Pharmaceutical preparations containing highly volatile silicones

Abstract

The subject of the present invention is a transdermal preparation containing pharmaceutically active ingredient, wherein the particles of the active ingredient are coated with highly volatile silicones or a mixture thereof, and these coated particles are dispersed in a gel or cream base. The volatile silicone component is hexamethyldisiloxane and/or octamethyltrisiloxane and/or decamethylpentacyclo-siloxane. A further subject of the present invention is a method for the preparation of such pharmaceutical compositions.

Claims

1. A pharmaceutical composition in gel or cream form for transdermal administration of a pharmaceutically active ingredient, comprising: a multiplicity of particles of an active pharmaceutical ingredient; a highly volatile silicone or a mixture of highly volatile silicones coated on the multiplicity of particles of an active pharmaceutical ingredient, the particles coated with the highly volatile silicone or mixture of highly volatile silicones prior to addition to the composition; a hydrated gel or cream base, in which the multiplicity of particles of the active pharmaceutical ingredient, coated with the highly volatile silicone or mixture of highly volatile silicones, are dispersed; wherein the coating of highly volatile silicone or mixture of highly volatile silicones substantially prevents contact between the active pharmaceutical agent and the remainder of the pharmaceutical composition at least until application; and wherein a mass ratio of the highly volatile silicone or the mixture of highly volatile silicones to the active pharmaceutical ingredient is about 2:1 or greater.

2. The pharmaceutical composition of claim 1 wherein the pharmaceutically active ingredient is selected from the group consisting of acyclovir, piroxicam, meloxicam, ibuprofen, diclofenac sodium or potassium, clotrimazol, bifonazol, metronidazol, nifedipin, nitroglycerine and cetirizin.

3. The pharmaceutical composition of claim 1 wherein the highly volatile silicone or mixture of highly volatile silicones is selected from the group consisting of hexamethyldisiloxane, octamethyltrisiloxane, decamethylpentacyclosiloxane and mixtures thereof.

4. The pharmaceutical composition of claim 1 wherein the hydrated gel or cream base is selected from the group consisting of hydrated carboxyvinyl polymer, hydrated hydroxypropyl-methyl cellulose and mixtures thereof.

5. The pharmaceutical composition of claim 1 wherein the pharmaceutically active ingredient is diclofenac sodium or potassium.

6. The pharmaceutical composition of claim 1, wherein the highly volatile silicone or mixture of highly volatile silicones comprises hexamethyldisiloxane.

7. The pharmaceutical composition of claim 1, wherein the hydrated gel or cream base comprises hydrated carboxyvinyl polymer.

8. The pharmaceutical composition of claim 1, wherein the application comprises application to the surface of the skin.

9. The pharmaceutical composition of claim 1, further comprising a menthol.

10. The pharmaceutical composition of claim 1, wherein the mass ratio is between about 2:1 and about 6:1.

11. The pharmaceutical composition of claim 1, wherein the mass ratio is between about 2:1 and about 5:1.

12. The pharmaceutical composition of claim 1, wherein the mass ratio is about 6:1 or greater.

13. The pharmaceutical composition of claim 1, where a mixture of highly volatile silicones is coated on the multiplicity of particles of an active pharmaceutical ingredient.

14. A pharmaceutical composition of claim 13, wherein the mixture of highly volatile silicones comprises at least a first silicone and a second silicone, and the first silicone has a viscosity of 0.65 cSt.

15. A pharmaceutical composition of claim 14, wherein the weight ratio of the first silicone to the second silicone ranges from 1:4.3 to 10:1.

16. A pharmaceutical composition of claim 13, wherein the highly volatile silicone or mixture of highly volatile silicones comprises hexamethyldisiloxane.

17. A pharmaceutical composition of claim 14, wherein the highly volatile silicone or mixture of highly volatile silicones comprises hexamethyldisiloxane.

18. A pharmaceutical composition of claim 15, wherein the highly volatile silicone or mixture of highly volatile silicones comprises hexamethyldisiloxane.

19. A pharmaceutical composition of claim 13, wherein the hydrated gel or cream base comprises hydrated carboxyvinyl polymer.

20. A pharmaceutical composition of claim 14, wherein the hydrated gel or cream base comprises hydrated carboxyvinyl polymer.

21. A pharmaceutical composition of claim 15, wherein the hydrated gel or cream base comprises hydrated carboxyvinyl polymer.

22. A pharmaceutical composition of claim 13, wherein the application comprises application to the surface of the skin.

23. A pharmaceutical composition of claim 14, wherein the application comprises application to the surface of the skin.

24. A pharmaceutical composition of claim 15, wherein the application comprises application to the surface of the skin.

25. A pharmaceutical composition of claim 13, further comprising a menthol.

26. A pharmaceutical composition of claim 14, further comprising a menthol.

27. A pharmaceutical composition of claim 15, further comprising a menthol.

28. A pharmaceutical composition of claim 13, wherein the mass ratio is between about 2:1 and about 6:1.

29. A pharmaceutical composition of claim 14, wherein the mass ratio is between about 2:1 and about 6:1.

30. A pharmaceutical composition of claim 15, wherein the mass ratio is between about 2:1 and about 6:1.

31. A pharmaceutical composition of claim 13, wherein the mass ratio is between about 2:1 and about 5:1.

32. A pharmaceutical composition of claim 14, wherein the mass ratio is between about 2:1 and about 5:1.

33. A pharmaceutical composition of claim 15, wherein the mass ratio is between about 2:1 and about 5:1.

34. A pharmaceutical composition of claim 13, wherein the mass ratio is about 6:1 or greater.

35. A pharmaceutical composition of claim 14, wherein the mass ratio is about 6:1 or greater.

36. A pharmaceutical composition of claim 15, wherein the mass ratio is about 6:1 or greater.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 demonstrates the kinetics of evaporation from silane containing system, which was studied in the mass decrease experiments. 5 samples were stored in a standard humidity exsiccator and were measured on analytical scales at certain intervals. The results of 5 measurements are demonstrated by the curves. Black pots indicate the curve demonstrating the mean value.

(2) FIG. 2 demonstrates the kinetics of evaporation from silane containing system, which was studied in the mass decrease experiments. 3 samples were stored in a standard humidity exsiccator and were measured on analytical scales at certain intervals. The results of 3 measurements are demonstrated by the curves. Black pots indicate the curve demonstrating the mean value.

(3) FIG. 3 relates to the release of piroxicam from the silane composition through a lipophil membrane. The results of the diffusion experiments through apolar membrane are demonstrated here. Black pots indicate the curve demonstrating the mean value of 6 measurements.

(4) FIG. 4 relates to the release of piroxicam from Hotemin® ointment through a lipophil membrane. The results of the diffusion experiments through apolar membrane are demonstrated here. Black pots indicate the curve demonstrating the mean value of 3 measurements.

(5) FIG. 5 relates to a comparative test, which demonstrates the release of piroxicam from silane system and from Hotemin® cream through a lipophil membrane. FIG. 5 shows the released percentage of the active ingredient comparing to the whole amount in case of the two compositions.

(6) FIG. 6 relates to a comparative test, which demonstrates the release of piroxicam from silane system and from Hotemin® cream through a lipophil membrane. FIG. 6 demonstrates the released amount of the active substance on a certain surface of the skin in mg/cm.sup.2 in case of the two compositions.

(7) FIG. 7 relates to the release of piroxicam from the silane composition through a semipolar membrane. The results of the diffusion experiments through semipolar membrane are demonstrated here. Black pots indicate the curve demonstrating the mean value of 5 measurements.

(8) FIG. 8 relates to the release of piroxicam from Hotemin® ointment through a semipolar membrane. The results of the diffusion experiments through semipolar membrane are demonstrated here. Black pots indicate the curve demonstrating the mean value of 3 measurements.

(9) FIG. 9 relates to a comparative experiment, which demonstrates the release of piroxicam from the “silane system” and Hotemin® composition through a semipolar membrane.

(10) FIG. 10 relates to a comparative experiment, which demonstrates the release of piroxicam from the “silane system” and from Hotemin® composition through a semipolar membrane. FIG. 10 demonstrates the released amount of the active substance on a certain surface of the skin in mg/cm.sup.2 in relation the half time of the diffusion. (Q root (t))

(11) FIG. 11 relates to a comparative test, wherein the release of piroxicam from 6 different pharmaceutical preparations was studied. The diffusion time was 6 hours.

CHEMICAL STABILITY TEST

(12) One of the chemical stability problems of the gel type pharmaceutical formulations containing active substance in dispersed form is caused by the reactions occurring at the contact points of the surfaces, which can lead to the change of the chemical condition of the active ingredient.

(13) The polymorph form I of piroxicam is a white substance with crystalline structure, which turns into a bright yellow colour when dissolved in water or in other solvents. In case of traditional ointments and gels containing this active substance, the above described chemical reactions change the intensity of colour of the pharmaceutical preparation.

(14) It has been found that contrary to the cream and gel formulations of the state of the art, the colour of the aqueous gel of the present invention containing the active ingredient coated with volatile silicone oils (hexamethyldisiloxane and/or octamethyltrisiloxane, or a mixture thereof in a ratio of 1:1) does not change. The pharmaceutical preparations of the present invention were examined with stability tests complying with the current ICH (International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use) rules, and the white colour of the preparations did not change during the experiments.

(15) The active ingredient is coated with the volatile silicon oils in a manner that the other ingredients of the gel formulation do not have contact with the active ingredient as a result of which the preparation has good chemical stability.

(16) Experiments for Mass Decrease

(17) A basic requirement of good bioavailability is that the active substance should have a good release from the pharmaceutical preparation. The active ingredient of the composition of the present invention releases after the evaporation of the silicon oils serving as a coating. This process is shown by the weight decrease of the preparation. As a reference we used Hotemin® cream which is a cream with a fatty basis.

(18) The ingredients of Hotemin® cream 1% are: methyl parahydroxybenzoate, macrogol cetylstearyl ether, sorbitan stearate, stearic acid, cetyl stearil alcohol, white vaseline, liquid paraffin, purified water.

(19) The samples were stored in a standard humidity exsiccator and they were measured on analytical scales at certain intervals. FIGS. 1 and 2 demonstrate the mass decrease and its relation to time.

(20) The results of the measurements show that the evaporation is faster from the system containing the volatile silicones than from the reference preparation. After 24 hours only the active ingredient and a small amount of the polymer adjuvant remained on the scales. The reference ointment had lower mass decrease; only the 60% of the whole mass evaporated.

(21) Experiments Concerning the Transport Through the Biological Membranes

(22) Another basic condition of good bioavailability is the easy diffusion of the active substance after release through the biological membrane by active or passive transport.

(23) The transport of the active ingredient through apolar and semipolar biological membranes (for example: skin) was studied with the help of an apparatus operating according to the operation principle of the vertical diffusion cell developed by the Hanson Company (Hanson Microette™ Topical & Transdermal Diffuson Cell System, Hanson Research Corporation).

(24) The reference composition of the experiments is Hotemin® ointment.

(25) Diffusion Through Apolar Membrane

(26) Diffusion through apolar membrane was studied because the upper layer of the skin, the stratum corneum, has a lipophil, apolar character because of the chemical characteristics of its components. Therefore, first of all pharmacones having the ability of dissolving in the stratum corneum are able to get into it as well as the drugs which have apolar characteristics.

(27) FIG. 3 shows the results of the experiments carried out using a membrane impregnated with isopropyl myristate.

(28) FIG. 4 demonstrates the release of the reference composition and FIGS. 5 and 6 are comparative examples.

(29) FIG. 5 shows the released percentage of the active ingredient comparing to the whole amount and FIG. 6 demonstrates the released amount of the active substance on a certain surface of the skin in mg/cm.sup.2.

(30) Usually the process taking place in time is described with a root function. The general formula of the root function is:
Q=Q.sub.0t  (1),
wherein Q represents the released amount of the active ingredient during t time, Q.sub.0 represents the released amount of the active ingredient at t=0 (it is usually 0) and m represents the gradient of the linearized function. If m is 1, the amount of the released active ingredient increases linearly in time, but usually m has a lower value than 1. When m is approximately 0.5, Q is shown by a linear function at t.sub.0.5 function. The gradients of the linears (angular coefficient) are the velocity constant of the release.

(31) Evaluating the functions mathematically it can be stated that the root function of equation (1) can be exactly matched to the measurement points. Table 1 shows the constant of Q.sub.0, m and R.sup.2 which represents the degree of the regression.

(32) TABLE-US-00001 TABLE 1 The kinetics of the release of piroxicam. The constants of the root function matched to the measurement points and the values of the correlation coefficient Experiment No. Q.sub.0 m R.sup.2 Silicone containing system Measurement 1 0.061 0.754 0.982 Measurement 2 0.025 0.909 0.986 Measurement 3 0.039 0.791 0.973 Measurement 4 0.031 0.839 0.979 Measurement 5 0.069 0.752 0.994 Measurement 6 0.063 0.779 0.984 mean value 0.047 0.798 0.988 Reference composition Measurement 1 0.0006 0.948 0.934 Measurement 2 0.0007 0.927 0.926 Measurement 3 0.0003 1.065 0.953 mean value 0.0005 0.975 0.945

(33) The values of Table 1 show that the kinetics of the process is described precisely by the root function. The value of Q.sub.0 is around 0, the value of m is between 0.5 and 1, therefore the process is not linear in time, but the velocity of the process is continuously decreasing. The root transformation was not carried out as the value of m is different from 0.5.

(34) During the six-hour long experiment the release of the active ingredient from sample containing silicone oil was approximately 5%. From the reference composition less than 1% was released during the experiment (the maximum release of the active was approximately 0.2%).

(35) As to the results of our experiments it can be concluded that the composition prepared according to the present invention is able to release much more of the active ingredient than the reference composition.

(36) Diffusion Through Semipolar Membrane

(37) The experiments of transport through a semipolar membrane gives a model of entering into the living cell, and passing through the living cell, which is a condition of the pharmacological efficacy.

(38) The semipolar membrane was prepared by impregnating it with ethyl alcohol. The results of our experiments are demonstrated by FIGS. 7-10.

(39) Comparing the Release of the Active Ingredients of the Composition of the Present Invention and Hotemin® Ointment:

(40) Studying the kinetics of the process, it has been found that value m is ˜0.5 of the equation (1), therefore the root transformation was carried out. The results demonstrated by FIG. 11 and the R.sup.2 values of the regression line show a close match. Table 2 shows the values of Q.sub.0, m and R.sup.2.

(41) TABLE-US-00002 TABLE 2 The release of the active ingredient through a semipolar membrane Experiment No. Q.sub.0 m R.sup.2 Silicone containing system Measurement 1 0.932 0.449 0.945 Measurement 2 0.644 0.471 0.994 Measurement 3 0.843 0.435 0.894 Measurement 4 1.032 0.465 0.961 Measurement 5 1.369 0.343 0.949 Measurement 6 1.191 0.415 0.895 mean value 0.990 0.429 0.962 Reference composition Measurement 1 0.024 0.340 0.923 Measurement 2 0.013 0.494 0.922 Measurement 3 0.031 0.249 0.903 mean value 0.021 0.373 0.941

(42) The ratio between the composition containing silicon and the reference Hotemin® ointment is 50:1, namely the amount of the released active ingredient is fifty fold more than the released amount of the active ingredient from the reference composition.

(43) Comparing the Release of the Active Ingredients of the Composition of the Present Invention and Other Transdermal Pharmaceutical Preparations Containing Piroxicam:

(44) The diffusion of the composition of the present invention through a semipolar membrane was compared with the following preparations:

(45) Erazon® 1% cream,

(46) Erazon® 1% gel,

(47) Feldene® 0.5% gel,

(48) Feldene-Top Creme®,

(49) Hotemin® ointment.

(50) The above compositions contain piroxicam, but the carriers and the ingredients thereof are different from the composition of the invention.

(51) It has been discovered that the release of the active ingredient from the composition containing volatile silicones is greater than the above examined creams and gels. (See FIG. 11.)

(52) The pharmaceutical composition of the invention is further elucidated by means of the following Examples without restricting the scope of the present invention to the examples.

(53) In the examples Silicon Fluid carriers are methylsiloxanes, namely hexamethyldisiloxane and/or octamethyltrisiloxane, or the mixtures thereof in a ratio of 1:1. In the examples the viscosity of the siloxane solutions is 0.65 cSt or 100 cSt.

EXAMPLES

Example 1

(54) Gel Composition Containing Piroxicam as Active Ingredient:

(55) TABLE-US-00003 Piroxicam 0.500 g Silicone fluid 0.65 cSt 0.500 g Silicone fluid 100 cSt 2.150 g Carbopol 980 NF 0.250 g Triethanolamine 0.200 g Hydroxypropyl-methylcellulose 1.000 g Purified water ad 50.000 g

(56) According to the recipe of the above example the gel was prepared in a batch size of 7 kg with a Brogtech apparatus suitable for the preparation of ointments.

(57) 1.1. Method of Preparation of the Suspension Containing the Active Ingredient:

(58) Micronized piroxicam powder (70.0 g) is mixed with Silicone fluid 0.65 cSt (301.0 g) and Silicone fluid 100 cSt (70.0 g) in an 800 ml beaker glass, and the mixture in an Ultra-Turrax apparatus, at 4000 revs/minute for 5 minutes. The prepared suspension is stored in an airtight place until application.

(59) 1.2. Method of Preparation of the Gel Base:

(60) Purified water (6000 g) is poured into the Brogtech apparatus and the temperature is set at 25° C. In an anchor mixer in position 4, hydroxypropyl-methylcellulose (140.0 g) is added stepwise to the mixture and it is stirred at the same revs/minute speed until total dissolution of the ointment base (approximately 1.5 hours). After dissolution Carbopol 980 NF (35.0 g) is added to the reaction mixture and it is stirred for 4 hours. The mixture is neutralized with a solution of triethanolamine (28.0 g) and purified water (100.0 g) and stirring is continued until the mixture has gel consistency.

(61) 1.3. Method of Preparation of the End Product (Drug-Gel Composition):

(62) To the gel base prepared according to point 1.2, the suspension of the drug obtained according to point 1.1 is added stepwise, and the gel is completed to 7.00 kg with purified water. The obtained gel is homogenized for 5 minutes in the built-in homogenizer of the Brogtech apparatus at 1200 revs/min, at the maximum diameter of the slits (1.5 mm).

Example 2

(63) Gel Composition Containing Clotrimazol as Active Ingredient:

(64) TABLE-US-00004 Clotrimazol 0.200 g Silicone fluid 0.65 cSt 1.000 g Silicone fluid 100 cSt 0.200 g Carbopol 980 NF 0.100 g Triethanolamine 0.200 g Hydroxypropyl-methylcellulose 0.400 g Purified water ad 20.000 g

(65) According to the recipe of the above example the gel was prepared in a batch size of 7 kg with a Brogtech apparatus suitable for the preparation of ointments.

(66) 2.1. Method of Preparation of the Suspension Containing the Active Ingredient:

(67) Micronized clotrimazol powder (70.0 g) is mixed with Silicone fluid 0.65 cSt (350.0 g) and Silicone fluid 100 cSt (70.0 g) in a 800 ml beaker glass, and the mixture is homogenized in an Ultra-Turrax apparatus, at a 4000 revs/minute for 5 minutes. The prepared suspension is stored in an airtight place until application.

(68) 2.2. Method of Preparation of the Gel Base:

(69) Purified water (6000 g) is put into the Brogtech apparatus and the temperature is set at 25° C. In an anchor mixer in position 4, hydroxypropyl-methylcellulose (140.0 g) is added stepwise to the mixture and it is stirred at the same revs/minute speed until total dissolution of the ointment base (approximately 1.5 hours). After dissolution Carbopol 980 NF (35.0 g) to the reaction mixture and it is stirred for 4 hours. The mixture is neutralized with a solution of triethanolamine (28.0 g) and purified water (100.0 g) and stirring is continued until the mixture has gel consistency.

(70) 2.3. Method of Preparation of the End Product (Gel Composition):

(71) To the gel base prepared according to point 2.2, the suspension of the drug obtained according to point 2.1 is added stepwise, and the gel is completed to 7.00 kg with purified water. The obtained gel is homogenized for 5 minutes in the built-in homogenizer of the Brogtech apparatus at 1200 revs/min, at the maximum diameter of the slits (1.5 mm).

Example 3

(72) Gel Composition Containing Metranidazol as Active Ingredient:

(73) TABLE-US-00005 Metronidazol 1.000 g Silicone fluid 0.65 cSt 2.000 g Silicone fluid 100 cSt 0.200 g Carbopol 980 NF 0.250 g Triethanolamine 0.200 g Hydroxypropyl-methylcellulose 0.400 g Purified water ad 20,000 g

(74) According to the recipe of the above example the gel was prepared in a batch size of 7 kg with a Brogtech apparatus suitable for the preparation of ointments.

(75) 3.1. Method of Preparation of the Suspension Containing the Active Ingredient:

(76) Micronized metronidazol powder (350.0 g) is mixed with Silicone fluid 0.65 cSt (700.0 g) and Silicone fluid 100 cSt (70.0 g) in a 800 ml beaker glass, and the mixture in an Ultra-Turrax apparatus, at a 4000 revs/minute for 5 minutes. The prepared suspension is stored in an airtight place until application.

(77) 3.2. Method of Preparation of the Gel Base:

(78) Purified water (5500 g) is put into the Brogtech apparatus and the temperature is set at 25° C. In an anchor mixer in position 4, hydroxypropyl-methylcellulose (140.0 g) is added stepwise to the mixture and it is stirred at the same revs/minute speed until total dissolution of the ointment base (approximately 1.5 hours). After dissolution Carbopol 980 NF (35.0 g) is added to the reaction mixture and it is stirred for 4 hours. The mixture is neutralized with a solution of triethanolamine (28.0 g) and purified water (100.0 g) and stirring is continued until the mixture has gel consistency.

(79) 3.3. Method of Preparation of the End Product (Gel Composition):

(80) To the gel base prepared according to point 3.2, the suspension of the drug obtained according to point 3.1 is added stepwise, and the gel is completed to 7.00 kg with purified water. The obtained gel is homogenized for 5 minutes in the built-in homogenizer of the Brogtech apparatus at 1200 revs/min, at the maximum diameter of the gaps (1.5 mm). The obtained gel is stored in an airtight place or put into an airtight packaging (metal tube).

Example 4

(81) Gel Composition Containing Cetirizin as Active Ingredient:

(82) TABLE-US-00006 Cetirizin 0.200 g Menthol 0.200 g Ethyl alcohol 0.200 g Silicone fluid 0.65 cSt 1.000 g Silicone fluid 100 cSt 0.200 g Carbopol 980 NF 0.250 g Triethanolamine 0.200 g Purified water ad 20.000 g

(83) According to the recipe of the above example the gel was prepared in a batch size of 7 kg with a Brogtech apparatus suitable for the preparation of ointments.

(84) 4.1. Method of Preparation of the Suspension Containing the Active Ingredient:

(85) Micronized cetirizin powder (70.0 g) is mixed with Silicone fluid 0.65 cSt (350.0 g) and Silicone fluid 100 cSt (70.0 g) in an 800 ml beaker glass, and the mixture is homogenized in an Ultra-Turrax apparatus, at a 4000 revs/minute for 5 minutes. The prepared suspension is stored in an airtight place until application.

(86) 4.2. Method of Preparation of the Menthol Solution:

(87) Menthol (70.0 g) is dissolved in ethyl alcohol in a 300 ml beaker glass. It is stored airtight until utilization.

(88) 4.3. Method of Preparation of the Gel Base:

(89) Purified water (6000 g) is poured into the Brogtech apparatus and the temperature is set at 25° C. In an anchor mixer in position 4, hydroxypropyl-methylcellulose (140.0 g) is added stepwise to the mixture and it is stirred at the same revs/minute speed until total dissolution of the ointment base (approximately 1.5 hours). After dissolution Carbopol 980 NP (35.0 g) to the reaction mixture and it is stirred for 4 hours. The mixture is neutralized with a solution of triethanolamine (28.0 g) and purified water (100.0 g) and stirring is continued until the mixture has a gel consistency.

(90) 4.3. Method of Preparation of the End Product (Gel Composition):

(91) To the gel base prepared according to point 4.2, the suspension of the drug obtained according to point 4.1 is added stepwise, and the gel is completed to 7.00 kg with purified water. The obtained gel is homogenized for 5 minutes in the built-in homogenizer of the Brogtech apparatus at 1200 revs/min, at the maximum diameter of the slits (1.5 mm). The obtained gel is stored in an airtight place or put into an airtight packaging (metal tube).