Capsular form of clofazimine

FIELD: medicine.

SUBSTANCE: invention concerns a simplified capsular form of clofazimine, containing clofazimine, bee wax, soya bean lecithin, butylhydroxy toluene, soya bean oil, gelatine, glycerol, sorbitol, methylparabene, propylparabene, titanium dioxide, brown chocolate and purified water with preserving high efficacy.

EFFECT: simplifying the form.

4 tbl, 3 ex

 

The present invention relates to the field of pharmacology, and relates to the new capsule form of antibacterial means clofazimine, which finds application in the treatment of leprosy and tuberculosis.

Clofazimine chemical name 3-(p-chloroanilino)-10-(p-chlorophenyl)-2,10-dihydro-2-isopropylaminomethyl, originally known as B663, was first synthesized in 1954 as an antibacterial agent and has been found effective against leprosy.

Installed also protivotuberkuleznoe activity clofazimine (Clin Microbiol Infect, 2011 Nov 7. doi: 10.1111/j.1469-0691, 2011. 03716.x. [Epubahead of print] "of Clofazimine in the treatment of multidrug-resistant tuberculosis), Xu HB, Jiang RH, Xiao HP.

In China patent CN 101658523 A, 03.03.2010 described the use of clofazimine for the treatment of tuberculosis. Also indicated dosage forms, which may include a drug - tablet, capsule, pill, injection preparations. However, the specific composition of such dosage forms, qualitative and quantitative, is not disclosed.

Swiss drug Lamprene (Clofazimine) manufactured by Novartis. Capsules include clofazimine, citric acid anhydrous, stabilizer, propylene glycol, rapeseed oil, soy lecithin, the mixture of waxes (beeswax, hydrogenated soybean oil, hydrogenated vegetable oil), gelatin, glycerol, ethylvanillin, parametersize�opinon, metilparagidroksibenzoat sodium parahydroxybenzoate sodium, iron oxide black, iron oxide red.

The drug contains a large number of excipients, including thickeners, preservatives, plasticizers, emulsifiers, sweeteners, colorants, flavoring, namely the wax mixture, the anhydride of citric acid, propylene glycol, ethylvanillin, iron oxide black, iron oxide red, parameterization, which complicates the structure and increases the size of the capsules, while maintaining the necessary amount of the active ingredient in the capsule.

The object of the present invention is to provide a simpler capsule form of clofazimine while maintaining high efficiency of the drug.

In accordance with the invention describes a capsule form of clofazimine, characterized in that it contains clofazimine, beeswax, soy lecithin, stabilizer, soybean oil, gelatin, glycerin, sorbitol (70%), methylparaben, propylparaben, titanium dioxide, chocolate brown and purified water in the following ratio of components, wt.%:

Contents of capsule (based on the weight of the capsule):

Clofazimine6.0-40.0
Beeswax 0.4-3.4
Soy lecithin2.0-9.0
Stabilizer0.005-0.04
Soybean oil15.0-55.0

The contents of the shell (based on the weight of the capsule):

Gelatin7.0-30.0
Glycerin3.0-14.0
Sorbitol2.0-10.0
Methylparaben0.02-0.1
Propylparaben0.001-0.03
Titanium dioxide0.04-0.3
Chocolate brown0.03-0.3
Purified water2.5-10.5

The drug is characterized by an optimal qualitative and quantitative composition to achieve a high technical result, i.e. this dosage form is equivalent to therapeutic relationship.

Table 1 shows the preferred interest and the weight composition of the described drug and percentage composition in �intervale values.

Table 1
A. the contents of the capsules
Sl. No.ComponentsQuantity per capsule, mg% sod-I in a capsuleAssign component
1Clofazimine105.0021.0Active ingredient
6.0-40.0
2Beeswax6.0001.2Thickener
0.4-3.4The hydrophobic agent
3Soy lecithin22.54.5Emulsifier
2.0-9.0Simachev�describing Dispersion Stabilizing agent, Thickener Antioxidant Helps in encapsulation
4Stabilizer0.1000.02Antioxidant
0.005-0.04
5Refined soybean oil171.40034.28Solvent
15.0-55.0Forming substance is a Hydrophobic agent
Weight (mg), (I)305.0061.0
B. the contents of the capsule shell
Sl. No.ComponentsQuantity per capsule, mg% sod-I in a capsuleAssign component
1Gelatin89.846 17.97The basis of the capsule shell
7.0-30.0Formative substance
2Glycerin40.7448.15 3.0-14.0plasticizer
3Sorbitol (p-p 70%)30.0636.01Sweetener
2.0-10.0Plasticizer
4Methylparaben0.2930.058Preservative
0.02-0.1
5Propylparaben0.0630.013Preservative
0.001-0.03
6Titanium dioxide0.6270.125Pigment dye
0.04-0.3
7Chocolate brown0.3140.09Dye
0.03-0.3
8Purified water33.0506.61Solvent
2.5-10.5
Weight capsules, mg (II)195.00039.0
The total mass, mg (I+II)500.000100.000

Technological scheme of manufacture consists of three stages: preparation of gelatin on�of alocci, preparation preparation (capsule), the process of encapsulation.

Example 1

The preparation of the gelatin shell. Weigh 330,50 g (6,61%) purified water, 300,63 g (6,01%) solution of sorbitol, 407,44 g (8,15%) of glycerol, 2,93 g (0,0586%) of methylparaben and 0.63 g (0,0126%) of propyl paraben. In mixing container load 898,46 g (17,97%) gelatin while stirring under vacuum and heated to 70°C. carry out the dissolution of the components at 60°C for 1.5 hours. After the process is stopped the stirrer. The molten mass was charged 6,27 g (0,125%) of titanium dioxide and 3,14 g (0,0628%) of the dye chocolate brown. Spend the dissolution of the components with a stirrer under vacuum for 1.5 hours. Prepared gelatin mixture in amounts of 1950 is collected in a storage tank of gelatin. The temperature was maintained at 60-70°C.

Preparation preparation. Weigh 1050,0 g (21,0%) of clofazimine, 60,00 g (1,2%) of beeswax 225,00 g (4,5%) soy lecithin, 1.00 g (0,02%) butylhydroxytoluene, 1714,00 g (34,28%) of refined soybean oil. The exact number of measured components is transferred to a planetary mixer. Stand under vacuum for 30 minutes. Further medicinal mixture enters the capsule hopper of the machine.

The process of encapsulation. Prepared gelatin mixture is charged into a hopper of the machine. The mixture is distributed in a thin strip on either one hundred�ons from the car cooled rotary drums. The drug mixture is metered and fed through an injector on a thin strip containing the gelatin mixture. During rotation of the encapsulator is the formation of capsules, sealing and separation from the tape. The final capsule was washed with n-hexane, and dried at a temperature of 21-27°C and a relative humidity of 20-30%.

Get 9989 capsules with a total weight of 4994,50 g and the mass of each capsule 500 mg±10%. The appearance of the capsules are oblong soft gelatin capsules chocolate-brown color, containing a reddish-brown oily mass. The capsules obtained meet all of the requirements of the pharmaceutical agent.

Example 2

The preparation of the gelatin shell. Weigh 387,59 g (7,75%) purified water, 447,00 g (8.94% of) g of sorbitol, 649,99 g (13,0%) of glycerol, 1,46 g (0,029%) of methylparaben and 0.95 g is 0.019%) of propyl paraben. In mixing container load 460,00 g (9,2%) gelatin with stirring. The stirrer and the mixture was heated under vacuum to 70°C. carry out the dissolution of the components at 60°C for 1.5 hours. After the process is stopped the stirrer. The molten mass was charged 1,71 g (0,034%) of titanium dioxide and 1.61 g (0,032%) of the dye chocolate brown. Spend the dissolution of the components with a stirrer under vacuum for 1.5 hours. Prepared gelatin mixture in the amount of 1946,96 g is collected in a storage tank of gelatin. Temperature p�derivat at 60-70°C.

Preparation preparation. Weigh 320,00 g (6.4%) of clofazimine, 30,80 g (0,62%) of beeswax, 115,00 g (2,3%) soy lecithin, 0,51 g (0,01%) butylhydroxytoluene, 2583,39 g (of 51.67%) of refined soybean oil. The exact number of measured components is transferred to a planetary mixer. Stand under vacuum for 30 minutes. Further medicinal mixture enters the capsule hopper of the machine.

The process of encapsulation. Prepared gelatin mixture is charged into a hopper of the machine. The mixture is distributed in a narrow band on both sides from the car cooled rotary drums. The drug mixture is metered and fed through pipe injector on a thin strip containing the gelatin mixture. During rotation of the encapsulator is the formation of capsules, sealing and separation from the tape. The final capsule was washed with n-hexane and dried at a temperature of 21-27°C and a relative humidity of 20-30%.

Get 9993 capsules with a total weight of 4996,5 g and the mass of each capsule 500 mg±10%. The appearance of the capsules are oblong soft gelatin capsules chocolate-brown color, containing a reddish-brown oily mass. The capsules obtained meet all of the requirements of the pharmaceutical agent.

Example 3

The preparation of the gelatin shell. Weigh 144,86 g (2,90%) purified water, 121,25 g (2,425%) solution of sorbitol, 224,92 g (4,5%) of glycerol of 3.78 g (0,076%) of methylparaben and 0.37 g (0,007%) of propyl paraben. In mixing container load 1435,62 g (28,71%) gelatin while stirring to avoid any lumps. The stirrer and lead the process under vacuum. The mixture was heated to 70°C. carry out the dissolution of the components at 60°C for 1.5 hours. After the process is stopped the stirrer. Into a molten mass load of 8.79 g (0,176%) of titanium dioxide and 10.28 g (0,206%) of the dye chocolate brown. Spend the dissolution of the components with a stirrer under vacuum for 1.5 hours. Prepared gelatin mixture in the amount of 1949,00 g is collected in a storage tank of gelatin. The temperature was maintained at 60-70°C.

Preparation preparation. Weigh 1856,00 g (37,12%) of clofazimine, 100,00 g (2"0%) of beeswax 299,00 g (5,98%) soy lecithin, 1.5 g (0,03%) butylhydroxytoluene, 799,92 g (16,0%) of refined soybean oil. The exact number of measured components is transferred to a planetary mixer. Stand under vacuum for 30 minutes. Further medicinal mixture enters the capsule hopper of the machine.

The process of encapsulation. Prepared gelatin mixture is charged into a hopper of the machine. The mixture is distributed in a narrow band on both sides from the car cooled rotary drums. The drug mixture is metered and fed through pipe injector on a thin strip containing the gelatin mixture. During rotation capsulate�and the formation of capsules, sealing and separation from the tape. The final capsule was washed with n-hexane. Dried at a temperature of 21-27°C and a relative humidity of 20-30%.

Get 9980 capsules with a total weight of 4990,00 g and the mass of each capsule 500 mg±10%. The appearance of the capsules are oblong soft gelatin capsules chocolate - brown color, containing a reddish-brown oily mass. The capsules obtained meet all of the requirements of the pharmaceutical agent.

Table 2
Examples of formulations of the drug within the established framework of variance
No. ComponentsThe content of solids, %/KAPS
Capsule contents
Example 1Example 2Example 3
1Clofazimine21.006.4037.12
2Beeswax1.200.62 2.00
3Soy lecithin4.502.305.85
4Stabilizer0.020.010.03
5Refined soybean oil34.2851.6716.00
Capsule shell
1Gelatin17.979.2028.71
2Glycerin8.1513.004.50
3Sorbitol (p-p 70%)6.018.942.425
4Methylparaben0.0590.0290.076
5Propylparaben 0.0130.0190.007
6Titanium dioxide0.1250.0340.176
7Chocolate brown0.0630.0320.206
8Purified water6.617.7462.90

Tests were carried out several series of drug disintegration and solubility

The test for disintegration:

Equipment: the Device "Rotating basket".

Conditions: using discs.

A temperature of (37±1)°C.

Methodology:

- put 6 capsules in the basket of the device test dissolution, added wheels;

- put the basket in a container of the apparatus with distilled water, heated to (37±1)°C, included machine;

- recorded the disintegration time of each capsule. The results are shown in table 3.

Table 3
SampleExample 1Example 3
110,1610,2510,17
2Case 9.8310,1710,33
39.66 as per10,1710,42
4For 10.08For 10.0810,25
510,1710,2510,5
69,9110,3310,25
Average9,9710,21Of 10.32
RSD, %0,2040,0870,122

Conclusion:

The obtained results are fully consistent with the established norm, which suggests the existence of optimal qualitative and quantitative composition, i.e., this dosage form is equivalent to therapeutic relationship.

Test for solubility:

Equipment: the Apparatus - Blade stirrer.

Conditions: dissolution Medium was 0.1 N hydrochloric acid solution.

The volume of dissolution medium is 500 ml.

The rotation speed is 50 rpm.

Time - 30 min.

Rate of dissolution: at least 70% of clofazimine.

Procedure: Put one capsule in each of the 12 tanks of the apparatus with a pre-warmed dissolution medium consisted of mixing device. After the preset time, turn off the stirrer, selected the suitable volume of solution and was filtered. Determined the amount released to the environment of dissolution of a substance by determining the optical density of the test and standard solutions at a wavelength of 491 nm.

The results are shown in table 4

Table 4
SampleExample 1Example 2Example 3
The result of the release, %
191,590,489,9
289,390,8 90,1
388,284,590,6
491,6Of 89.492,0
5Of 86.992,893,4
693,895,498,5
791,990,890,3
889,791,290,5
988,6To 84.991,0
1091,289,091,6
1186,592,493,0
1293,495,098,1
Average90,2 90,692,4
Min86,584,589,9
Max93,895,498,5
RSD, %2,63,73,2

Conclusion:

The obtained results are fully consistent with the established norm, which suggests the existence of optimal qualitative and quantitative composition, i.e., this dosage form is equivalent to therapeutic relationship.

The capsule form of clofazimine, characterized in that it contains clofazimine, beeswax, soy lecithin, stabilizer, soybean oil, gelatin, glycerin, sorbitol, methylparaben, propylparaben, titanium dioxide, chocolate brown and purified water in the following ratio of components, wt.%:
Contents of capsule (based on the weight of the capsule):

Clofazimine6.0-40.0
Beeswax0.4-3.4
Soy lecithin2.0-9.0
Stabilizer0.005-0.04
Soybean oil15.0-55.0

The contents of the shell (based on the weight of the capsule):
Gelatin7.0-30.0
Glycerin3.0-14.0
Sorbitol2.0-10.0
Methylparaben0.02-0.1
Propylparaben0.001-0.03
Titanium dioxide0.04-0.3
Chocolate brown0.03-0.3
Purified water2.5-10.5



 

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9 cl, 12 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to novel heterocyclic compounds of formula (1) and/or to their pharmaceutically acceptable salts, where A1 represents CH; A4and A5 independently represent CR2 or N; A2 and A3 together with ring B represent 5-membered heteroaryl or heterocycle, with said 5-membered heteroaryl or heterocycle being selected from where t represents 1 or 2; and R3 is independently selected from H, C1-C6 alkyl, C6-aryl, C3-C6-membered cycloalkyl, C(O)NRcRd, -ORb, heteroaryl, representing pyridine, and heterocycle, representing piperidine and tetrahydropyran; and each of said alkyl, aryl, cycloalkyl, heteroaryl and heterocycle can be substituted with one group, independently selected from C1-C6 alkyl, possibly substituted with one substituent, selected from -CONMe2, C3-membered cycloalkyl, -CN, -OMe, -pyridine, tetrahydropyran, -CO-morpholine, -CO-pyrrolidine, (3-methyl)oxetane; -OH; -C(O)Ra; -CN; -C(O)NRcRd; -NRcRd; -ORb; -S(O)nRe; halogen, and substituted with one group -COMe heterocycle, representing piperidine, on condition that when A4 represents CR2, A2 and A3 together with ring B are selected from structure (3), (5) or (6); represents single bond or double bond; R1 represents heteroaryl, representing 6-membered or 9-10-membered aromatic mono- or bicyclic ring, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; possibly substituted with one or two groups, independently selected from C1alkyl, C2alkinyl, -NRcRd, -NRcS(O)nRe, -ORb, halogen, halogenalkyl; R2 is independently selected from H; each Ra, Rb, Rc, Rd, and Re is independently selected from H; C1-C4alkyl, possibly substituted with one substituent, selected from -OH, -OMe, -CN, -NH2, -NMe2, C3-cycloalkyl; C2-C3alkenyl; C3alkinyl; C6aryl, possibly substituted with one or more substituents, selected from fluorine or methyl group; C3-membered cycloalkyl, possibly substituted with one substituent, selected from -OH and -CN; halogenalkyl; heteroaryl, representing pyridine; and substituted with one methyl group heterocycle, representing piperidine, or Rc and Rd together with atom (atoms) which they are bound to form 5-6-membered heterocyclic ring, representing pyrrolidine or morpholine; and in each case n is independently equal 2. Invention also relates to particular compounds, pharmaceutical composition, based on claimed compounds; method of inhibiting PI3K and/or mTOR activity and to application of claimed compounds.

EFFECT: novel compounds, useful for inhibiting PI3K and/or mTOR activity have been obtained.

15 cl, 16 ex

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