WO2013095313A1

WO2013095313A1 - Pharmaceutical formulations comprising cefdinir

Info

Publication number: WO2013095313A1
Application number: PCT/TR2012/000217
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Individual
Current assignee: Individual
Priority date: 2011-12-19
Filing date: 2012-12-17
Publication date: 2013-06-27
Anticipated expiration: 2014-06-19

Abstract

The present invention relates to pharmaceutical formulations comprising cefdinir so as to be used in treatment of a number of diseases caused by gram positive and gram negative bacteria; and the preparation methods of said formulations.

Description

PHARMACEUTICAL FORMULATIONS COMPRISING CEFDINIR

The present invention relates to pharmaceutical formulations comprising cefdinir so as to be used in treatment of a number of diseases caused by gram positive and gram negative bacteria.

Cefdinir was first disclosed in the application numbered BE897864. It has been disclosed in said document that cefdinir is effective in treatment of a number of diseases caused by gram positive and gram negative bacteria.

Cefdinir is found in capsule and suspension form on the market.

During preparation of formulations comprising cefdinir, it has been observed that formulation composition does not have a proper flow due to the reasons that free flow of the obtained granules cannot be enabled and/or friction between granule particles cannot be reduced; therefore, homogeneity cannot be provided in the obtained pharmaceutical composition and the composition loses its homogeneity during the processes. Therefore, during the conversion of formulations into any solid dosage form, said issues cause changes in weight of the final product and increase in relative standard deviation values. Weight and content uniformity in the final product cannot be ensured due to the deviations observed in the weight of final product and failure to provide homogeneity of the formulation. Thus, said points pose problems to producers in production and quality control processes and at the same time, patients cannot take same amounts of drug during the treatment because of weight and content uniformity loss observed in the dosage forms obtained; therefore, efficiency of the treatment decreases.

As it is seen, it is still needed to develop new approaches so as to obtain homogeneous cefdinir formulations which are produced such that no change is observed in unit dosage weight for the purpose of carrying out an effective treatment by preventing the changes observed in weight and content of the final product obtained and for preventing problems resulting from weight uniformity loss in the production processes. As a result of the studies conducted in line with said necessity, inventors have found that some physical characteristics of the formulations they developed for preparation of dosage forms comprising cefdinir are effective on relative standard deviation of the dosage weight of the drug obtained and said problems which are encountered during both quality control and administration processes can be solved by said formulations developed by adjusting their physical characteristics.

Description of the Invention

The present invention relates to pharmaceutical formulations comprising cefdinir and methods for preparation of said formulations. In the case that formulations in which the average particle size of the granules comprising cefdinir, at least one excipient and optionally a second active agent is in the range of 300-2500 μηι, preferably in the range of 350-2000 μιη, more preferably in the range of 500-1750 μπι are converted into any solid dosage form; it has surprisingly been observed that relative standard deviation value remains low; a homogeneous pharmaceutical composition is obtained; weight and content uniformity are ensured by preventing the changes in weight.

In this regard, the subject of the present invention is that average particle size of the granules comprising cefdinir, at least one excipient and optionally a second active agent is in the range of 300-2500 μηι, preferably in the range of 350-2000 μηι, more preferably in the range of 500-1750 μπι during the preparation of formulations comprising cefdinir.

The term "average particle size" refers to volumetric average particle diameter and is indicated by d₅₀ in short. In this sense, the term d₅₀ means that half of the said substance by volume has a particle size above the value stated with d₅₀ and the other half has a particle size below the value stated with d₅o.

D₅₀ value can be measured by one of the known measurement devices such as a device measuring the particle distribution with laser diffraction (for example; Malvern Mastersizer etc).

In another aspect, the present invention relates to a process that will be used in production of granules having an average particle size in the range of 300-2500 μηι, preferably in the range of 350-2000 μπι, more preferably in the range of 500-1750 μπι which comprise cefdinir, at least one excipient and optionally a second active agent characterized in that said granules having an average particle size in the range of 300-2500 μη , preferably in the range of 350- 2000 μηι, more preferably in the range of 500-1750 μηι are obtained by;

• Sieving the granules with a proper sieve or

• Grinding them by devices such as impact mill, jet mill, blade mill etc.

Grinding process is performed by the effect of rolling blades within the device in the case that blade mill is used.

Grinding process is performed by the effect of rolling hammers within the device in the case that impact mill is used.

Grinding process is performed by making the particles collide with each other with the help of compressed and high speed air stream in the case that jet mill is used.

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

• Mixing the granules obtained after the active agent cefdinir and, if available, the second active agent are granulated with a granulation solution comprising at least one of the excipients homogeneously and drying the obtained composition; if necessary, converting the average particle size into 300-2500 μιη by a suitable method and optionally treating the mixture with at least one other excipient or

• Mixing the granules obtained after the active agent cefdinir and, if available, the second active agent are mixed with at least one of the excipients and granulated with a granulation solution optionally comprising at least one excipient homogeneously and drying the obtained composition; if necessary, converting the granules into an average particle size in the range of 300-2500 μηι by a proper method and optionally treating the mixture with at least one other excipient or

• Using any of the above mentioned methods separately for each active agent composition and combining the formulations obtained in the case that two active agents are used.

The inventors have observed the relative standard deviation of the weight by changing the average particle size values of the granules in order to find out the effect of the average particle size values of the granules sieved after the granulation and drying processes on weight changes of the solid dosage form obtained and therefore their effect on weight uniformity. Accordingly, average particle size values of the granules obtained after the sieving process and therefore their relative standard deviation values (RSD %) are given in Table 1. As seen in the table, it is observed that RSD % values of the obtained granules are about 2% or below in the case that their average particle sizes are in the range of 300-2500 μπι, preferably in the range of 500-2000 μιη. According to this, they have found that the relative standard deviation of the formulations in solid dosage form which are prepared from granules having an average particle size in the range of 300-2500 μπι and more preferably in the range of 500-2000 μηι is low; therefore, weight uniformity is ensured.

Table 1: Average particle sizes of the granules and their relative standard deviation values accordingly

During the studies conducted, the inventors have observed that parameters such as drying temperature and moisture content of the granules obtained play an important role in obtaining optimum values in hardness, brittleness and stability characteristics of the granules and the final product in solid form which is prepared from said granules used in preparation of formulations comprising cefdinir and accordingly in preventing the problems that can be encountered during quality control and administration processes. According to the studies conducted, the inventors have surprisingly seen that granules which are obtained by drying the granules at a temperature in the range of 10-120°C, preferably in the range of 20-100°C and more preferably in the range of 25-70°C according to the process of the invention have proper flow characteristics and the solid forms prepared from said granules have the desired hardness and brittleness.

According to this, in another aspect, the present invention relates to drying the granules comprising cefdinir, at least one excipient and optionally a second active agent at a temperature in the range of 10-120°C, preferably in the range of 20-100°C and more preferably in the range of 25-70°C during the preparation of formulations comprising cefdinir.

In line with the studies conducted, the inventors have found that moisture content of the granules obtained during the preparation of formulations comprising cefdinir is effective on the final product in solid form to have desired physical characteristics, on enabling weight certainty and stability of the product obtained.

According to this, in another aspect, the present invention relates to drying the granules comprising cefdinir, at least one excipient and optionally a second active agent such that they have a moisture content less than 1%, preferably in the range of 0.1 to 0.9% during the preparation of formulations comprising cefdinir.

Cefdinir comprised in the pharmaceutical formulations prepared according to the process of the present invention can be in form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof in terms of chemical structure. In terms of polymorphic structure, it can be in amorphous or crystalline form or a combination thereof.

Pharmaceutical formulations comprising cefdinir and prepared according to the process of the present invention can be prepared in any solid dosage form such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet.

Pharmaceutical formulations comprising cefdinir and prepared according to the process of the present invention are preferably in water-soluble powder, tablet and granule form, more preferably in effervescent tablet, effervescent granule or effervescent dry powder form. Pharmaceutical formulation obtained according to the invention can be prepared in any dosage form mentioned above. 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, delayed release coating agents or coating compositions comprising a combination thereof.

As sugar-based coating agent, saccharose can be used alone or optionally 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 agent can be selected from 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; and polysaccharides such as pullulan or combinations thereof.

Enteric-coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose ftalat, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate ftalat; 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.

Delayed release coating agents can be selected from cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer emulsion or combinations thereof.

Pharmaceutical formulations comprising cefdinir and prepared according to the process of the present invention can comprise various excipients together with the active agent cefdinir.

Pharmaceutical formulations comprising cefdinir and prepared according to the process of the present invention comprise at least one excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic and one basic agent, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent in addition to the active agent cefdinir. The disintegrant that can be used in pharmaceutical formulations comprising cefdinir and prepared according to the process of the invention 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, sodium starch glycolate.

The diluent that can be used in pharmaceutical formulations comprising cefdinir and prepared according to the process of the invention 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 comprising cefdinir and prepared according to the process of the invention can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, talc.

The binder that can be used in pharmaceutical formulations comprising cefdinir and prepared according to the process of the invention can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose sodium, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch.

The acidic agent constituting the effervescent couple comprising at least one acidic and one basic agent that can be used in the pharmaceutical formulations comprising cefdinir and prepared according to the process of the invention can be selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid; and the basic agent is selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.

The pH regulating agent that can be used in pharmaceutical formulations comprising cefdinir and prepared according to the process of the invention can be selected from a group comprising citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.

The surfactant that can be used in pharmaceutical formulations comprising cefdinir and prepared according to the process of the invention can be selected from a group comprising agents such as sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and so forth.

The stabilizing agent that can be used in pharmaceutical formulations comprising cefdinir and prepared according to the process of the invention can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.

The sweetener and/or taste regulating agent that can be used in pharmaceutical formulations comprising cefdinir and prepared according to the process of the invention can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.

The flavouring agent that can be used in pharmaceutical formulations comprising cefdinir and prepared according to the process of the invention can be selected from flavors such as menthol, lemon, orange, vanillin, strawberry, raspberry, caramel and so forth.

Pharmaceutical formulations comprising cefdinir and prepared according to the process of the invention can comprise cefdinir in the range of 0.1 to 99.9%, preferably in the range of 1 to 99%, more preferably in the range of 5 to 95% by weight.

Pharmaceutical formulations comprising cefdinir and prepared according to the process of the invention can optionally comprise a second excipient in addition to cefdinir. The second active agent can be selected from a group comprising antacid, anticholinergic, antispasmodic, antiemetic, anti-diabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianaemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiaritmic, antiadrenergic, antiepileptic, anti-Parkinson, antiprotozoal, antihelminthic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, tiazolidinedion, biguanide, immunostimulant, neuromuscular blocker, analgesic, psycholeptic, psycho analeptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin B|, vitamin C, vitamin E, vitamin B₆, vitamin B₂, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium. Pharmaceutical formulations comprising cefdinir and prepared according to the process of the invention can preferably comprise clavulanic acid as the second active agent in addition to cefdinir.

In the case that the two active agents are in the same formulation, pharmaceutical formulations comprising clavulanic acid together with cefdinir and prepared according to the process of the present invention can be prepared in any solid dosage form such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet; in the case that the two active agents are in different formulations but in the same dosage form, said formulations can be prepared in dosage forms such as layered tablet, capsule; in the case that the two active agents are in different formulations and different dosage forms, said formulations can be prepared in form of a treatment package comprising any combination of solid dosage forms such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet or in form of capsule comprising micro tablet and/or micro pellet.

The pharmaceutical formulation of the invention can be used in treatment of a number of diseases caused by gram positive and gram negative bacteria.

Example: Formulation and process for preparation of effervescent tablet

In order to obtain the formulation that will be used within the scope of said invention; effervescent base, effervescent acid, sweetener, binder and cefdinir are granulated with water or an aqueous solution; obtained granules are dried; sieved such that their average particle size is 700 μιη and following this; lubricant, colouring agent, sweetening agent and flavouring agent are added to the mixture and stirred; the mixture is compressed in tablet form.

Claims

1. A process so as to be used in preparation of pharmaceutical formulations comprising cefdinir characterized in that;

- The granules comprising cefdinir, at least one excipient and optionally a second active agent are

- sieved or ground such that the average particle size is in the range of 300-2500 μιη,

- The granules are dried and

- The granules are mixed with at least one excipient.

2. The process according to claim 1 characterized in that the granules comprising cefdinir, at least one excipient and optionally a second active agent are sieved or ground such that the average particle size is in the range of 350-2000 μηι.

3. The process according to claims 1-2 characterized in that the granules comprising cefdinir, at least one excipient and optionally a second active agent are sieved or ground such that the average particle size is in the range of 500-1750 μηι.

4. The process according to claims 1-3 characterized in that

- sieved such that the average particle size is in the range of 300-2500 μηι,

- The granules are dried and

- The granules are mixed with at least one excipient.

5. The process according to claims 1-3 characterized in that

- ground such that the average particle size is in the range of 300-2500 μηι,

- The granules are dried and

- The granules are mixed with at least one excipient.

6. The process according to claims 1-3, 5 characterized in that grinding process is performed by impact mill, jet mill or blade mill.

' 7. The process according to claims 1-6 characterized in that the granules comprising cefdinir, at least one excipient and optionally a second active agent are dried at a temperature in the range of 10-120°C.

8. The process according to claims 1-7 characterized in that the granules comprising cefdinir, at least one excipient and optionally a second active agent are dried at a temperature in the range of 20-100°C.

9. The process according to claims 1-8 characterized in that the granules comprising cefdinir, at least one excipient and optionally a second active agent are dried at a temperature in the range of 25-70°C.

10. The process according to claims 1-9 characterized in that the granules comprising cefdinir, at least one excipient and optionally a second active agent are dried such that their moisture content is below 1%.

11. The process according to claims 1-10 characterized in that the granules comprising cefdinir, at least one excipient and optionally a second active agent are dried such that their moisture content is in the range of 0.1-0.9%.

12. The pharmaceutical formulation comprising cefdinir characterized in that;

• Said formulation comprises granules comprising cefdinir, at least one excipient and optionally a second active agent and

• Average particle size of the granules comprising cefdinir, at least one excipient and optionally a second active agent is in the range of 300-2500 μηι.

13. The pharmaceutical formulation comprising cefdinir according to claim 9 characterized in that;

• Average particle size of the granules comprising cefdinir, at least one excipient and optionally a second active agent is in the range of 350-2000 μιη.

14. The pharmaceutical formulation comprising cefdinir according to claims 9 and 10 characterized in that;

• Said formulation comprises granules comprising cefdinir, at least one excipient and optionally a second active agent and • Average particle size of the granules comprising cefdinir, at least one excipient and optionally a second active agent is in the range of 500-1750 μηι.

15. The pharmaceutical formulation according to any preceding claims, wherein said formulation is prepared in any dosage form such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet.

16. The pharmaceutical formulation according to any preceding claims, wherein said formulation is in effervescent tablet, effervescent granule or effervescent powder form.

17. The pharmaceutical formulation according to any preceding claims, wherein cefdinir is in form of its pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations thereof.

18. The pharmaceutical formulation according to any preceding claims, wherein said formulation comprises at least one excipient in addition to cefdinir selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic and one basic agent, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent .

19. The pharmaceutical formulation according to any preceding claims, wherein said formulation comprises cefdinir as active agent in the range of 0.1 to 99.9% by weight.

20. The pharmaceutical formulation according to any preceding claims, wherein said formulation comprises cefdinir as active agent in the range of 1 to 99% by weight.

21. The pharmaceutical formulation according to any preceding claims, wherein said formulation comprises cefdinir as active agent in the range of 5 to 95% by weight.

22. The pharmaceutical formulation according to any preceding claims, wherein said formulation optionally comprises a second active agent in addition to cefdinir selected from a group comprising agents such as antacid, anticholinergic, antispasmodic, antiemetic, antibiotic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianaemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiaritmic, antiadrenergic, antiepileptic, anti-Parkinson, antiprotozoal, antihelminthic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, tiazolidinedion, biguanide, immunostimulant, muscle relaxant, analgesic, psycholeptic, psycho analeptic peripheral vasodilator, beta blocker, calcium channel blocker and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and its analogues, vitamin Bi, vitamin C, vitamin E, vitamin B₆, vitamin B₂, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.