BG3870U1 - Ketoprofen containing peroral solution granules - Google Patents

Abstract

The utility model relates to a composition of ketoprofen containing granules, in particular ketoprofen lysine salt, mannitol, povidone K25, anhydrous silicon dioxide (silica), sodium chloride, sweetener and flavour, in the following weight ratios of the components in the composition: 80 mg ketoprofen lysine salt, from 1701 to 1735 mg mannitol, from 66 to 100 mg povidone K25, 4 mg anhydrous silicon dioxide, 150 mg sweetener, from 40 to 45 mg substance with flavouring effect and 20 mg sodium chloride. The sweetener used in the composition of the granules is a combination of saccharin sodium and saccharin cyclamate mixed in a ratio from 1:6 to 1:10. The advantages of the peroral solution granules, according to the utility model, are their good rheological properties, the even distribution of the active substance, the good and fast solubility, whereby a clear and stable solution is obtained with good organoleptic characteristics.

Description

Field of technology

The utility model relates to granules for oral solution containing ketoprofen and in particular ketoprofen lysine salt, which are used in pharmacy and medicine for rapid pain relief and as an antipyretic.

BACKGROUND OF THE INVENTION

Ketoprofen is a non-steroidal anti-inflammatory drug derived from propionic acid. Due to its good tolerability and effectiveness, as well as the relatively few side effects, ketoprofen is widely used in medical practice with its anti-inflammatory, analgesic and antipyretic properties. It is used in medical practice in the form of solid oral dosage forms, in the form of capsules, tablets, suppositories and granules, parenterally in the composition of injectable solutions, as well as as dosage forms applied topically, such as creams, lotions, gels or ointments. .

Ketoprofen is composed of an aromatic nucleus with a hydrophobic side chain and an acidic carboxyl group. The free acid is practically very slightly soluble in water, so in the composition of pharmaceutical compositions intended for oral use and parenteral administration, adaptive ketoprofen salts with organic and inorganic bases are used, which have good solubility. Particularly preferred salts are those with d, I-lysine and 1-lysine, described in US Pat. No. 4,279,926. Ketoprofen lysine salt has a good water solubility profile, is rapidly and completely adsorbed by the body, which is why it is often is used in the composition of liquid and solid dosage forms.

Dosage forms in the form of granules, water-soluble effervescent and non-effervescent dosage forms are known, which include the ketoprofen lysine salt. These formulations provide rapid release of the active substance in aqueous solution before administration, or immediate disintegration, placed in the oral cavity.

It is known that the quality of a water-soluble granular oral composition is determined both by the rheological properties and solubility of the dosage form and by the taste of the solution, which is determined by the organoleptic properties of the substances included in the composition. It is known in the art that to mask the bitter and unpleasant taste of solutions intended for oral use, sweetening, flavoring and / or flavor masking agents are added to the drug compositions.

European patent EP 0418043 describes the possibility of improving the taste of aqueous solutions of non-steroidal anti-inflammatory drug compositions and eliminating the unpleasant sensation of irritation of the oral mucosa that usually follows after their intake. According to the invention, this is achieved by adding a sweetener, a flavoring agent, as well as monoalkaline salts of carbonic acid, phosphoric acid or tribasic nitrate salts of alkali metals in an amount sufficient to mask the unpleasant taste.

European patent EP 1312355 describes a water-soluble non-effervescent pharmaceutical composition of a granule containing 80 mg of ketoprofen lysine salt, to which is added a mixture of 100 mg of disodium tartrate and 250 mg of trical potassium citrate to improve the taste of the aqueous solution intended for use. The composition also includes granular mannitol and sweeteners such as saccharin and aspartame and does not include flavoring agents.

A commercially available product is Ketonal intensive® oral solution granules containing 80 mg of ketoprofen lysine salt. As excipients in the composition of the granule are included mannitol, povidone, anhydrous colloidal silicon dioxide, and to improve the quality of the aqueous solution intended for intake in the composition is included saccharin sodium, a substance with an aroma of mint and sodium chloride.

The objective of the utility model is to obtain granules for oral solution containing ketoprofen, in particular ketoprofen lysine salt, with good rheological properties, uniformity of the content of ketoprofen in the granules, rapid solubility with the formation of clear, stable and with good organoleptic characteristics aqueous solution , before use.

2191 Descriptions to utility registration certificates № 10.1 / 15.10.2020

Technical essence of the utility model

The problem is solved by the composition of granules for the preparation of an oral solution containing ketoprofen, which includes ketoprofen lysine salt, mannitol, povidone K25, anhydrous silica, sodium chloride, sweetener and flavor, in the following weight ratios of the components in the composition in mg: 80 mg ketoprofen lysine salt, 1701 to 1735 mg mannitol, 66 to 100 mg povidone K25, 4 mg anhydrous silica, 150 mg sweetener, 40 to 45 mg flavoring agent and 20 mg sodium chloride.

The sweetener in the composition of the granules is a combination of saccharin sodium and saccharin cyclamate, mixed in a ratio of 1: 6 to 1:10.

In a preferred embodiment of the utility model, the ketoprofen lysine salt and the mannitol in the granule composition have the same average particle size ranging from 180 to 200 pm. This ensures even mixing, good flowability and prevents segregation of the components in the complex powder mixture.

Sodium chloride is used as a flavor masking agent.

To obtain the granules for oral solution, according to the utility model, the pre-measured and sieved amounts of ketoprofen lysine salt, povidone K25 and part of the required amount of mannitol and anhydrous colloidal silica are homogenized in a mixer. The resulting pre-powder mixture is sieved, then the remaining amounts of mannitol and anhydrous silica are added to it, as well as the pre-measured and sieved amounts of sodium chloride, sweetener and flavoring substance. The mixture is homogenized again and fed to the Roller compactor for granulation.

The advantages of granules for oral solution, according to the utility model, are their good rheological properties, uniform distribution of the active substance, good and fast solubility, which results in a clear and stable solution with good organoleptic characteristics.

Examples of implementation of the utility model

The utility model is illustrated by the following embodiments.

Example 1.3a Preparation of a pharmaceutical granule for the preparation of an oral solution containing 80 mg of ketoprofen lysine salt The following components were used:

Ingredients Quantity mg / in sachets Ketoprofen lysine salt Θ0.00 (such as ketoprofen) 50.0 Mannitol (Pearlitol 200 SD) 1706.0 Povidone K25 100 0 Sodium chloride 20 0 Sodium cyclamate 130 0 Saccharin sodium 20 0 Substance with mint aroma Peppermint flavor * 0087В663 4D.0, Anhydrous colloidal silicon dioxide 40 / Aerosil 200 / Everything 2100.0

2192 Descriptions to utility registration certificates № 10.1 / 15.10.2020

The required amounts of active ingredients and excipients were measured and sieved through a 0.800 mm sieve to prepare the granule for oral solution. The required amount of ketoprofen lysine salt and povidone K25, as well as 835.94 mg (49% of the amount indicated in the table) of mannitol and 2 mg (50% of the amount indicated in the table) of anhydrous colloidal silicon dioxide were dosed into a diffusion mixer. The powder mixture was homogenized for 30 minutes at a mixer speed of 14 rpm. The resulting pre-homogeneous powder mixture was sieved through a 0.800 mm sieve, after which the remaining mannitol and anhydrous colloidal silica, as well as 20 mg of sodium chloride, 130 mg of sodium cyclamate, 20 mg of saccharin sodium and 40 mg of the substance with a mint aroma. Homogenization of the mixture continued for another 30 minutes at mixer speed - 14 rpm (± 1 rpm). The powder mixture thus obtained was fed for granulation in a machine "Roller compactor type RC 100x30", with a productivity of 0.200 kg to 30 kg / h. The granulation was performed with the following parameters: rotation of the feed mechanism - 25 rpm (± 0.2 rpm); roller speed - 9 rpm (± 0.2 rpm); hydraulic pressure - 50 bars (± 2 bars); rotary mill - 100 rpm (± 2 rpm); sieve - 1.00 mm.

The resulting granule was metered into a sachet of three-layer foil.

Example 2. Preparation of granules containing 80 mg of ketoprofen lysine salt in a sachet per dose.

The following quantities of active substances and excipients were used to prepare the granules according to the utility model:

Ingredients Quantity gpd / in sachet Ketoprofen lysine salt (as ketoprofen) S0 00 50.0 Mannitol (Pearlitol 200 3D) 1735.0 POVIDON K25 65.0 Sodium chloride 20.0 Sodium cyclamate 130.0 Saccharin sodium 20.0 Substance with mint aroma Peppermint flavor * 00070668 45.0 Anhydrous colloidal silicon dioxide / Aerosrl 200 / 4.0 Total _______________________________________________._______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ 2100.0

The granulate was prepared by the method described in Example 1 and dosed in a sachet of three-layer foil.

Example 3. For the preparation of granules for oral solution, including as active substance 80 mg of ketoprofen lysine salt for the preparation of 1000 pcs. sachets the following components were used:

2193 Descriptions to utility registration certificates № 10.1 / 15.10.2020

Ingredients Quantity гпд / в са ше Quantities for a batch of 1000 pcs. sachet, in g Ketaprsfen liZinyva sol woo 60.0 (as ketaprofen) 50.0 50.0 Mannitol (Pearlitol 200 SD) 1701.0 1701.0 Пойидсш К25 100.0 100.0 Sodium chloride 20.0 20 0 Sodium cyclamate । 130.0 130.0 Saccharin sodium 20.0 20.0 Substance with mint aroma Peppermint flavor * Q037B668 45.0 45.0 Anhydrous colloidal silicon dioxide / Aerosil 200 / 40 4.0 Total 2100.0 2100

The granules were prepared according to the method described in Example 1 and dosed in three-layer foil sachets.

Example 4. Examination of the parameters for determining the quality of the granules with the composition described in Example 1 of the utility model.

The following tests were performed to determine the quality of the granules:

1. The rheological properties of the granules tested by the "Hausner ratio" method in accordance with the requirements of Ph. Eur. The results of the study are reflected in Table 1, lines 1,2,3.

2. The dissolution time was examined. The result shown in the table was obtained by dissolving the granules in 150 ml of drinking water at a temperature of 21 ° C, with stirring.

3. The appearance of the solution was also examined for unacceptable foaming, the presence of undissolved particles or sediment visually, and its taste was assessed organoleptically.

Table 1 shows the results of the tests performed.

Table 1. Results of tested parameters

Tested parameters Test results of the granule composition described in Example 1 Bulk density ro _g e / ml 0.526 Shake density pv, e / ml 0.586 Hausner ratio, hf = p ^ r pa 1,118 th most common Dissolution time (min) / reconslilulion time / 2.0

2194 Descriptions to utility registration certificates № 10.1 / 15.10.2020

Appearance of the solution Clear solution, 5 ez particles pH of the solution 5.62 Taste of the solution Pleasant, sweet, with a faint smell of mint

Hausner ratio data show low values, which proves that the Pearlitol 200 SD diluent provides very good flow properties and prevents segregation of the components in the complex powder mixture.

The particle size of the ketoprofen lysine salt (D90 <200 pm) is the same as that of mannitol - an average diameter of 180 ppm, which favors the process of homogeneous mixing.

The results show a relatively short dissolution time of the sample - 2 min, compared to the rate of dissolution of granules for oral solution, which is "not more than 5 min".

The results of the studies shown in the table show that the concentrations of sweeteners saccharin sodium, sodium cyclamate and flavoring are in an amount that provides the optimal effect of masking the taste and irritation of ketoprofen lysine salt.

Example 5. Study to evaluate the suitability of the prepared oral solution after dissolving a sachet in terms of the content of active substance in a single dose.

An oral solution was prepared for the study to be taken immediately. The solution was analyzed at initial time intervals - 0, 5, 10, 15 min in order to assess its quality - content of active substance and its impurities.

Each sachet sample was dissolved in 150 ml of water at 20 ° C. The temperature was kept constant for 15 minutes, and samples were taken from the analysis solution at regular intervals.

The results of the analysis are presented in Table 2.

Table 2. Results of the analysis of the solution obtained by dissolving the granules for oral solution with a composition according to Example 3.

Time min Ketoprofen test results, mg (%) Impurities. % 0 49.6 Impurity A n.d. (99.2) Impurity C 0.003 Unspecified 0.080 impurity 0.083 Total impurities 5 49.4 Impurity A n.d.

2195 Descriptions to utility registration certificates № 10.1 / 15.10.2020

(38.8) Impurity C Unspecified impurity Total impurities 0.003 о.оео 0.083 10 48.Θ (j7.j) Impurity A Impurity C Unspecified impurity Total impurities n.d. 0.003 0.084 0.087 15 48.6 (S7-2) Impurity A Impurity C Unspecified impurity Total impurities 0.002 0.004 0.08G О.092

The results given in the table show that the quality of the reconstituted granule solution, according to the utility model, remains usable for up to 15 minutes with respect to the content of the active substance ketoprofen in the product - 100 ± 5% of the active substance. The content of total impurities in the solution up to 15 minutes remains within the specified limits.

Claims (2)

Claims Granules for the preparation of an oral solution containing ketoprofen, in particular ketoprofen lysine salt, mannitol, povidone, anhydrous silica, sodium chloride, sweetener and flavor, characterized in that the povidone is povidone K25, the sweetener being a mixture of 1 parts of saccharin sodium with 6 to 10 parts of saccharin cyclamate, and the ratio of components in the composition of the granules is: 80 mg ketoprofen lysine salt, from 1701 to 1735 mg mannitol, from 66 to 100 mg povidone K25, 4 mg anhydrous silicon dioxide, 20 mg of sodium chloride, 150 mg of sweetener and 40 to 45 mg of flavoring substance. Ketoprofen-containing oral solution granules according to claim 1, characterized in that the ketoprofen lysine salt and the mannitol have the same average particle size ranging from 180 to 200 pm.