WO2013100880A1

WO2013100880A1 - Formulations comprising cefuroxime

Info

Publication number: WO2013100880A1
Application number: PCT/TR2012/000236
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Mahmut Bilgic
Priority date: 2011-12-27
Filing date: 2012-12-27
Publication date: 2013-07-04

Abstract

The present invention relates to pharmaceutical formulations comprising cefuroxime for use in treatment and prophylaxis of gram positive and gram negative bacteria-related upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as, pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.

Description

FORMULATIONS COMPRISING CEFUROXIME

Cefuroxime was first disclosed in the application numbered US3974153. It has been disclosed in said document that use of cefuroxime is effective in treatment and prophylaxis of gram positive and gram negative bacteria-related upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as, pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.

Cefuroxime is found in form of 100-5000 mg tablet and suspension on the market.

During the preparation of formulations comprising cefuroxime, it is observed that the formulation adheres to machine parts such as inner walls of the die and the punch. This causes some part of the drug to remain on the punches and in the dies and this poses problems for producers during preparation phase of the drug. One of these problems is the loss of weight uniformity observed during the compression of the tablet. The drug particles remained on the machine parts cause the weight variations in the total weight of the tablet therefore the weight uniformity of the formulation can be lost. In addition, since some part of the drug remains on the punches and in the dies, the obtained dosage form is not in desired form and smoothness and this poses problems in quality control processes. At the same time, in the case that the formulations are compressed in tablet form, corrosion and wear are observed on the machine parts in time due to the friction between tablet surface and the punch or inner wall of the die during ejection of the tablets. Therefore, these problems observed during preparation of the formulations comprising cefuroxime bring along difficulties for producers during production and quality control processes and impede to obtain the final product efficiently.

As it is seen, in order to prevent problems such as adhesion of the formulation to machine parts like the die and the punch during preparation and possible loss of some part of the drug during tablet compression resulting in weight nonuniformity, it is required to develop new approaches to obtain drugs comprising cefuroxime that are produced in a way that no problem is experienced in production and quality control processes.

As a result of the studies they conducted in line with said needs, the inventors have found out that the problems encountered in production and quality control processes during the preparation of the drugs can be solved by the formulations developed for preparation of dosage forms comprising cefuroxime. Description of the Invention

The present invention relates to pharmaceutical formulations comprising cefuroxime and methods for preparation of said formulations. Surprisingly, the inventors have seen that the formulation comprising cefuroxime does not adhere to the punch and the inner walls of the die and and does not cause the loss of weight uniformity in the case that the formulation comprises a combination of lubricant and a combination of disintegrant wherein total amount of lubricant is in the range of 1-10% and total amount of disintegrant is in the range of 10- 30% in proportion to total weight of the formulation.

In this regard, the present invention relates to formulations comprising cefuroxime characterized in that said formulation comprises a combination of lubricant consisting of a first lubricant and a second lubricant and a combination of disintegrant consisting of a first disintegrant and a second disintegrant wherein

• total amount of lubricant in the formulation is in the range of 1 - 10% and

• total amount of disintegrant in the formulation is in the range of 10-30% in proportion to total weight of the formulation. In a preferred embodiment of the invention, total amount of lubricant is in the range of preferably 1-5% in proportion to total weight of the formulation.

In another preferred embodiment of the invention, total amount of disintegrant in the formulation is preferably in the range of 15-25% in proportion to total weight of the formulation.

As already stated above, adherence of the formulation to machine parts such as inner walls of the die and the punch damages the integrity of the drug formulation and poses problems during manufacture. Based on the studies performed by the inventors, it is observed that the ratio of lubricants to each other composing the lubricant combination affects the required parameters during manufacture and helps to eliminate previously mentioned problems.

Concerning this, according to a preferred embodiment of the invention, the pharmaceutical formulation comprising cefuroxime is characterized in that the ratio of the first lubricant to the second lubricant is in the range of 5: 1 to 1 :5, preferably 2:1 to 1 :2 and more preferably 1 :1. During the studies conducted for solving the problem of the formulations comprising cefuroxime which cause the corrosion and wear in time resulting from the friction between tablet surface and the punch or the inner walls of the dies during ejection of the tablets, the inventors have unexpectedly observed that the ratio of disintegrants to each other composing the disintegrant combination also plays an important role in solving said problem in an efficient way. In this regard, another characteristic of the present invention is cefuroxime formulations characterized in that the ratio of the first disintegrant to the second disintegrant is in the range of 5:1 to 1 :5, more preferably 3: 1 to 1 :3.

The lubricants that can be used in pharmaceutical formulations of the invention can be selected from a group comprising comprising talc, magnesium stearate, PEG 6000, silicon dioxide, sodium benzoate, potassium benzoate, hydrogenated plant oil, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate.

According to a preferred embodiment of the invention, the first lubricant is preferably sodium lauryl sulfate and the second lubricant is preferably hydrogenated plant oil.

In a preferred embodiment of the invention, the ratio of sodium lauryl sulfate to hydrogenated plant oil is in the range of 5: 1 to 1 :5, preferably 2: 1 to 1 :2 and more preferably 1 :1. The disintegrants that can be used in pharmaceutical formulations of the invention comprising cefuroxime and lubricant can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, pregelatinized starch, sodium starch glycolate.

In a preferred embodiment of the invention, the first disintegrant is preferably pregelatinized starch and the second disintegrant is preferably carboxymethyl cellulose sodium.

According to a preferred embodiment of the invention, the ratio of pregelatinized starch to carboxymethyl cellulose sodium is in the range of 5:1 to 1 :5, more preferably 3: 1 to 1 :3. Cefuroxime comprised in the pharmaceutical formulations of the present invention can be in form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in respect to its chemical structure; in crystalline, amorphous form or combinations thereof in respect to its polymorphic structure. Cefuroxime is preferably in ester, more preferably in 1-acetoxyethyl ester (i.e. cefuroxime axetil) form. Pharmaceutical formulations of the invention comprising cefuroxime can be prepared in any of the dosage forms such as tablet, film coated tablet, enterically coated tablet, powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet.

Pharmaceutical formulations of the present invention comprising cefuroxime are preferably in powder, tablet and granule forms, more preferably in film tablet form. In another aspect, the present invention relates to pharmaceutical formulations in film tablet form comprising cefuroxime, lubricant and disintegrant combinations.

Obtained pharmaceutical formulation can be formed into any of the abovementioned dosage forms. In the case that it is in tablet form, obtained tablets can be treated with film coating agents such as sugar-based coating agents, water-soluble film coating agents, enteric coating agents and delayed release coating agents or a coating composition comprising any combination thereof.

As sugar-based coating agent, saccharose can be used alone or together with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or any combination thereof. Water-soluble film coating agents can be selected from a group comprising cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl amino acetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone; polysaccharides such as pullulan or combinations thereof.

Enteric coating agents can be selected from a group comprising cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combinations thereof.

Other film coating agents can be selected from a group comprising titanium dioxide, polyvinyl alcohol, polyethylene glycol, talc, lecithin and/or combinations thereof. For example, a film coating agent branded as Opadry® can be used in the present invention.

Pharmaceutical formulations of the invention can comprise various excipients in addition to the active agent cefuroxime, lubricant and disintegrant.

Pharmaceutical formulations of the invention comprise at least one excipient selected from a group comprising diluent, glidant, binder, stabilizing agent, sweetener and/or taste regulating agent in addition to the active agent cefuroxime, lubricant and disintegrant.

The diluent that can be used in pharmaceutical formulations of the invention comprising cefuroxime can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.

The glidant that can be used in pharmaceutical formulations of the invention comprising cefuroxime can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.

The pharmaceutical formulation of the invention can comprise cefuroxime in the range of 25 to 90%, preferably in the range of 40 to 80%, more preferably in the range of 45 to 75%. The pharmaceutical formulation of the invention can comprise 25 to 90% of cefuroxime, 1 to 10% of lubricant, 10 to 30% of disintegrant, 5 to 20% of glidant and 1 to 10% of coating agent in proportion to total weight of the formulation.

The pharmaceutical formulation of the invention can be used in treatment and prophylaxis of gram positive and gram negative bacteria related upper respiratory tract infections such as otorhinolaryngological infections, otitis media, sinusitis, tonsillitis, pharyngitis; lower respiratory tract infections such as, pyelonephritis, cystitis and urethritis; skin and soft tissue infections such as furuncle, pyoderma, impetigo; gonorrhea and lyme diseases.

The pharmaceutical formulation of the invention can be obtained by a method comprising the steps of;

• Mixing disintegrant combination and the first lubricant homogeneously to form a first mixture,

• Adding a part of the first mixture to cefuroxime axetil and compacting it and then adding diluent,

• Mixing the rest of the first mixture with glidant to form a second mixture,

• Combining the second mixture with the previous one and stirring homogeneously,

• Adding the second lubricant to the final mixture,

• Compressing it in tablet form and coating the tablets with a film coating solution comprising a film coating agent.

Another problem seen during the production of the cefuroxime formulation disclosed in the present invention due to the adherence of the formulation to machine parts is the loss of smoothness of the formulation. Thus, the formulation fails to have the required quality control specifications resulting in not providing the desired product. The inventors have conducted a study for solving this problem and surprisingly found out that forming a first mixture composed of the disintegrant combination and the first lubricant and using this first mixture in two different steps of the preparation method eliminates the abovementioned problem.

In this regard, another characteristic feature of the present invention is that the method for the preparation of cefuroxime formulations claimed in the present invention comprises a process of • Adding a part of the first mixture composed of the disintegrant combination and the first lubricant to cefuroxime axetil, compacting it and then adding diluent,

• Mixing the rest of the first mixture with glidant to form a second mixture.

As already stated, the adherence of cefuroxime formulations to machine parts causes weight variations in the weight of the obtained tablets and leads to the loss of weight uniformity of the obtained product. During the manufacturing process of cefuroxime formulations, it is observed that these weight variations result from the fact that cefuroxime granules do not have the desired flow uniformity. This flow nonuniformity of granules containing cefuroxime causes weight variations and eventually affects the total weight of the formulation negatively. Based on the studies conducted by the inventors, four different formulations are prepared and three of them are prepared in accordance with the claimed range of lubricant and disintegrant in the present invention. The RSD (Relative Standard Deviation) values of the granules obtained in each formulation corresponding to the weight changes thereof are measured. Accordingly, the amount of lubricant and disintegrant used in each formulation and the RSD values of the obtained granules are given in Table I.

In obtainment of the formulation to be used in scope of the present invention, a first mixture comprising disintegrant combination, one of the lubricants and cefuroxime is prepared and compacted, diluent is added and stirred. A second mixture comprising disintegrant combination, one of the lubricants and glidant is prepared and combined with the first mixture. Other lubricant is added to the final mixture and it is compressed in tablet form. The tablets obtained are coated with solution containing a film coating agent.

Example 1: Formulation and process for preparation of cefuroxime axetil film tablet

*total amount of disintegrant in the range of 10-30% and total amount of ubricant in the range of 1-10

Comparative Example 1: Formulation and process for preparation of cefuroxime film tablet

*total amount of disintegrant in the range of 10-30% and total amount of lubricant out of the range of 1-10%

Comparative Example 2: Formulation and process for preparation of cefuroxime film tablet

*total amount of disintegrant out of the range of 10-30% and total amount of lubricant the range of 1-10%

Comparative Example 3: Formulation and process for preparation of cefuroxime film tablet

*total amount of disintegrant out of the range of 10-30% and total amount of lubricant out of the range of 1-10%

Table 1 - Total amount of disintegrant and total amount of lubricant used in the formulations and the RSD% values thereof

As seen in Table 1 , it is observed that RSD% values of the obtained granules are about 2% or below in the case that total amount of lubricant in the formulation is in the range of 1-10% and total amount of disintegrant in the formulation is in the range of 10-30% in proportion to total weight of the formulation. Consequently, the inventors have found that cefuroxime formulations containing lubricant in the range of 1-10% and disintegrant in the range of 10- 30% in proportion to total weight of the formulation have the desired RSD values showing the flow uniformity of the formulation thereby ensuring the weight uniformity.

Claims

1. A pharmaceutical formulation comprising cefuroxime characterized in that said formulation comprises a combination of lubricant consisting of a first lubricant and a second lubricant and a combination of disintegrant consisting of a first disintegrant and a second disintegrant wherein

• total amount of lubricant in the formulation is in the range of 1 - 10% and

• total amount of disintegrant in the formulation is in the range of 10-30% in proportion to total weight of the formulation.

2. The pharmaceutical formulation comprising cefuroxime according to claim 2 characterized in that the amount of lubricant is in the range of 1-5% in proportion to total weight of the formulation.

3. The pharmaceutical formulation comprising cefuroxime according to claims 1-3 characterized in that the amount of disintegrant is in the range of 15-25% in proportion to total weight of the formulation.

4. The pharmaceutical formulation according to claims 1-4, wherein the ratio of first lubricant to the second lubricant is in the range of 5:1 to 1 :5.

5. The pharmaceutical formulation according to claim 5, wherein the ratio of first lubricant to the second lubricant is in the range of 2: 1 to 1 :2.

6. The pharmaceutical formulation according to claim 6, wherein the ratio of first lubricant to the second lubricant is 1 : 1.

7. The pharmaceutical formulation according to claims 1-7, wherein the ratio of first disintegrant to the second disintegrant is in the range of 5:1 to 1 :5.

8. The pharmaceutical formulation according to claims 1-8, wherein the ratio of first disintegrant to the second disintegrant is in the range of 3:1 to 1 :3.

9. The pharmaceutical formulation according to any preceding claims, wherein lubricants are selected from a group comprising talc, magnesium stearate, PEG 6000, silicon dioxide, sodium benzoate, potassium benzoate, hydrogenated plant oil, stearic acid, sodium stearyl fumarate, sodium lauryl sulfate.

10. The pharmaceutical formulation according to claim 10, wherein the first lubricant is sodium lauryl sulfate and the second lubricant is hydrogenated plant oil.

1 1. The pharmaceutical formulation according to any preceding claims, wherein disintegrants are selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, pregelatinized starch, sodium starch glycolate.

12. The pharmaceutical formulation according to claim 12, wherein the first disintegrant is pregelatinized starch and the second disintegrant is carboxymethyl cellulose sodium.

13. The pharmaceutical formulation comprising cefuroxime according to any preceding claims, wherein said formulation is prepared in any of tablet, film coated tablet, powder, granule, capsule dosage forms.

14. The pharmaceutical formulation comprising cefuroxime according to claim 14, wherein said formulation is prepared in film coated tablet form.

15. The pharmaceutical formulation comprising cefuroxime according to any preceding claims, wherein cefuroxime is in form of its pharmaceutically acceptable derivatives; salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in respect to chemical structure.

16. The pharmaceutical formulation comprising cefuroxime according to claim 16, wherein cefuroxime is in pharmaceutically acceptable 1-acetoxy ethyl ester form.

17. The pharmaceutical formulation comprising cefuroxime according to any preceding claims, wherein said formulation comprises at least one excipient selected from a group comprising diluent, glidant and film coating agent, in addition to cefuroxime, lubricant and disintegrant.

18. The pharmaceutical formulation comprising cefuroxime according to claim 18, wherein glidant is selected form a group comprising selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.

19. The pharmaceutical formulation comprising cefuroxime according to claim 18, wherein diluent is selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.

20. The pharmaceutical formulation comprising cefuroxime according to claim 18, wherein film coating agent is selected from a group comprising titanium dioxide, polyvinyl alcohol, polyethylene glycol, talc, lecithin and/or combinations thereof.

21. The pharmaceutical formulation comprising cefuroxime according to any preceding claim, wherein said formulation comprises 25 to 90% of cefuroxime, 1 to 20% of lubricant, 10 to 30% of disintegrant, 5 to 20% of glidant and 1 to 10% of coating agent in proportion to total weight of the formulation.

22. The method for the preparation of a pharmaceutical composition according to claim 1, wherein said method comprises a process of

• Adding a part of the first mixture composed of the disintegrant combination and the first lubricant to cefuroxime axetil, compacting it and then adding diluent,

• Mixing the rest of the first mixture with glidant to form a second mixture.

23. The method for the preparation of a pharmaceutical composition according to claim 22, wherein said method comprises a process of

• Mixing the rest of the first mixture with glidant to form a second mixture,

• Adding the second lubricant to the final mixture,

• Compressing it in tablet form and coating the tablets with a film coating solution comprising a film coating agent