1000 mg (without wetting agent) Reference (R): Biaxin XL (2X 500 mg) tablets Table 2: Summary of pharmacokinetic parameters Parameters Cmax (ng/ml) AUC (o-t) (ng. hr AUC (o-cc) (ng. hr /ml)/ml) Ratio % (A/R) 67. 58 58. 72 60. 46 90% Confidence 55.74-81. 95 44. 67-77. 18 46. 43-78.73 intervals

A similar study was carried out using extended release tablets prepared according to Examples 1 and 2 in healthy male subjects under fasting conditions. Values for the pharmacokinetic parameters, including observed Cmax, AUCo-t and AUCo «, were calculated using standard non-compartmental methods. The results as indicated by ratio of test to reference are shown in Table 3.

Test (C): Clarithromycin XL 1000 mg tablets of Example 1 Test (D): Clarithromycin XL 1000 mg tablets of Example 2 Reference (R): Biaxin XL (2 X 500 mg) tablets Table 3: Summary of pharmacokinetic parameters Parameters Cmax (ng/ml) AUC (O-t) (ng. hr AUC (o-oc) (ng. hr /ml)/ml) Ratio % (C/R) 108.96 98.20 98. 65 90% Confidence 93. 56-126. 90 79. 47-121. 34 79. 52-122.38 intervals Ratio % (D/R) 107.84 95.75 96.63 90% Confidence 92.35-125.92 77.23-118.71 77.64-120.28 intervals

As is evident from the results in Table 3, the Area Under the Curve is comparable to the test formulation when the clarithromycin tablets are prepared using a wetting agent.

While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. For example, the clarithromycin used in the pharmaceutical compositions does not necessarily need to include only micronized clarithromycin but instead can be made up of a mixture of micronized and unmicronized clarithromycin, e. g. , a first batch of clarithromycin is micronized and then mixed with a second batch of clarithromycin which has not been micronized. Moreover, the micronized clarithromycin may be administered with (e. g. , as a single pharmaceutical combination composition, simultaneously, or within a short time) other drugs and drug products to treat conditions that may be related to or occur concurrently with a condition that involves the need to provide antibacterial activity using clarithromycin. Such drugs that may be co-administered with the micronized clarithromycin generally include one or more of omeprazole, metronidazole, amoxicillin, rifampicin, lansoprazole, ciprofloxacin, ethambutol, and ritonavir. For example, the combinations may include a single pharmaceutical composition or joint administration of : (1) omeprazole, metronidazole, and clarithromycin; (2) omeprazole, amoxicillin, and clarithromycin; (3) rifampicin and clarithromycin ; (4) lansoprazole and clarithromycin; (5) ciprofloxacin and clarithromycin; (6) lansoprazole, amoxicillin, and clarithromycin; and (7) ethambutol, ritonavir, and clarithromycin.