Technical Field of the Invention
The present invention relates to stable solid dosage form and a dry process for the preparation of amorphous Cefditoren pivoxil solid dosage forms and coating the dosage form with one or more layers of aqueous dispersion of film forming agents.
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 β-cyclodextrin along with an ionic surfactant in a pharmaceutically acceptable carrier (EP 0339465).
US Appl. No. 2006/0051411 discloses a pharmaceutical composition comprising amorphous cefditoren pivoxil and a sugar ester fatty acid, which is obtainable by mixing
or wet-granulating particles containing amorphous cefditoren pivoxil with the sugar ester fatty acid while amorphous cefditoren pivoxil maintains its particle state.
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.
Cefditoren pivoxil, apart from exhibiting low solubility, has another unfavorable 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.
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.
In addition 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, use of synthetic surfactant can be an alternative way in administering such poorly water-soluble drug products.
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 film-coat can suitably be applied to the preparations of the tablet form.
Film coating of Pharmaceuticals is a common manufacturing stage for the following reasons: (i) to provide physical and chemical protection for the drug, (ii) to mask the taste, odour or colour of the drug or (iii) to control the release rate or site of the drug from the tablet. When a coating composition is applied to a batch of tablets or granules, the core surfaces become covered with a polymeric film that is formed as the surfaces dries. The major component in a coating formulation is a film forming agent, which ideally is a high molecular-weight polymer that is soluble or dispersible in the proper solvent (today, most preferably in aqueous-based media). The polymer forms a gel and produces an elastic, cohesive and adhesive film coating.
In pharmaceutical industry, organic-solvent based film coatings have been used for over 40 years. However, interest in the use of aqueous-based film coating systems has been rapidly increasing owing to the well-documented drawbacks (unsafe, toxic, polluting and uneconomic) associated with organic-solvent-based coating systems. Consequently, and for the reasons mentioned above, efforts has been focused on the research and development work of new aqueous-based film coating formulations. Up to
date, aqueous-soluble/dispersible polymers available on the market consist primarily of either cellulosic polymers or acrylate copolymers, such as hydroxypropyl methylcellulose (HPMC), cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), and methacrylic acid polymers and copolymers. An example of an aqueous dispersion for conventional film coating of tablets is Opadry® (HPMC). There are, however, some material related limitations in using these polymers in aqueous-based film coating such as logo-bridging, cracking and edge splitting.
WO 2002/092708 discloses a method for preparing an aqueous coating dispersion of starch having good film-forming properties and usability in the room temperature. The films have satisfactory mechanical strength properties and as a consequence of their hydrophilicity good oxygen barriers.
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, with enhanced stability and 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 a dry process for the preparation of amorphous Cefditoren pivoxil solid dosage form wherein the dosage form is coated with one or more layers of aqueous dispersion of film forming agents.
According to one of the embodiments, the process for the preparation of solid dosage form of Cefditoren pivoxil involves dry processes like, dry granulation and direct compression.
It is another general aspect to provide a process for the preparation of solid dosage form of amorphous Cefditoren pivoxil wherein the process 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; forming solid dosage form and coating with one or more layers of aqueous dispersion of film forming agents.
It is another general aspect to provide a process for the preparation of solid dosage form of amorphous Cefditoren pivoxil wherein the process 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; compressing into tablets and coating with one or more layers of aqueous dispersion of film forming agents.
It is another general aspect to provide process for the preparation of amorphous Cefditoren pivoxil solid dosage form wherein the process comprise blending Cefditoren pivoxil with one or more pharmaceutically acceptable excipient(s); directly compressing into solid dosage form and coating with one or more layers of aqueous dispersion of one or more film forming agents.
It is another general aspect to provide process for the preparation of solid dosage forms of amorphous Cefditoren pivoxil wherein the process comprise blending Cefditoren pivoxil with one or more pharmaceutically acceptable excipient(s); directly compressing into tablets and coating with one or more layers of aqueous dispersion of film forming agents.
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 process and coating with one or more layers of aqueous dispersion of film forming agents.
According to one of the embodiments, film forming agents of the aqueous dispersion
comprise one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose,
methyl cellulose, carboxymethylcellulose, hydroxymethylcellulose,
hydroxyethylcellulose, ethyl cellulose, 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.
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.
Particularly, the surfactant utilized is an anionic surfactant and more particularly, the surfactant is sodium lauryl sulfate.
It is another general aspect to provide dry process for the preparation of amorphous Cefditoren pivoxil solid dosage form wherein the process comprise blending amorphous Cefditoren pivoxil, a surfactant and one or more pharmaceutically acceptable excipient(s); forming into a solid dosage form and coating with one or more layers of aqueous dispersion of 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 process and coated with one or more layers of aqueous dispersion of film forming agents.
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 solid dosage form is further coated with aqueous dispersion of film forming agents, to enhance its physicochemical stability.
The aqueous dispersion coating over the solid dosage forms ensures that the amorphous form of Cefditoren pivoxil remains thermodynamically stable and resistant to crystallize. Generally amorphous materials are plasticized by sorbed water, leading to increase in the free volume and enhanced molecular mobility, causing crystallization. Aqueous dispersion coating over the solid dosage forms of Cefditoren pivoxil reduces the molecular mobility in significant way and has good stability during storage, over other solvent coatings.
In addition to that the process is simple, economical and environmental friendly, as it does not require any solvents, which are commonly used in conventional coating process.
Example of film forming agents include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, ethyl cellulose, 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 aqueous dispersion coating weight build ranges about 1 to 10% (w/w), based on the weight of the solid dosage form.
Coating 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 process for the preparation of solid dosage forms of Cefditoren pivoxil comprising amorphous Cefditoren pivoxil, optionally a suitable surfactant, involves dry processes like, dry granulation and direct compression. The dry processes as such have resistance for the conversion of amorphous form to crystalline form. The dry processes can be any of the methods known in the art for the preparation of solid dosage forms by dry processes also by methods described in our co-pending Indian Patent Application No. /DEL/2006, which is incorporated here in entirety.
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 is further coated with aqueous dispersion of one or more layers of 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 in entirety.
Cefditoren pivoxil is added in an amount of ranging from 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 form 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 amorphous 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 to granules 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 granules obtained as above may be filled into capsules or packed in a sachet. Alternatively the granules may 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 in 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 blending equipment, under low-shear conditions. The blended formulation is thereafter directly compressed using conventional types of tableting equipments.
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 influenzae, 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.
EXAMPLES 1-4: Amorphous Cefditoren pivoxil 1

(Table Removed)
Propylene glycol was dissolved in acetone. Cefditoren pivoxil was added to the solution formed and crospovidone was dispersed in it. The solvent was removed to obtain the amorphous Cefditoren pivoxil.
Amorphous Cefditoren pivoxil 2

(Table Removed)
Hydroxypropyl cellulose was dissolved in acetone. Cefditoren pivoxil was added to the solution formed and colloidal silicon dioxide was dispersed in it. The solvent was removed to obtain the amorphous Cefditoren pivoxil.
Amorphous Cefditoren pivoxil 3

(Table Removed)
Cefditoren pivoxil was dissolved in acetone and colloidal silicon dioxide was dispersed in it. The solvent was removed to obtain the amorphous Cefditoren pivoxil.
Amorphous Cefditoren pivoxil 4

(Table Removed)
Hydroxypropyl methylcellulose was dissolved in the mixture of Dichloromethane and isopropyl alcohol. Cefditoren pivoxil was added to the solution formed and colloidal silicon dioxide was dispersed in it. The solvent was removed to obtain the amorphous Cefditoren pivoxil.
EXAMPLE 5:

(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 using 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.
EXAMPLE 6:

(Table Removed)
Procedure:
The procedure was similar to that followed in Example 5.
EXAMPLE 7:
Tablets prepared in Example 5 and Example 6 were subjected to accelerated stability studies at 40° C with 75% relative humidity (RH) for the period of one month and three months. The samples were analyzed for the presence of crystallinity. The results are provided in Table 1.
Table 1
Crystallinity detection from Cefditoren pivoxil tablets subjected to stability studies under 40°C with 75% RH for the period 1 month & 3 months.

(Table Removed)
EXAMPLE 8:
Tablets prepared in the Example 5 were studied for other stability parameters - water content, dissolution and related substances after charging them at accelerated stability condition of 40° C and 75% RH in HDPE bottles for the period of three months. The results of this study are provided in Tables 2, 3 and 4.
Table 2
Water content detection by Karl Fischer (KF) method for Cefditoren pivoxil tablets of Example 5, subjected to stability studies under 40°C with 75% RH for the period 3 months.

(Table Removed)
Table 3
In vitro release of Cefditoren pivoxil from tablets prepared according to Example 5, subjected to stability studies under 40°C with 75% RH for the period 3 months, in 900 ml water, USP Apparatus II, at 75 rpm and 37°C.

(Table Removed)
Table 4
Related substances detection from Example 5, which was subjected to stability studies under 40°C with 75% RH for the period 3 months.

(Table Removed)
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
form wherein the dosage form is coated with one or more layers of aqueous
dispersion of film forming agents.
2. The process according to claim 1 wherein the Cefditoren pivoxil constitutes
about 20 to 80% (w/w), based on the weight of the solid dosage form.
3. The process according to claim 1 wherein the dry process comprises dry
granulation or direct compression.
4. The process according to claim 1 wherein the aqueous dispersion of film forming
agents constitutes about 1 to 10% (w/w) based on the weight of the solid
dosage form and are selected from one or more of hydroxypropyl
methylcellulose, hydroxypropyl cellulose, methyl cellulose,
carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, ethyl
cellulose, hydroxypropyl methyl phthalate, cellulose acetate, cellulose acetate
trimelliatate, cellulose acetate phthalate, waxes, copolymers of acrylic and
methacrylic acid or mixtures thereof.
5. The process according to claim 1 wherein the dosage form further comprises a
surfactant.
6. The process according to claim 5 wherein the surfactant constitutes about 1 to
20% (w/w) based on the weight of the solid dosage form and comprises at least
one of anionic, cationic, zwitterionic and nonionic surfactants.
7. The process according to claim 1 wherein the dosage form further comprises
one or more pharmaceutically acceptable excipients.
8. The process according to claim 7 wherein the pharmaceutically acceptable
excipients comprise at least one or more of fillers, binders, disintegrants,
lubricants, glidants, coloring agents and flavoring agents.
9. The process according to preceding claims 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 and
e. coating the tablets with one or more layers of aqueous dispersion of film
forming agents.
10. The process according to preceding claims 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 and
c. coating the tablets with one or more layers of aqueous dispersion of film
forming agents.
11. A solid dosage form comprising amorphous Cefditoren pivoxil, a surfactant and
one or more pharmaceutically acceptable excipients, wherein the dosage form is
prepared by dry process and is coated with one or more layers of aqueous
dispersion of film forming agents.