Technical Field of the Invention
The present invention relates to a dry process for the preparation of amorphous Cefditoren pivoxil solid dosage forms wherein the process comprises mixing amorphous Cefditoren pivoxil optionally with a surfactant, and one or more pharmaceutically acceptable excipient(s) and forming into a solid dosage form.
Background of the Invention
'Cefditoren' is the generic name of a cepham compound {chemical name: 7-[2-methoxyimino-2- (2-aminothiazol-4-yl) acetamido]-3-[2-(4-methylthiazol-5-yl) vinyl]-3-cephem-4-carboxylic acid (syn-isomer, cis-isomer)}. Cefditoren synthesis is disclosed in U.S. Pat. Nos. 4,839,350 and 4,918,068; and an injectable cefditoren preparation is disclosed in U.S. Pat. No. 5,595,986. Cefditoren pivoxil, synthesized by forming a pivaloyloxymethyl (pivoxil) ester with cefditoren at the carboxylic acid moiety, exhibits better oral absorption and is quickly hydrolyzed to cefditoren by enzymatic esterases upon absorption.
Cefditoren exhibits a broad antibacterial spectrum relatively having low toxicity and is very useful for the therapy and prophylaxis of diseases induced by gram-positive and gram-negative bacteria. Cefditoren pivoxyl is, by itself, antibacterially inactive but is useful as a pro-drug which is administrable orally and can be converted into the antibacterially active Cefditoren in the digestive tubes of mammals, with cleaving the ester-forming pivaloyloxymethyl group therefrom.
Crystals of Cefditoren pivoxil are known to have high purity, high heat stability and in addition satisfactory stability even when stored under high humidity conditions (US patent No. 6294669). However crystals of Cefditoren pivoxil, have low solubility in water and thus have not been very suitable for oral administration. Low-solubility drugs often show poor bioavailability or irregular absorption, the degree of irregularity being affected by factors such as dose level, fed state of the patient, and form of the drug.
Over the years, compositions and methods have been developed to achieve improved solubility of such poorly or sparingly soluble drugs.
US Appl. No 2003/0060451 discloses the method of preventing the premature de-esterification of pro-drug esters and enhancing the oral bioavailability by formulating the prodrug ester i.e. cefditoren pivoxil in a non-emulsified formulation with lecithin.
One of the reported methods involves the conversion of a medicinal compound sparingly soluble in water into an amorphous substance, thus to improve the solubility of the compound in water. Conversion of crystalline form of Cefditoren pivoxil to amorphous substance leads to high water solubility and improves the usefulness of Cefditoren pivoxil in the therapy of disease.
US Patents No's 6,342,493 and 6,486,149 disclose the conversion of crystalline Cefditoren pivoxil to amorphous form. In this method the crystalline Cefditoren pivoxil is dissolved in an acidic aqueous solution containing a water-soluble polymeric additive, the acidic aqueous solution is then neutralized to coprecipitate Cefditoren pivoxil together with the water-soluble polymeric additive, and the precipitate is then collected, washed and dried. According to this method a yellow colored powdery composition comprising solid particles of an intimate mixture of an amorphous form of Cefditoren pivoxil having a high level of dissolvability in water and high heat stability with the water-soluble polymeric additive (0.5 to 5%) can be provided. This method however involves many steps and thus requires process control and relatively lot of time.
US Appl. No 2004/0115272 discloses another method of conversion of crystalline Cefditoren pivoxil to amorphous form by grinding crystalline Cefditoren pivoxil in the presence of a pharmaceutically acceptable organic polymeric compound.
EP 0629404 discloses a pharmaceutical composition comprising cefditoren pivoxil and a water soluble polymer like hydroxypropylcellulose. This preparation showed improved wettability, dispersibility and absorbability without increasing its bitterness. Improved dispersibility and absorbability was also shown by composition containing cefditoren pivoxil and B-cyclodextrin along with an ionic surfactant in a pharmaceutically acceptable carrier (EP 0339465).
Cefditoren pivoxil, apart from exhibiting low solubility, has another property -bitterness. Cefditoren does not exhibit the bitter taste by itself upon oral administration thereof, whilst Cefditoren pivoxil exhibits a strong bitter taste on oral administration. Thus, there
is a need that the bitter taste of Cefditoren pivoxil should be minimized to such an extent that the oral administration of Cefditoren pivoxil would be acceptable by patients.
Various methods for masking or reducing the bitter taste of medicinal compositions or formulations containing a drug compound having a bitter taste are generally known hitherto. For instance, the known methods of masking the bitter taste of a drug compound embraces a method of coating the surfaces of the particles of the drug compound with a coat-film. This method of coating the particle surfaces of the drug compound with the coat-film can suitably be applied to the preparations of the tablet form. However, when this method is effected for the preparations of granule or the fine granule form, the surfaces of the granules or the fine granules so coated become rough and give gritty feel to tongue, and moreover the steps for the production of the coated granules or the fine granules are complicated and time-consuming.
US Appl. No 2003/0026843 discloses a method relating to amorphous drug beads comprising an amorphous active drug and an organic surfactant (casein) having improved solubility, absorption and wettability characteristics.
Addition of a water-soluble casein salt to Cefditoren pivoxil has been disclosed in US 5,958,915 as a method for enhancing solubility of the drug, with minimized bitter taste. However, this method includes the steps of granulating, drying, milling, compressing, etc for preparing the tablets which is time-consuming and tedious.
However, for people with lactose intolerance (inability to digest significant amounts of lactose, which is the predominant sugar), consumption of formulations using water-soluble casein makes difficult to accept. In such conditions, usage of synthetic surfactant can be an alternative way in administering such poorly water-soluble drug products.
Synthetic surfactants have widely been used in recent years for improving solubility of poorly water soluble drug products. A number of studies have demonstrated that these surfactants can mimic, to some extent, the naturally occurring surfactants and micellar media in the gastrointestinal tract. Among common surfactants, sodium lauryl sulfate (SLS) is the most widely used due to its excellent solubilization capacity, low cost, and the ease of use as a solid.
WO 2005/034957 discloses a solid dispersion composition which enables non-crystalline Cefditoren pivoxil in the presence of sucrose/fatty acid ester which is to be held in a suspension for long periods.
Amorphous formulations with improved bioavailability have another setback, i.e. stability. Amorphous materials are thermodynamically unstable and therefore show some tendency to crystallize spontaneously. The transition from the amorphous to the crystalline form will depend on the molecular mobility, which is related to the glass transition temperature (Tg). Many amorphous materials are plasticized by sorbed water. Once incorporated into the amorphous region, water can increase the free volume and lead to enhance molecular mobility within the amorphous material, causing crystallization.
Also it is found that most of amorphous materials are very fine and fluffy material, with relatively low bulk and tap density. This property can make it difficult to formulate into a dosage form with uniformity of weight, hardness and other desirable tablet properties. Wet granulation can solve this problem, but it should to be avoided, as addition of a solvent along with and subsequent removal in way of drying the granules at elevated temperatures may covert the amorphous form to crystalline form. Direct compression could be a method of choice for preparing the formulations containing amorphous materials.
WO 2005/087198 discloses preparation of pharmaceutical solid dosage comprising amorphous drug material by dry process. The formulation has shown improved stability even after storage for two months at 40°C and 75% RH.
However, no known methods provide an acceptable dosage form containing Cefditoren pivoxil with improved solubility and stability employing a simple process which is easy, cost-effective and time saving.
Hence, there is a need for simple method of production, which does not require wet granulation with organic solvents or water and do not require an additional step of drying.
Summary of the Invention
It is one of the aspects to provide dry processes for the preparation of amorphous Cefditoren pivoxil solid dosage forms wherein the processes comprise blending amorphous Cefditoren pivoxil with one or more pharmaceutically acceptable excipient(s) and forming into a solid dosage form.
According to one of the embodiments, the dry processes for preparation of solid dosage form of Cefditoren pivoxil involve dry granulation.
According to one of the embodiments, the dry processes for preparation of solid dosage form of Cefditoren pivoxil involve direct compression.
It is another general aspect to provide dry processes for the preparation of solid dosage forms of amorphous Cefditoren pivoxil wherein the processes comprise compacting Cefditoren pivoxil with one or more pharmaceutically acceptable excipient(s) by, for example, roller compaction or slugging; sizing the compacts into granules by milling; optionally mixing the granules with one or more pharmaceutically acceptable excipients and forming solid dosage forms.
It is another general aspect to provide a processes for the preparation of solid dosage forms of amorphous Cefditoren pivoxil wherein the processes comprise compacting Cefditoren pivoxil with one or more pharmaceutically acceptable excipient(s) by, for example, roller compaction or slugging; sizing the compacts into granules by milling; optionally mixing the granules with one or more pharmaceutically acceptable excipients and compressing into tablets.
It is another general aspect to provide processes for the preparation of amorphous Cefditoren pivoxil solid dosage forms wherein the processes comprise blending Cefditoren pivoxil with one or more pharmaceutically acceptable excipient(s) and directly compressing into solid dosage forms.
It is another general aspect to provide processes for the preparation of solid dosage forms of amorphous Cefditoren pivoxil wherein the processes comprise blending
Cefditoren pivoxil with one or more pharmaceutically acceptable excipient(s) and directly compressing into tablets.
It is another general aspect to provide a solid dosage form comprising amorphous Cefditoren pivoxil with one or more pharmaceutically acceptable excipient(s) prepared by dry processes.
According to one of the embodiments the solid dosage form comprises at least one pharmaceutically acceptable excipient. According to another embodiment, at least one pharmaceutically acceptable excipient is a surfactant.
It is another general aspect to provide dry processes for the preparation of amorphous Cefditoren pivoxil solid dosage forms wherein the processes comprise blending amorphous Cefditoren pivoxil, a surfactant and one or more pharmaceutically acceptable excipient(s) and forming into a solid dosage form.
Particularly, the surfactant utilized is an anionic surfactant and more particularly, the surfactant is sodium lauryl sulfate.
It is another aspect to provide a solid dosage form comprising amorphous Cefditoren pivoxil, a surfactant and one or more pharmaceutically acceptable excipients, wherein the surfactant is an anionic surfactant.
According to one of the embodiments, the anionic surfactants is one or more of alkyl sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, dioctyl sodium sulfosuccinate, phosphatidyl glycerol, phosphatidylinositol, diphosphatidylglycerol, phosphatidyl inosine, phosphatidylserine, phosphatidic acid and their salts, cholic acid and other bile acids and salts thereof.
It is another general aspect to provide a solid dosage form comprising amorphous Cefditoren pivoxil, a surfactant and one or more pharmaceutically acceptable excipient(s) prepared by dry processes.
According to one of the embodiments, the dry processes for the preparation of solid dosage forms of amorphous Cefditoren pivoxil include dry granulation or direct compression.
According to one of the embodiments, the solid dosage forms are further coated with one or more film forming agents.
It is yet another aspect to provide methods for treating bacterial infections by administering to a person in need thereof, a solid dosage form of amorphous Cefditoren pivoxil, wherein the solid dosage form is prepared by dry processes.
The methods include one or more of the following embodiments. For example in one embodiment, the method further comprises concurrently or sequentially administering other antibacterial agents.
In another embodiment, the solid dosage forms further comprises other antibacterial agents.
The details of one or more embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and claims.
Detailed Description of the Invention
The present invention provides a process for the preparation of amorphous Cefditoren pivoxil solid dosage forms comprising amorphous Cefditoren pivoxil, optionally a suitable surfactant, by a dry process. The process is simple and economical, as it does not require any solvents, as in the case of wet granulation processes, the most commonly followed process, which requires additional steps of drying the granules. The dry processes as described herein resist the conversion of amorphous form to crystalline form.
The solid dosage forms comprising amorphous Cefditoren pivoxil may be prepared by mixing the amorphous Cefditoren pivoxil, optionally with a surfactant and one or more pharmaceutically acceptable excipient(s) and forming into solid dosage forms. The
dosage form may be coated with one or more film forming agents. The amorphous Cefditoren pivoxil can be prepared by any of the methods known in the art for preparation of amorphous Cefditoren pivoxil and also by methods described in our co-pending Indian Patent Application No. 207/DEL/2005, which is incorporated herein entirety.
Cefditoren pivoxil may be added in an amount of about 20 to 80% (w/w), based on the weight of the solid dosage form.
The amorphous Cefditoren pivoxil solid dosage form of the present invention may contain one or more surfactant. Suitable surfactant can be anionic, cationic, zwitterionic and nonionic surfactants. Preferably, the compositions include at least one anionic surfactant. Suitable anionic surfactants include but are not limited to alkyl sulfonates, alkyl phosphates, alkyl phosphonates, potassium laurate, sodium lauryl sulfate, sodium dodecylsulfate, alkyl polyoxyethylene sulfates, dioctyl sodium sulfosuccinate, phosphatidyl glycerol, phosphatidylinositol, diphosphatidylglycerol, phosphatidyl inosine, phosphatidylserine, phosphatidic acid and their salts, cholic acid and other bile acids (e.g., cholic acid, deoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid) and salts thereof (e.g., sodium deoxycholate, etc.).
The surfactant may be added in an amount of about 1 to 20% (w/w), based on the weight of the solid dosage form. Surfactant helps in increasing the solubility of Cefditoren pivoxil and hereby increases the dissolution rate.
The pharmaceutically acceptable excipients are those known to the skilled in the art and may be selected from fillers, binders, disintegrants, lubricants, glidants coloring agents and flavoring agents. These excipients may be present intragranularly or extragranularly or both.
Examples of fillers include, but are not limited to, corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch and starch pregelatinized.
Examples of binders include, but are not limited to, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pregelatinized starch, agar, tragacanth, sodium alginate and propylene glycol.
Examples of disintegrants include, but are not limited to, starch, cross-linked carboxy methyl cellulose sodium, cross-linked polyvinyl pyrrolidone, sodium starch glycolate and low substituted hydroxy propyl cellulose.
Examples of lubricants and glidants include, but are not limited to, colloidal anhydrous silica, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax and white beeswax.
The coloring agents and flavoring agents of the present invention may be selected from any FDA approved colors and flavors for oral use.
The amorphous Cefditoren pivoxil solid dosage forms of the present invention may be formulated into various pharmaceutical preparations for oral administration, e.g., in the form of tablet or capsule in accordance with any of the conventional procedure known in the field of art.
In one general aspect of the process, the Cefditoren pivoxil can be mixed with optionally a surfactant, one or more of pharmaceutical excipients such as filler, binder, disintegrant and lubricant described above in a suitable blender. The resultant blend can either be directly compressed into solid dosage form or compacted by roller compaction. The dry process prevents the conversion of amorphous Cefditoren pivoxil to crystalline form.
The compaction of the drug or the mixture comprising the drug and excipient (s) into compacts may be carried out by slugging or by roller compaction, particularly suitable is roller compaction.
The roller compactor functions by uniformly applying pressure on a mixed powder blend by passing the blend between two counter-rotating rollers. The pressure imparted on
the blend by the rollers compresses the powder into a compact, such as a sheet or ribbon, which is typically milled to produce granules.
The resultant blend for compaction is subsequently transferred to a roller compactor in a mown manner. The roller speed, roller gap width and force of compaction are then adjusted and the blend is fed through the roller compactor. The typical force and other conditions can be easily selected and adjusted by those skilled in the art.
The granules obtained as above may be filled into capsules or packed in a sachet. The granules can also be mixed with one or more of pharmaceutically acceptable excipients and compressed into tablets.
As an alternative to roller compaction, slugging may be used for preparing solid dosage forms such as a tablet. The process is simple, low cost and effective. Slugging may be carried out by means of a tablet press. The drug either alone or mixed with optionally surfactant, other excipients are precompressed on a heavy duty press. The slug so formed is milled into granules and recompressed into tablet. The granules may also optionally be mixed with other extragranular excipients prior to compression into a tablet.
Both the processes, i. e., roller compaction and slugging generate fines during the milling step. A portion of these fines can be mixed with granules and compressed into a tablet or can be easily recycled by collecting them and compacting again.
In one embodiment, processes provided herein comprise blending amorphous Cefditoren pivoxil, a surfactant, filler, binder, disintegrant and lubricant and compacting the mixture using roller compactor; milling and sizing the compacts into granules with a desired particle size distribution; mixing with one or more of filler, binder, disintegrant and lubricant and compressed into a tablet using appropriate tooling.
Alternative to dry granulation, direct compression may be carried out for preparing solid dosage forms such as tablets. The direct compression process for preparing Cefditoren pivoxil tablets, comprises mixing of amorphous Cefditoren pivoxil, optionally a surfactant with one or more pharmaceutically acceptable excipients using conventional
lending equipment, under low-shear conditions. The blended formulation is thereafter directly compressed using conventional types of tableting equipments.
The tablets prepared by the present invention may be coated with one or more layers comprising film forming agents and/or pharmaceutically acceptable excipients.
The coating layers over the tablet may be applied as solution/ dispersion of coating ingredients using any conventional technique known in the prior art such as spray coating in a conventional coating pan or fluidized bed processor or dip coating. The coating weight build up can be of about 1 to 10% (w/w), based on the weight of the solid dosage form.
The solvents used for coating the film forming agents is aqueous or non-aqueous. Example of solvents used for preparing a solution/dispersion of the coating ingredients include, but are not limited to, methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, water and mixtures thereof.
Example of film forming agents include, but are not limited to, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methyl phthalate, cellulose acetate, cellulose acetate trimelliatate, cellulose acetate phthalate; Waxes such as polyethylene glycol; copolymers of acrylic and methacrylic acid such as those marketed under the brand names Eudragit® RL and RS; or mixtures thereof. Alternatively, commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® may also be used for coating.
The solid dosage form according to the present invention containing amorphous Cefditoren pivoxil may be used as antibacterial agents. Bacteria referred to herein include for example gram-positive bacteria such as staphylococcus and streptococcus, gram-negative bacteria such as Escherchia coli, Branhamella catarrhalis, klebsiella, Proteus, and Haemophilus influenzas, and anaerobes such as Peptostreptococcus, Propionibacterium acnes, and Bacteriocides. Further, the amorphous Cefditoren pivoxil solid dosage form according to the present invention is useful for the prophylaxis or therapy of diseases induced by gram-positive bacteria or gram-negative bacteria.
The amorphous Cefditoren pivoxil solid dosage form according to the present invention comprising amorphous Cefditoren pivoxil may be administered in combination with other medicines, for example, other antibacterial agents.
The following example is illustrative of the invention, and not to be construed as limiting the invention.
(Table Removed)Procedure:
1. Amorphous Cefditoren pivoxil was blended with mannitol, cross-linked carboxy
methyl cellulose sodium, sodium lauryl sulfate, hydroxypropyl cellulose and
magnesium stearate and compacted with roller compactor.
2. The compacts prepared in step 1 were sized into granules by milling and
blended with extragranular cross-linked carboxy methyl cellulose sodium,
colloidal silicon dioxide and magnesium stearate.
3. The blend obtained from step 2 was compressed into tablets using appropriate
tooling.
4. The compressed tablets were coated with the given coating composition.
(Table Removed)The above data clearly shows that with sodium lauryl sulfate, rate of dissolution of Cefditoren pivoxil enhanced.
While there has been shown and described what are the preferred embodiments of the invention, one skilled in the pharmaceutical formulation art will appreciate that various modifications in the formulations and process can be made without departing from the scope of the invention as it is defined by the appended claims.

WE CLAIM:
1. A dry process for the preparation of amorphous Cefditoren pivoxil solid dosage
forms wherein the processes comprise blending amorphous Cefditoren pivoxil
with one or more pharmaceutically acceptable excipient(s) and forming into a
solid dosage form.
2. The process according to claim 1 wherein the amorphous Cefditoren pivoxil solid
dosage forms further comprises a surfactant.
3. The process according to claim 1 or 2 wherein the Cefditoren pivoxil constitutes
about 20 to 80% (w/w), based on the weight of the solid dosage form.
4. The process according to claim 2 wherein the surfactant comprises at least one
of anionic, cationic, zwitterionic and nonionic surfactants.
5. The process according to claim 4 wherein the surfactant is an anionic surfactant
selected from one or more of alkyl sulfonates, alkyl phosphates, alkyl
phosphonates, potassium laurate, sodium lauryl sulfate, sodium dodecylsulfate,
alkyl polyoxyethylene sulfates, dioctyl sodium sulfosuccinate, phosphatidyl
glycerol, phosphatidylinositol, diphosphatidylglycerol, phosphatidyl inosine,
phosphatidylserine, phosphatidic acid and their salts, cholic acid and other bile
acids and salts thereof.
6. The process according to claim 2 wherein the surfactant constitutes about 1 to
20% (w/w) based on the weight of the solid dosage form.
7. The process according to claim 1 or 2 wherein the pharmaceutically acceptable
excipients comprise at least one or more of fillers, binders, disintegrants,
lubricants, glidants, coloring agents and flavoring agents.
8. The process according to claim 1 or 2 wherein the process comprises:
a. blending
i. amorphous Cefditoren pivoxil,
ii. optionally a surfactant, and
iii. one or more pharmaceutically acceptable excipients,
b. compacting or slugging the blend,
c. milling and sizing the compacts into granules,
d. optionally mixing the granules with one or more of pharmaceutically
acceptable excipients and compressing into tablets or filling the granules
into capsules.
9. The process according to claim 1 or 2 wherein the process comprises:
a. blending
i. amorphous Cefditoren pivoxil,
ii. optionally a surfactant, and
iii. one or more pharmaceutically acceptable excipients,
b. directly compressing the blend formed in step (a) into a tablet.
10. The process according to claim 1 or 2 wherein the amorphous Cefditoren pivoxil
solid dosage forms may be coated with one or more film forming agents.
11.A solid dosage form comprising amorphous Cefditoren pivoxil, a surfactant and one or more pharmaceutically acceptable excipients, wherein the surfactant is an anionic surfactant.