Field of the invention

The present invention relates to a slow release pharmaceutical composition of cefdinir or a pharmaceutically acceptable salt thereof.

Background of the Invention

7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid known as Cefdinir, is a third generation broad-spectrum oral cephalosporin antibiotic, active against many gram-positive and gram-negative bacteria. Commercially available as Omnicef®, the drug acts against respiratory tract pathogens such as H. influenza, S. pneumoniae, and M. catarrhazis. Cefdinir is highly stable in the presence of P-lactamase enzymes and many plactamase- producing bacterias those are resistant to penicillins, and some cephalosporins, are susceptible to Cefdinir.

The drug is used for treatment of otitis media, soft tissue infections and respiratory tract infections, such as community-acquired pneumonia, bronchitis and acute sinusitis, caused by several gram-negative and gram-positive bacteria. It is a generally well tolerated antibiotic, with most adverse effects being mild and self-limiting.

Cefdinir was first disclosed in U.S. Pat. No. 4,559,334, which is incorporated herein by reference. Different polymorphs of cefdinir are disclosed in U.S. Pat. 4,935,507, U.S. Pat. 7,307,072, U.S. Pat. 7,244,842 and U.S. Pat. Application 20030204082. W005100368 discloses a stable amorphous cefdinir, methods for its preparation, and pharmaceutical compositions comprising stable amorphous cefdinir. All the patents and patent applications cited in this paragraph are hereby incorporated herein by reference.

Slow release pharmaceutical formulations provide a significant advantage over immediate release formulations to both clinicians and their patients. Slow release dosage forms are administered to patients in much fewer daily doses than their immediate release counterparts and generally achieve improved therapeutic effect and efficiency in the fewer daily doses.

While formulating p-lactam antibiotics (e.g. cephalosporins), it is important to note that the half-life of these agents are merely 1-2 hrs which thus requires frequent administration. In addition, it is believed that these agents are more effective as continuous infusions rather than periodic bolus administrations. This may be due to the fact that high concentrations of these agents are generally associated with reduced therapeutic efficacy underlining the need for continuous administration.

Cefdinir is absorbed from the gastrointestinal tract after oral administration of immediate release formulation achieving peak plasma concentrations at 2-4 h after a single dose. As the biological half-life of cefdinir is very short (around 2 hours), there is rapid reduction of plasma drug concentration below minimum inhibitory concentration (MIC). Again, bioavailability of cefdinir after oral administration has been estimated in a range of 16 to 25% and it decreases when the dose is increased. As 85% of cefdinir absorption from gastrointestinal track is through active transport process, at high dose there will be saturation of active process and hence results in decrease of bioavailability.

Cefdinir is insoluble in water, slightly soluble in dilute hydrochloric acid and sparingly soluble in 0.1 M pH 7.0 phosphate buffer. Such limited solubility reduces the number of formulations and delivery options available for cefdinir. Limited water solubility also results in low bioavailability of cefdinir.
Therefore, there is a need to maximize the dissolution of cefdinir from a dosage form, potentially during in-vivo exposure and simultaneously slowing the release rate of the drug in the gastrointestinal tract over the period of time to increase in bioavailability during in-vivo exposure. Further, slowing the release rate of cefdinir will enhance of efficacy of active transport process and hence bioavailability. Therefore, there is a need to develop a suitable dosage form of cefdinir which will increase its solubility and slows the release rate of active agent, over a period of time.

WO05030178 provides a controlled drug delivery formulation of P-lactam antibiotics with one or more carbomers. Further, U. S. Pat. 4,250,166, U. S. Pat. 4,713,247, U.S. Pat. 4,968,508, U. S. Pat. 5,948,440 disclose slow release of various cephalosporins using various drug delivery systems. As cefdinir is poorly soluble as well absorbed mainly through active transport process, special consideration has to be taken to design a formulation to increase the bioavailability of the drug by simultaneously increasing the solubility of cefdinir and slowing release rate of the drug from the dosage form. But none of the prior art teaches how to prepare a slow release composition of cefdinir to increase the solubility and slowing the release rate of the drug in the gastroinstinal tract simultaneously, thereby increasing the bioavailability. Hence the object of the invention is to develop a slow release dosage form of cefdinir which increase the solubility and simultaneously slow the release rate of the drug from the dosage form.

Summary of invention

It is the object of the present invention to provide a slow release pharmaceutical composition of cefdinir. The pharmaceutical composition of the present invention comprises cefdinir or a pharmaceutically acceptable salt thereof, wherein the composition increases the solubility of cefdinir and simultaneously slows the release rate of the drug from it.

One embodiment of the invention provides a slow release pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof, a surface-active agent and a release rate controlling agent.

Another embodiment of the invention provides a slow release pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof, wherein the composition has the following in-vitro release rate, measured by the USP Apparatus II (Paddle) at 50 rpm using pH 6.8 phosphate buffer at 37°C:

3 to 35% by weight (based on 100% by weight active agent) cefdinir released after 1 hour,
5 to 60% by weight cefdinir released after 2 hour, 10 to 80% by weight cefdinir released after 4 hours, 15 to 95% by weight cefdinir released after 6 hours, more than 50% by weight cefdinir released after 12 hours, more than 70% by weight cefdinir released after 16 hours, and more than 80% by weight cefdinir released after 24 hours.

Another embodiment of the invention provides a slow release pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof, wherein the cefdinir is amorphous powder, crystalline particles, matrix particles, or a mixture thereof.

Another embodiment of the invention provides a slow release pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof, a surface-active agent and a rate controlling agent, wherein the surface-active agent is sodium lauryl sulfate, sodium dioctyl sulphosuccinate, sodium monoglycerate, sorbitan monooleate, sorbitan monolaurate, sorbitan monooleate, bile salts, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, sucrose fatty acid esters, Vitamin E derivatives, lecithin or a combination thereof. The surface-active agent is present in the range from about 0.05 to about 10.0% (W/W).

Another embodiment of the invention provides a slow release pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof, sodium lauryl sulfate and a release rate controlling agent,

Another embodiment of the invention provides a slow release pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof, a surface-active agent and a rate controlling agent, wherein the rate controlling agent is cellulose, cellulose ethers, cellulose esters, acrylic resins, materials derived from proteins, fats, waxes, fatty alcohols or fatty acid esters or a mixture thereof. The release rate controlling agent is present in the range from about 1.0 to about 90.0% (W/W).

Another embodiment of the invention provides a slow release pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof, a surface-active agent and hydroxypropyl methylcellulose.

Another embodiment of the invention provides a slow release pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof, sodium lauryl sulfate and hydroxypropyl methylcellulose.

Another embodiment of the invention provides a slow release pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof, a surface-active agent and a combination of two or more different grades of hydroxypropyl methylcellulose.

Another embodiment of the invention provides a slow release pharmaceutical composition comprising cefdinir or a pharmaceutical^ acceptable salt thereof, a surface-active agent and a rate controlling agent, wherein the composition is a tablet, a capsule, a pill, granules, powder, suspension or a mixture thereof.

Another embodiment of the invention provides a slow release pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof, a surface-active agent and a rate controlling agent, wherein said cefdinir is in a single dose amount ranging from 10 to 1,000 mg, preferably from 50 to 750 mg, more preferably from 100 to 600 mg.

Another embodiment of the invention provides a slow release pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof, which is administered once daily.

Another embodiment of the invention provides a method of treating a microbial infection in a patient which comprises administering to a patient in need thereof, a pharmaceutical composition comprising effective amount of cefdinir or a pharmaceutically acceptable salt thereof, wherein the composition is a slow release pharmaceutical composition. The microbial infection may be one or more of community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute maxillary sinusitis, pharyngitis, tonsillitis, uncomplicated skin and skin structure infections, acute bacterial otitis media.

Detailed Description of the Invention

This invention relates to a slow release pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof. More particularly, the invention relates to a pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition simultaneously increases the solubility of cefdinir and slows the release rate of the drug from it.

In a one embodiment, the slow release pharmaceutical composition comprises cefdinir or a pharmaceutically acceptable salt thereof, a surface-active agent and a rate controlling agent.
In another embodiment, the slow release pharmaceutical composition comprises cefdinir or a pharmaceutically acceptable salt thereof, has the following in-vitro release rate, measured by the USP Apparatus II (Paddle) at 50 rpm using pH 6.8 phosphate buffer at 37°C:

3 to 35% by weight (based on 100% by weight active agent) cefdinir released after 1 hour, 5 to 60% by weight cefdinir released after 2 hour, 10 to 80% by weight cefdinir released after 4 hours, 15 to 95% by weight cefdinir released after 6 hours, more than 50% by weight cefdinir released after 12 hours, more than 70% by weight cefdinir released after 16 hours, and more than 80% by weight cefdinir released after 24 hours.

The term "cefdinir" includes various forms of cefdinir such hydrates, solvates, polymorphs, isomers, stereoisomers, enantiomers, racemates, esters, prodrugs, complexes or mixture thereof and all other forms as per the cited references.

In one of the embodiment, a slow release pharmaceutical composition comprises cefdinir or a pharmaceutically acceptable salt thereof, wherein the cefdinir is amorphous powder, crystalline particles, matrix particles, or a mixture thereof.

The term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.

The active ingredient, active agent and drug herein can be interchangeably used.
In an embodiment, the slow release pharmaceutical composition comprises cefdinir or a pharmaceutically acceptable salt thereof, wherein the composition comprises an immediate release composition and a slow release composition.

Slow release rate of an active agent is the rate of release of the active agent other than that of an immediate release formulation as per USP. Examples of slow release includes but not limited to sustained release, controlled release, prolonged release, delayed release, pulsatile release, extended release, timed release etc., which terms are generally known in the art and to the extent they mean a release other than an immediate release. Slow release may be achieved by various technologies such as reservoir, matrix, osmotic, gastro-retention, bioadhesion, complexation, conjugation etc.
Composition includes, without limitation, tablets, capsules, caplets, powders, pellets, granules, microcapsules, liquid dispersions, beads, microspheres, suspension etc. The tablets may be minitablets, multi-layered tablets, coated or uncoated tablets, tablet in tablet etc. those are known in art. It may also include kits.

In one of preferred the embodiment, a slow release composition comprising cefdinir or a pharmaceutically acceptable salt thereof, is a tablet. In another preferred embodiment, the slow release composition is a suspension.

In one of the embodiment, the slow release composition of the invention comprises about 10 to 90% of cefdinir by weight of total weight of cefdinir in the composition, preferably about 15 to 80 % of cefdinir and more preferably about 18 to 65 % of cefdinir by weight of total weight of cefdinir in the composition.

Surface-active agents otherwise called solubilizing agents, help to solubilize the active agent either in composition or in-situ at the site of absorption or action. Surface-active agents include but are not limited to surfactants, cyclodextrin and its derivatives, lipophilic substances or any combination thereof. Non-limiting examples of surfactants include non-ionic, anionic, cationic, amphoteric or zwitterionic or any combination thereof.

Examples of suitable non-ionic surfactants include ethoxylated triglycerides; fatty alcohol ethoxylates; alkylphenol ethoxylates; fatty acid ethoxylates; fatty amide ethoxylates; fatty amine ethoxylates; sorbitan alkanoates; ethylated sorbitan alkanoates; alkyl ethoxylates; Pluronics®; alkyl polyglucosides; stearol ethoxylates; and alkyl polyglycosides.

Examples of suitable anionic surfactants include alkylether sulfates; alkylether carboxylates; alkylbenzene sulfonates; alkylether phosphates; dialkyl sulfosuccinates; sarcosinates; alkyl sulfonates; soaps; alkyl sulfates; alkyl carboxylates; alkyl phosphates; paraffin sulfonates; secondary n-alkane sulfonates; alpha-olefin sulfonates; and isethionate sulfonates.

Examples of suitable cationic surfactants include fatty amine salts; fatty diamine salts; quaternary ammonium compounds; phosphonium surfactants; sulfonium surfactants; and sulfonxonium surfactants.

Examples of suitable zwitterionic surfactants include N-alkyl derivatives of amino acids (such as glycine, betaine, aminopropionic acid); imidazoline surfactants; amine oxides; and amidobetaines.
Mixtures of surface-active agents may be used. In such mixtures there may be individual components which are liquid, provided that the carrier material overall, is a solid. The concentration of surface-active agent in the composition is from range of about 0.05 to about 10.0% W/W (based on the total mass of the pharmaceutical composition), preferably, about 0.1 to about 5%, more preferably of about 0.1 to about 3%.

The preferred surface-active agents include, but are not limited to, sodium salts of fatty alcohol sulphates such as sodium lauryl sulphate; or sulphosuccinates such as sodium dioctyl sulphosuccinate; or partial fatty acid esters of polyhydric alcohols such as glycerol monostearate, glyceryl monooleate, glyceryl monobutyrate; or block copolymers of ethylene oxide and propylene oxide, also known as polyoxyethylene polyoxypropylene block copolymers or polyoxyethylene polypropyleneglycol, such as Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 388, Poloxamer 407 (BASF Wyandotte Corp.); or fatty acid esters of sorbitan such as sorbitan mono laurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan stearate, sorbitan monolaurate etc. such as Span® or Arlacel®, Emsorb®, Capmul®, or Sorbester®, Triton X-200 etc.; or a fatty acid esters of polyhydroxyethylene sorbitan such as polyoxyethylene (20) sorbitan, e.g. polyoxyethylene (20) sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitan monostearate (Tween® 60), polyoxyethylene (20) sorbitan monopalmitate (Tween® 40), polyoxyethylene (20) sorbitan monolaurate (Tween® 20); or polyethylene glycol fatty acid esters, e.g. PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate, PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate; alkylene glycol fatty acid mono esters, e.g. propylene glycol monolaurate (Lauroglycol®); or hydrogenated castor oil and polyoxyethylene castor oil derivates, e.g. polyoxyethyleneglycerol triricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.); or polyoxyethyleneglycerol oxystearate such as polyethylenglycol 40 hydrogenated castor oil (Cremophor RH® 40) or polyethylenglycol 60 hydrogenated castor oil (Cremophor RH® 60); or sucrose fatty acid esters, such as sucrose stearate, sucrose oleate, sucrose palmitate, sucrose laurate, and sucrose acetate butyrate; or vitamin E and its derivatives such as Vitamin E-TPGS® (d-alpha-tocopheryl polyethylene glycol 1000 succinate); or phospholipids, glycerophospholipids (lecithins, kephalins, phosphatidyl serine), glyceroglycolipids (galactopyransoide), sphingophospholipids (sphingomyelin), and sphingoglycolipids (ceramides, gangliosides), DSS (docusate sodium), docusate calcium, docusate potassium, SDS (sodium dodecyl sulfate or sodium lauryl sulfate), dipalmitoyl phosphatidic acid, sodium caprylate; or bile acids and salts thereof; or ethoxylated triglycerides; or quaternary ammonium salts such as cetyl-trimethylammonium bromide, cetylpyridinium chloride; or glycerol acetates such as acetin, diacetin and triacetin; or triethanolamine, lecithin, monohydric alcohol esters such as trialkyl citrates, lactones and lower alcohol fatty acid esters, nitrogen-containing solvents, glycerol fatty acid esters such as mono-, di- and triglycerides and a cetylated mono- and di-glycerides; propylene glycol esters, ethylene glycol esters, glycerol, cholic acid or derivatives thereof, lecithins, alcohols and glycine or taurine conjugates, ursodeoxycholic acid, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, N-Hexadecyl-N, N-dimethyl-3-ammonio-1-propanesulfonate, anionic (alkyl-arylsulphonates) monovalent surfactants, palmitoyl lysophosphatidyl-L-serine, lysophospholipids (e.g. l-acyl-sn-glycero-3-phosphate esters of ethanolamine, choline, serine or threonine), alkyl, alkoxyl (alkyl ester), alkoxy (alkyl ether)- derivatives of lysophosphatidyl and phosphatidylcholines, e.g. lauroyl and myristoyl derivatives of lysophosphatidylcholine, dipalmitoylphosphatidylcholine, and modifications of the polar head group, that is cholines, ethanolamines, phosphatidic acid, serines, threonines, glycerol, inositol, and the postively charged DODAC, DOTMA, DCP, BISHOP, lysophosphatidylserine and lysophosphatidylthreonine, zwitterionic surfactants (e.g. N-alkyl-N, N-dimethylammonio-1 -propanesulfonates, 3-cholamido-l-propyldimethylammonio-l -propanesulfonate, dodecylphosphocholine, myristoyl lysophosphatidylcholine, hen egg lysolecithin), cationic surfactants (quarternary ammonium bases), fusidic acid derivatives-(e.g. sodium tauro-dihydrofusidate etc.), long-chain falty acids and salts thereof C6-C12 (eg. oleic acid and caprylic acid), acylcarnitines and derivatives, N-a-acylated derivatives of lysine, arginine or histidine, or side-chain acylated derivatives of lysine or arginine, N-a-acylated derivatives of dipeptides comprising any combination of lysine, arginine or histidine and a neutral or acidic amino acid, N-a-acylated derivative of a tripeptide comprising any combination of a neutral amino acid and two charged amino acids, or the surfactant may be selected from the group of imidazoline derivatives, or mixtures thereof. Each one of these specific surface-active agent constitutes an alternative embodiment of the invention.

More preferred surface-active agents are sodium lauryl sulfate, sodium dioctyl sulphosuccinate, sodium monoglycerate, sorbitan monooleate, sorbitan monolaurate, sorbitan monooleate, bile salts, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, sucrose fatty acid esters, Vitamin E derivatives, lecithin or a combination thereof. The most preferable surface-active agent is sodium lauryl sulfate.

The use of surface-active agents in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 21th edition, 2006.
Release rate controlling agents are defined as hydrophilic or hydrophobic agents, which can be polymeric or non-polymeric and which are capable of controlling the release rate of an active agent. The release controlling agents may be natural, semi-synthetic and synthetic agents or mixtures thereof. The release controlling agent can be used in the concentration ranges from about 1 to about 90.0% of the total composition.

In one embodiment of the present invention, a slow release composition comprises cefdinir or a pharmaceutically acceptable salt thereof, mixed with at least one hydrophilic release rate controlling agent.

In one embodiment of the present invention, a slow release composition comprises cefdinir or a pharmaceutically acceptable salt thereof, mixed with at least one hydrophilic release rate controlling agent and at least one surface-active agent.

The non limiting examples of hydrophilic release rate controlling agents suitable for use in the slow release pharmaceutical composition include: one or more natural or partially or totally synthetic hydrophilic gums such as acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum, celluloses and cellulose derivatives such as methylecllulose, hydroxomethylcellulose, hydroxypropyl methylecllulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxyinethylcellulose, hydroxybutylmethyl cellulose, sodium carboxymethyl cellulose, polycarbonates, polyalkylenes, polyalkylene glycols such as poly(ethylene glycol), polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols (PVA), polyvinylphenol, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone (PVP), polyglycolides, polysiloxanes, polyurethanes, polystyrene, polylactides, poly (butyric acid), poly (valeric acid), poly(lactide-co-glycolide), poly (ethyleneterephthalate), poly (lactide-co-caprolactone), polyanhydrides (e.g., poly (adipic anhydride)), polyorthoesters, poly(fumaric acid), poly(maleic acid), polyvinyl acetate, polystyrene; polymers of acrylic and methacrylic esters; carbomer, carbopol®; proteinaceous substances such as agar, pectin, carrageen, gluten, serum albumin, or collagen, chitosan, oligosaccharides and alginates; and other hydrophilic polymers such as carboxypolymethylene, gelatin, casein, bentonite, magnesium aluminum silicate, polysaccharides, modified starch derivatives, and other hydrophilic polymers known to those of skill in the art or a combination of such polymers.

The hydrophilic release rate controlling agents preferably, hydrophilic polymers gel and dissolve slowly in aqueous acidic media thereby allowing cefdinir to diffuse from the gel in the gastrointestinal track. When the gel reaches the intestines, it dissolves in controlled quantities in the higher pH medium, where the cefdinir itself is fairly absorbable, to allow sustained release of cefdinir throughout the digestive tract.

In one embodiment of the present invention, a slow release composition comprises cefdinir or a pharmaceutically acceptable salt thereof, mixed with at least one hydrophobic release rate controlling agent.

In one embodiment of the present invention, a slow release composition comprises cefdinir or a pharmaceutically acceptable salt thereof, mixed with at least one hydrophobic release rate controlling agent and at least one surface-active agent.

The non limiting examples of hydrophobic release rate controlling agents includes but are not limited to hydrogenated vegetable oil, but other suitable agents include purified grades of beeswax; fatty acids; long chain fatty alcohols, such as cetyl alcohol, myristyl alcohol, and stearyl alcohol; glycerides such as glyceryl esters of fatty acids like glyceryl monostearate, glyceryl distearate, glyceryl esters of hydrogenated castor oil and the like; oils such as mineral oil and the like, or acetylated glycerides; ethyl cellulose, stearic acid , paraffin, carnauba wax, talc; and the stearate salt(s) such as calcium, magnesium, zinc, cellulose derivatives like ethylcellulose and other materials known to the person skilled in the art.

In one embodiment of the present invention, a slow release composition comprises cefdinir or a pharmaceutically acceptable salt thereof, mixed with at least one hydrophilic release rate controlling agent and at least one hydrophobic release rate controlling agent.

In one embodiment of the present invention, a slow release composition comprises cefdinir or a pharmaceutically acceptable salt thereof, mixed with at least one hydrophilic release rate controlling agent, at least one hydrophobic release rate controlling agent and at least one surface-active agent.
In one of the embodiment, the slow release composition of the invention uses water-insoluble release rate controlling agents to control the release rate of the active agent from the composition. The water-insoluble release rate controlling agents generally do not dissolve in solutions of a pH below 5, and dissolve more slowly in basic solutions than the hydrophilic release rate controlling agent and are suitable for use in the slow release composition of the invention. Because the water-insoluble release rate controlling agent is insoluble in low pH environments such as those found in gastric fluid, it aids in retarding drug release in those regions. Likewise, because the water-insoluble release rate controlling agent dissolves more slowly in solutions of higher pH than hydrophilic release rate controlling agents, it aids in retarding drug release throughout the intestines.

The non limiting examples of water-insoluble release rate controlling agents suitable for use in this invention include: polyacrylamides, phthalate derivatives such as acid phthalates of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropylcellulose phthalate, hydroxypropylethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate, succinates such as hydroxypropylethylcellulose acetyl succinate, cellulose acetate trimellitate, styrene-maleic acid dibutyl phthalate copolymer, styrene-maleic acid polyvinylacetate phthalate copolymer, styrene and maleic acid copolymers, polyacrylic acids, acrylic resins, acrylic latex dispersions, polyacrylic acid derivatives such as acrylic acid and acrylic ester copolymers, polymethacrylic acid and esters thereof, poly acrylic methacrylic add copolymers, shellac, and vinyl acetate and crotonic acid copolymers, shellac, and zein and other polymers common to those of skill in the art.

A particularly preferred group of water-insoluble release rate controlling agents includes cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, anionic acrylic copolymers of methacrylic acid and methylmethacrylate, and copolymers comprising acrylic acid and at least one acrylic add ester. More preferred water-insoluble polymers are anionic acrylic copolymers of methacrylic acid and methylmethacrylate. Copolymers of this type are available from RohmPharma Corp, under the trademarks Eudragit-L® and Eudragit-S®. Eudragit-L® and Eudragit-S® are anionic copolymers of methacrylic add and methylmethacrylate. Mixtures of Eudragit-L® and Eudragit-S® may also be used.

In one embodiment of the present invention, a slow release composition comprises cefdinir or a pharmaceutically acceptable salt thereof, mixed with at least one hydrophilic release rate controlling agent and at least one water-insoluble release rate controlling agent.

In one embodiment of the present invention, a slow release composition comprises cefdinir or a pharmaceutically acceptable salt thereof, mixed with at least one hydrophilic release rate controlling agent, at least one water-insoluble release rate controlling agent and at least one surface-active agent.

In one embodiment of the present invention, a slow release composition comprises cefdinir or a pharmaceutically acceptable salt thereof, mixed with at least one hydrophilic release rate controlling agent, at least one hydrophobic release rate controlling agent, a water-insoluble release rate controlling agent and at least one surface-active agent.

The preferred rate controlling agents include, but are not limited to polymers generally have number average molecular weights over 50,000 grams per mole, such as between 50,000 and 10,000,000 grams per mole. Polymers having molecular weights between 300,000 and 8,000 000 grams per mole are preferred, and those having molecular weights between about 2,000,000 to 8,000,000 grams per mole are especially preferred. Polyethylene oxide having a number average molecular weight between about 5,000,000 to 8,000,000 grams per mole is most especially preferred, e.g. Polyox® 303 and Polyox® 308. Also, especially preferred are methylcellulose type/grade A15C, A4M, A18 M and hydroxypropyl methylcellulose type/grade K4M, K15M, K100M, E4M and F4M (Dow Chemical Company); hydroxyethyl cellulose such as Natrosole® HEC; hydroxypropyl cellulose such as Klucel® (Grades H, M, G, J, L, E- Aqualon Company); guar such as Supercol® Guar U (Aqualon Company); pectin such as GENU Pectin (Aqualon Company); carrageenan such as GENU® Carrageenan (Aqualon Company); poly(methyl vinyl ether/maleic anhydride) such as Gantrez® AN Copolymer (AN- 119, -139, -149, -169, -179, GAF Corporation); polyvinyl alcohol such as Elvanol® 71-30, Elvanol® 85-80, Elvanol® 55- 65, Elvanol® 50-42 and Elvanol® HV (DuPont); sodium carboxymethyl cellulose such as Aqualon cellulose gum grade 7H4; polyacrylic acids such as Carpobol resin grades 934P, 940, 941, 971P, 974P, 980, 981, 1382, 2984, 5984, ETD 2001, ETD 2050, calcium polyacrylic acids such as Noveon® resin grades AA-1, CA-1 and CA-2, and sodium polyacrylic acid (BF Goodrich, Cleveland, Ohio). More preferred is hydroxypropyl methylcellulose and combinations thereof.

Preferred hydrophilic polymer is the hydroxypropyl methylcellulose such as those manufactured by The Dow Chemical Company and known as Methocel ethers. In one preferred embodiment the hydrophilic polymer is Methocel such as Methocel E10M, E50LV, K100 or K4MCR Premium. In another preferred embodiment, a slow release composition comprises cefdinir and a combination of two or more different grades of hydroxypropyl methylcellulose. The two different grades of hydroxypropyl methylcellulose can be selected based on the viscosity of the polymers such as a combination of Methocel E50LV and K4MCR Premium or Methocel E10M and K100MCR.

The composition of the invention is presented in unit dosage form generally in an amount that yields a therapeutic effect in the subject. The composition of the invention is administered at a dose that is the lowest dose effective to produce a therapeutic effect. Generally, the dosage will effect from about 0.0001 to about l00mg per kg body weight per day. Preferably, the dosage will range from about 0.001 to 75mg per kg body weight per day and more preferably, the dosage will range from about 0.1 to about 50mg per kg body weight per day. Each unit dose may be, for example, 5, 10, 25, 50, 100, 125, 150, 200, 250, 300, 400, 500, or 600 mg of the compound of the invention.

In one of the embodiment, the slow release pharmaceutical composition comprising therapeutically effective amount of cefdinir or a pharmaceutically acceptable salt thereof, wherein a single dose amount ranging from 10 to 1,000 mg, preferably 50 to 750 mg and more preferably 100 to 600 mg.

In one of the embodiment, the slow release pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof, is meant for oral administration. The composition may be solid or liquid for oral administration.

In one of the embodiment, the slow release pharmaceutical composition comprising cefdinir or a pharmaceutically acceptable salt thereof, wherein the composition is administered twice daily or once daily. In one preferred embodiment, the slow release pharmaceutical composition is administered once daily.

In one of the embodiment, a method of treating a microbial infection in a patient which comprises administering to a patient in need thereof, a pharmaceutical composition comprising effective amount of cefdinir or a pharmaceutically acceptable salt, wherein the composition is a slow release composition. The slow release composition comprises effective amount of cefdinir or a pharmaceutically acceptable salt, a surface-active agent and a rate controlling agent. The effective amount of cefdinir or a pharmaceutically acceptable salt may range from a dose of 10 to 1000 mg per day.

In one of the embodiment, a method of treating a microbial infection in a patient which comprises administering to a patient in need thereof, a pharmaceutical composition comprising effective amount of cefdinir or a pharmaceutically acceptable salt, wherein the microbial infection is one or more of community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute maxillary sinusitis, pharyngitis, tonsillitis, uncomplicated skin and skin structure infections, acute bacterial otitis media etc. In one embodiment, the composition is used for the treatment of infections against wide spectrum of bacteria including, but not limited to Staphylococcus aureus, Steptococcus pneumoniae, Streptococcus pogenes, Hemophilus influenzae, Moraxella catarrhalis, E. coli, Klebsiella, Proteus mirabilis and Moraxella catarrhalis.

As used herein,"%" refers to the weight percent of a substance as it relates to the overall composition unless otherwise indicated.

The term "comprising", which is synonymous with "including", "containing", or "characterized by" here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.

In one of the embodiment, the pharmaceutical composition of the invention further comprises a pharmaceutically acceptable additive selected from the group consisting of filler, binder, disintegrant, lubricant, glidant, solubilizer, coating polymer, plasticizers or a mixture thereof.
In one of the embodiment, the pharmaceutical composition of the invention further comprises pharmaceutically acceptable additives such as an auxiliary substance, a stabilizing agent, a suspending agent, a surface tension modifier, a viscosity modifier, a colorant, a preservative, a flavoring agent, lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, sucrose or a mixture thereof.
The amount of excipients employed will depend upon the quantity of active agent to be used and the type of excipients used. One excipient can perform more than one function.

Non limiting examples of binders include starches and partially hydrolyzed starch such as potato starch, wheat starch, corn starch, celluloses and celluloses derivatives such as microcrystalline cellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxyl propyl cellulose, ethylhydroxyethylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, sodium carboxy methyl cellulose, natural gums like acacia, alginic acid, guar gum, tragacanth, locust bean gum, gelatine, alginates and xanthan; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinyl pyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinyl alcohol, poly-N-vinyl amide, polyethylene glycol, polymers of acrylic acid and its salts, gelatin, poly propylene glycol, maltrin, sucrose solution, dextrose solution, combinations thereof and other materials known to one of ordinary skill in the art and mixtures thereof. The binding agent may be present in the composition in an amount of from about 0.2 wt % to about 20 wt %, preferably from about 5 wt % to about 15 wt %.

Fillers or diluents include, but are not limited to cellulose powder, microcrystalline cellulose, silicified microcrystalline cellulose, calcium carbonate, calcium phosphate, calcium phosphate dihydrate, dicalcium phosphate, tricalcium phosphate, calcium sulfate, magnesium trisilicate, mannitol, maltitol, sorbitol, xylitol, lactose (anhydrous or as a hydrate, for example monohydrate), lactitol, dextrose, maltose, sucrose, glucose, fructose or maltodextrins, dextrates, dextrin, dextran, starches, sodium chloride, polyethylene glycol or any other inert filler. The filler may be present in the composition in an amount of from about 5.0 wt % to about 90.0 wt %, preferably from about 10 wt % to about 70 wt%.
Lubricants may be selected from, but are not limited to, those conventionally known in the art such as metallic stearate like magnesium, aluminium, sodium calcium and zinc stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc or mixtures thereof. Glidants include, but are not limited to, silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel or mixtures thereof. These lubricants should be present in amounts from about 0.1%-10% (w/w), with a preferred range of about 0.3%-3.0% (w/w).

Disintegrants may be selected from, but are not limited to, those conventionally known in the art such as carboxymethylcellulose, crosslinked sodium carboxymethyl cellulose (AC-DI-SOL®), sodium starch glycolate (EXPLOTAB®, PRIMOJEL®), crosslinked polyvinylpolypyrrolidone (Plasone-XL®), microcrystalline cellulose, L-HPC (low-substituted hydroxypropylcellulose), sodium carboxymethyl starch, sodium glycolate of potato starch, partially hydrolysed starch, wheat starch, maize starch, rice starch or potato starch, cornstarch, pregelatinized starch, crospovidone, for example, POLYPLASDONE XL® (International Specialty Products); Disintegrants are used to facilitate disintegration of the pellet upon administration and are typically present in an amount of about 3% to about 15% (w/w), with a preferred range of about 5% to about 10% (w/w).

Antiadherants, glidants and flow regulating agents may be selected from, but are not limited to, talc, cornstarch, silicon dioxide, colloidal silica dioxide, and metallic stearates like magnesium stearate, calcium stearate, zinc stearate etc.

The use of different types of excipients in pharmaceutical compositions is well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 21th edition, 2006.

In one of the embodiment, the slow release composition of the invention comprises different excipients in concentration of about 10% to 90 % w/w of microcrystalline cellulose, 2 % to 95 % w/w of lactose monohydrate, 0 % to 10% w/w of Polyoxyl 40 stearate, 0 % to 5 % w/w of sodium lauryl sulphate, 0.5 % to 5 % w/w of colloidal anhydrous silica, and 0.25 % to 2.5 % of magnesium stearate.

The slow release pharmaceutical composition of the invention may optionally have one or more non-functional coatings such as film coating or sugar coating, which has no or negligible impact on release of active agent form the composition. The slow pharmaceutical composition may further have one or more functional coating such as bioadhesive coating, diffusion coatings, non-permeable coating and semi-permeable coating, which modify the release of active agents from the composition.

The coating layers may comprise one or more excipients selected from the group comprising coating agents, opacifiers, taste-masking agents, fillers, polishing agents, colouring agents, anti-tacking agents, pore forming agents and the like, which are known in the art. The coating can be done by any method known in the art. Various coating methods known in the art are pan coating, spray coating, compression coating, dip coating etc.

In one of the embodiment, the slow release composition of cefdinir comprising cefdinir or a pharmaceutically acceptable salt thereof, wherein the slow release composition is prepared by technology known in the art to slow the release rate of active agent from the composition. The non limiting examples of the technologies are matrix type, reservoir type (coating controlled), osmotic type, enteric type, ion exchange resin type, gastro retentive types, mucoadhesive type, encapsulation, microencapsulation, bioadhesion, complexation, conjugation etc.

The slow release pharmaceutical composition may be manufactured by various methods such as by dry granulation, wet granulation, melt granulation, direct compression, double compression, extrusion spheronization, layering, complexation, conjugation, solid dispersion and by any methods known in the art. The process may be carried out under ambient conditions of temperature and humidity. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 21th edition, 2006.
The following experimental details are set forth to aid in an understanding of the invention, and are not intended, and should not be construed, to limit in any way the invention set forth in the claims that follow thereafter. A person skilled in the art will readily recognize the various modifications and variations that may be performed without altering the scope of the present invention. Such modifications and variations are encompassed within the scope of the invention and the examples do not in any way limit the scope of the invention.


Method of preparation:

Cefdinir, a part of microcrystalline cellulose, lactose monohydrate, a part of Methocel E 50 LV, Methocel K4M CR, Polyoxyl 40 stearate, sodium lauryl sulphate were sieved, mixed well and granulated with a binder solution prepared using sufficient quantity of water and a part of Methocel E 50 LV. The granules were dried and sized and finally compressed into tablets.

* Colloidal anhydrous silica & Magnesium Stearate were used after coating the pellets for preparation of capsule dosage form.

Method of preparation of capsule dosage form: cefdinir, lactose monohydrate, microcrystalline cellulose, Sodium lauryl sulfate, and Methocel E50 Premium LV were mixed well and granulated with suitable quantity of water. The granulated wet mass was passed through an extruder through suitable screen and then spheronized with a

spheronizer with optimum speed & time. The spheronized pellets were dried and coated with a solution of ethylcellulose in isopropyl alcohol, along with polyethylene glycol, using fluid bed processor with suitable parameters. Finally the coated pellets were lubricated using Magnesium stearate and Colloidal anhydrous silica and filled into hard gelatin capsule shell.

Method of preparation of tablet dosage form: cefdinir, lactose monohydrate, a part of microcrystalline cellulose, Sodium lauryl sulfate, and a part of Methocel E50 Premium LV were mixed well and granulated with suitable quantity of water. The wet granules were dried, mixed with remaining part of microcrystalline cellulose and Methocel E50 Premium LV and Colloidal anhydrous silica. The above granular mixture was lubricated with Magnesium stearate and compressed to tablets. The compressed tablets were dried and coated with a solution of ethylcellulose in isopropyl alcohol, along with polyethylene glycol, using fluid bed processor with suitable parameters.


Manufacturing procedure: Cefdinir, mannitol, microcrystalline cellulose, Polyoxyl 40 stearate, Sodium lauryl sulfate, Citric Acid Monohydrate, Polyethylene Oxide and Citric Acid Monohydrate were sifted through suitable sieve, mixed well and granulated with an aqueous solution of Methocel E50 Premium LV as binder. The granules were dried, sized, mixed with Colloidal anhydrous silica and Magnesium stearate; and compressed using round shaped punches of suitable size. The compressed tablets were coated with a solution of cellulose acetate, polyethylene glycol in isopropyl alcohol. Laser drilling technology was be used to drill orifice/pore on both side.

Dissolution study:

The In vitro dissolution test was performed at 50 rpm with USP apparatus II (Paddle), using pH 6.8 phosphate buffer as a dissolution media is accomplished by UV detection at 290nm. The dissolution medium used was 900 ml; maintained at 37 ± 0.5°C.

The dissolution profiles of various formulations tested are provided in Tables 4, 5 and 6.

Table 4

Note: The data represent the mean percent dissolved ± standard deviation of six replicates.
The above results show that the compositions of the present invention have good dissolution profiles. All the working examples show a slow but complete release of cefdinir from the compositions.
Stability Study:

Cefdinir compositions were packed in HDPE bottles with Child Resistance Caps (CRC) and induction sealed. These bottles were charged for stability study at 40°C/75% RH and 50°C for 3 months as per ICH. Physical parameters of composition, assay capabilities and dissolution profile were comparable to that of the initial formulation after 3 months storage at conditions mentioned.

Claims

We claim:

1. A slow release pharmaceutical composition of cefdinir comprising cefdinir or a pharmaceutically acceptable salt thereof, a surface-active agent and a rate controlling agent.

2. The pharmaceutical composition according to claim 1 further comprises a pharmaceutically acceptable additive selected from the group consisting of filler, binder, disintegrant, lubricant, glidant, solubilizer, coating polymer, auxiliary substance, a stabilizing agent, a suspending agent, a surface tension modifier, a viscosity modifier, a colorant, a preservative, a flavoring agent and a mixture thereof.

3. The pharmaceutical composition according to claim 1, wherein the cefdinir is amorphous powder, crystalline particles, matrix particles, or a mixture thereof.

4. The pharmaceutical composition according to claim 1, wherein the surface-active agent is selected from the group consisting of sodium lauryl sulfate, sodium dioctyl sulphosuccinate, sodium monoglycerate, sorbitan monooleate, sorbitan monolaurate, sorbitan monooleate, bile salts, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, sucrose fatty acid esters, Vitamin E derivatives, lecithin and a combination thereof.

5. The pharmaceutical composition according to claim 1, wherein the rate controlling agent is selected from the group consisting of cellulose, cellulose ethers, cellulose esters, acrylic resins, materials derived from proteins, fats, waxes, fatty alcohols or fatty acid esters and a mixture thereof.

6. The pharmaceutical composition according to claim 1, wherein the composition is a tablet, a capsule, a pill, granules, powder, a suspension or a mixture thereof.

7. The pharmaceutical composition according to claim 1, wherein said Cefdinir is in a single dose amount ranging from 10 to 1,000 mg.

8. The pharmaceutical composition of cefdinir according to claim 1, wherein the composition is administered once daily.

9. The slow release pharmaceutical composition of cefdinir comprising cefdinir or a pharmaceutically acceptable salt thereof, wherein the composition has the following in-vitro release rate, measured by the USP Apparatus II (Paddle) at 50 rpm using pH
6.8 phosphate buffer at 37°C: 3 to 35% by weight (based on 100% by weight active agent) cefdinir
released after 1 hour, 5 to 60% by weight cefdinir released after 2 hour, 10 to 80% by weight cefdinir released after 4 hours, 15 to 95% by weight cefdinir released after 6 hours, more than 50% by weight cefdinir released after 12 hours, more than 70% by weight cefdinir released after 16 hours, and
more than 80% by weight cefdinir released after 24 hours.

10. A method of treating a microbial infection in a patient which comprises administering to a patient in need thereof, a pharmaceutical composition comprising effective amount of cefdinir, wherein the composition is according to claim1.

11. The slow release pharmaceutical composition substantially as herein described and exemplified.