JPS589081B2 - Vehicle composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to improvements in the formulation of novel medicated cream compositions.

Medicated creams have been widely used for many years as a pharmaceutical technique for topical application of drugs.

It is now believed that vehicle composition plays an important role in determining the rate of release of drugs from creams and the rate of absorption of topically applied drugs from the skin.

In recent years, a number of proposals have been made for the formulation of new medicated creams that are essentially anhydrous and contain non-aqueous solvents such as glycols.

According to the invention, as described in more detail below,
It has been discovered that valuable advantages can be obtained by using certain novel aqueous cream compositions in the formulation of topically active drugs.

Our new cream composition therefore differs from the anhydrous compositions described above in that it contains a significant amount of water in its composition.

Very generally, the novel cream compositions consist of a dispersion of one or more waxes or wax-like ingredients in an aqueous phase, and the aqueous phase is also preferably a water-miscible solvent compatible with the skin. Hydroxylic solvents conveniently contain at least one glycol and/or glycerol.

This novel composition is advantageously used as a vehicle for drugs that are desired to be applied topically to the skin.

In fact, we have found that this new composition has certain extremely valuable advantages both from a formulation and application point of view.

Further according to the invention, particularly advantageous results can be obtained by using in the composition the amounts of wax, water and hydroxyl solvent specified below, wherein relatively small amounts of wax are used in the composition. It has been found that particularly favorable results can be obtained when it is present in the medium.

The present invention provides a substantially oil-free medicated cream composition comprising at least one wax dispersed in an aqueous phase comprising water along with at least one water-miscible hydroxyl solvent. In that case, the total amount of one or more waxes is 5.0 to 30%.
and the amount of water is 70 to 75% and the total amount of one or more hydroxyl solvents is 10 to 80%.
and such amounts are in each case based on the total weight of the composition.

In the novel cream compositions of the present invention, the drug with low water solubility can be present at least in part and preferably in solution in the aqueous phase, thus facilitating release of the drug from the vehicle. I can do it.

Another factor that governs the rate of drug release from a cream is the presence or absence of oil in the cream.

In the past, creams were formulated as oily emulsions containing up to 50 parts oil.

The presence of a substantial amount of oil in the cream will generally suppress the release of the drug to a greater or lesser extent, especially if the drug has significant solubility in the oil.

Even if the drug is deliberately dissolved in the aqueous phase of the cream, the presence of an oil phase will only have an adverse effect on the release of the drug, and some of the drug will be partitioned into the oil phase. Probably.

In contrast, the novel cream compositions of the present invention avoid the use of substantial amounts of oil components.

Furthermore, the inclusion of substantial amounts of water in the novel cream compositions of the present invention is substantially less effective when using conventional phase formulations based on non-aqueous solvents such as glycols, e.g. propylene glycol. In comparison, the severe irritation of the vehicle to the skin is reduced.

Furthermore, it has been found that the inclusion of water in the novel compositions described above facilitates their manufacture.

When producing the above conventional water-free compositions,
It has been common practice to employ some type of surfactant to mix the ingredients.

However, even if a suitable surfactant is used, special manufacturing techniques are still required, since the surfactant cannot adequately perform its normal "wetting effect" in the absence of water. .

In contrast, the novel composition of the present invention contains water,
And if desired, surfactants can be easily incorporated therein.

Moreover, the novel compositions of the present invention can be easily prepared using common techniques such as mixing, stirring, cooling, etc., and do not require the use of special operating conditions or techniques.

As indicated above, the novel compositions described above contain one or more waxes.

The term "wax" is used herein in its broadest sense and includes not only ordinary waxes but also other substances having physical and/or chemical properties similar to waxes.

Examples of waxes that can be used in this novel composition include glycerol monoesters of long chain (e.g. C16-C24) fatty acids, preferably saturated fatty acid esters such as glycerol monostearate, acetoglyceride ( triglycerides, including acetylated mono- and diglycerides), fatty alcohols, such as saturated fatty alcohols, preferably 16
a saturated fatty alcohol containing from to 24 carbon atoms;
In particular, saturated fatty acids with waxy properties, preferably 14 to 2
such saturated fatty acids containing 6 carbon atoms, especially stearic acid, and natural and synthetic waxes,
An example is beeswax.

All of the above waxes have hydrophobic properties and form dispersions in water with suitable surfactants.

If desired, hydrophilic waxes may additionally be present, which are dissolved in the water component.

Examples of such hydrophilic waxes include polyethylene glycols with waxy properties, such as those with a molecular weight of 1.
500 to 6000 polyethylene glycol.

The total amount of the above wax components is between IO and 2 of the composition.
Preferably, it is used in an amount of 0.

With respect to hydroxyl solvents, this may consist of or include, for example, one or more glycols, such that the drug of interest is dissolved at least to some extent so that the drug reaches the surface to be treated. Glycols that can be transferred into the vehicle in a similar manner are preferred.

The type and amount of glycol solvent can therefore be conveniently selected to ensure that the drug is partially or completely dissolved in the glycol.

Examples of particularly preferred glycol solvents for use in the novel compositions of the invention include propanediol such as 1,2-propanediol, 1,3-propanediol, liquid polyethylene glycols, especially 100 to 8
00, diglopylene glycol and mixtures thereof.

The above-mentioned hydroxyl solvents may consist of or contain trihydric alcohols such as glycerol, the latter substances being suitable for dermatological purposes where a non-irritating composition is desired, e.g. It is particularly useful in compositions for use.

Generally, it is preferred that the hydroxyl solvent make up 25 to 70 parts of the composition, especially when the solvent is a glycol.

However, in certain cases, such as trihydric alcohols such as glycerol, it is preferred that they make up at most 40 parts of the composition (25 parts being more preferred).

Preferably, the novel compositions described above contain 20 to 60 parts water.

As mentioned above, the novel compositions may optionally contain a surface-active agent which acts as a dispersant for the wax and also as a stabilizer of the resulting dispersion.

This surfactant, which may be a single substance or a mixture, may be nonionic and preferably has an HLB value of at least 8.

Examples of surfactants include polyoxyethylene ethers or esters such as Setomakol 1000 (i.e. polyethylene glycol 1000 monocetyl ether), polyoxyethylene stearate (or mixtures of stearates) especially polyoxyethylene 40 stearate, or Mention may be made of polyoxyethylene lanolin derivatives, especially polyoxyethylene 25 lanolin.

Alternatively, anionic surfactants such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate, etc. may be used.

The new composition advantageously contains 0.1 to 10% (preferably 1 to 5 parts) of surfactant, the proportion of surfactant and its nature being sufficient to release the drug. selected through preliminary experiments.

The cream compositions described above can advantageously be used topically, for example in formulating a drug or a mixture of drugs to be applied to affected areas of the skin.

Such agents include, in particular, agents for locally alleviating inflammatory conditions, such as anti-inflammatory steroids, especially steroids of the corticoid type.

Particular classes of anti-inflammatory steroid compounds that can be advantageously formulated using this new composition include British Patent Nos. 1,047,518, 1,047,519, 1,070. No. 751, No. 1,139,506, No. 1
, No. 253,831, No. 1,281,689, No. 1,
No. 261,650 and British Patent Application No. 3765
No. 6/72, No. 33834/72 and No. 2787/
This includes those described in the specification of No. 71.

Specific steroid compounds that can be formulated as described above include betamethasone 17-valerate, 21-chloro21-desoxybetamethasone 17-propionate (21-chloro9α-fluoro-11β-hydroxy-16β monomethyl- 17α-propionyloxypregna=1,4 diene-3,20-dione), betamethasone 17-penzoate, fluocinolone acetonide (6α,9α-difluoro-l1β,21-dihydroxy-16α,17α-ingropylidene dioxypre gunar-1,4-diene-3,20-dione) and its corresponding 21-acetate, 9α-fluoro-16-
Methyleneprednisolone-21-acetate, 6α,9
α-Difluoroprednisolone-21-acetate-
17-butyrate, 9α,11β-dichloro-6α,2
1-difluoro-16α,17α-isopropylidene dioxybregner 1,4-diene-3,20-dione,
11β,21-dihydroxy-16α,17α-isopropylidene dioxy pregner 1,4-diene-3,2
0-dione, 9α,11β-dichloro-6α-fluoro21-hydroxy-16α,17α-isopropylidene dioxypregner 1,4-diene-3,20-dione, beclomethazone 17.21-dipropionate (9
α-chlorol6β-methyl-prednisolone 17,2
1-digropionate), 21-chloro-21-desoxy-11-dehydrobetamethasone 17-butyrate, 21-desoxybetamethasone 17-gropionate, betamethasone 17-inbutyrate 21 acetate, △8(9)16β -Methyl-prednisolone 1
7.21-diglopionate and methyl lβ-hydroxy-3-oquine-17α-glopionyloxy-androster-4-ene l7β monocarpoxylate.

The novel compositions described above may optionally also contain preferred other conventional ingredients and/or additives, such as preservatives such as chlorocresol, parabens (e.g. methyl and probylbaraben) and mercury compounds, humectants such as sorbitol, Or, if necessary, suitable stabilizers such as sodium metapisulfite or ethylenediaminetetraacetic acid can be included.

Although the compositions of the present invention are substantially oil-free, they may contain relatively small amounts of oily lubricants, up to about 5 parts (preferably 1 to 2 parts) of the composition; Typical lubricants include silicone oil, liquid paraffin, castor oil, and isoprobyl myristate.

The composition may also contain one or more buffering compounds.

The base composition of the present invention may contain, for example, 0.0001 to 5%, conveniently 0.005 to 0.50% and preferably 0.01 to 0.0%. Anti-inflammatory steroids can be included, and the exact proportions used can be easily selected with reference to the potency of the steroid.

21-chloro-21-desoxybetamethasone 17-
For propionate, a convenient ratio is 0.054.

The novel cream compositions of the present invention can be prepared, for example, by suitably mixing the ingredients in a conventional manner, eg as illustrated in the following illustrative example. It can be easily manufactured.

Topically active pharmaceutical ingredients can be added to a preformed cream, and more preferably mixed into one of the cream's components before emulsification.

In order to further understand the present invention, an actual example will be given below.

Actual example 1 Cetostearyl alcohol 10 acetoglyceride IO cetomacrogol 1000
1.5 1,2-propanediol 35
, Methylparaben 0.08 Probylparaben 0.02 Sodium dihydrogen phosphate
0.10 water retention total amount 1oo. The above three waxes are melted together and heated to 75°C.

■, mixing most of 2-propanediol and water;
Dissolve the other ingredients and heat to create a paraben solution.

This solution is heated to 75°C and mixed with the melted wax above.

Stir and cool to 40°C.

To incorporate the active ingredient into the above composition, 21-chloro 21-desoxy-beta methazone 17-propionate is dissolved in a small amount of 1,2-propanediol and mixed with the wax and aqueous phases. Add later.

Alternatively, the steroid may be ball milled in an aqueous solution of surfactant and the resulting fine suspension added to the other ingredients listed above.

A similar manufacturing method as described above is used for the composition of Example 2 below.

Example 2 Stearic acid 8.0% Cetostearyl alcohol 8.0% ■,2-propanediol 45.0% Cetomacrogol 1000 0.5% Polyoxyethylene 40 stearate 2.00% Chlorocresol 0.05% Sodium citrate 0.15% Citric acid 0.15% water Total amount Amount to 100.006 Example 3 Glyceryl monostearate (G.M.S.) 10.0% Cetostearyl alcohol (C.S.A. ) 8.0 Polyoxyethylene 25 Lanolin derivative 3.0 1,2-propanediol 67.0 Thiomersal 0.01 Sodium dihydrogen phosphate 0.054 Disodium hydrogen phosphate 0.05 = Water Total amount 100.0 Width G. M. S. ,C. S. A. and lanolin derivative are both melted and heated to 75°C.

Mix most of the above propanediol and water, add other ingredients and heat to melt.

Both solutions are mixed at 75°C, stirred and cooled to 40°C.

Mill the above steroid in a ball mill and add to the above phase mixture.

Example 4 Glyceryl monostearate (G.M.S.) to. o Section cetostearyl alcohol (C.S.A.) 5.0 section Beeswax
2.0 acid stable self-emulsifying monostearin (Arlacel 165) 2.0 glycerol
IO. Part 0 sodium citrate
0.05 Citric acid 0.05
Chlorocresol 0.10 water
Total amount 100.0 G. M. S. ,C. S.
A. Melt the beeswax and monostearin together and heat to 75°C.

Separately, mix most of the glycerol and water, add the other ingredients and heat to make an acidic solution.

The two phases are mixed and stirred at 75°C and cooled to 40°C.

The steroid is ball milled and added to the two phase mixture.

Example 5 Prepared as in Example 4 with addition of 1% dimethylpolysiloxane oil.

Comparative Experiments The vasoconstrictor neuroactivity of clobetasol (21-chloro-21-desoxybetamethasone 17-propionate) in the substantially oil-free cream composition of the present invention was compared to that of the same steroid in a conventional standard cream base. compared with the activity of

This was done using both 0.1 Z-steroids (Experiments No. 1 and No. 2) and 0.05% steroids (Experiments No. 3 and No. 4).

The prescription and results are shown below.

[Experiment No. l and no. 2] Prescription A Prescription B (present invention) Person in charge w/w (prior art) Jealousy w/w
/w clobetasol clobetasol 17
-Propione l7-gropionate
0.1-to 0.1 prescription A
Formulation B (present invention) 'b/w (prior art)
Part W ~ Sollan C24 1.0 Liquid paraffin 6.0 (ethoxylated
(English Pharmacopoeia) Resterol) Setostearylua N
Lagoon Serilmonos Lucor (English Pharmacopoeia)
7.2 Tearate 12.0 Setomacrogol propylene glycotoo (English Pharmacopoeia)
1.8 ru (European Pharmacopoeia 56.0) White soft paraffin
hmm
15.0 Chlorocresol 0.05 (English Pharmacopoeia) Sodium dihydrogen phosphate
Um (trihydrate) 0.
3 Sodium/lium citrate (English Pharmacopoeia) 0.05 Add phosphoric acid to pH
Citric acid to 4.8-5.2 0.05 Chlorocresol
0.10 Purified water total volume 100 (English Pharmacopoeia) Purified water total volume lOO Maximum vasoconstriction rate sample Experiment/l6l Experiment/l62 Prescription A
80.8 83.3 Prescription B 43.4 49.2 Comparing A and B No. G value for 1 = 25.6
No. Compare A and B. G value for 2 36.2
[Experiment/No. 3 and no. 4) Prescription A Prescription B (present invention) 壬 w/w (prior art) l
w/w clobetasol l7 clobetasol l7-gropionate 0.05 -propionate 0.05 glyceryl monos
Cetostearyl atheate 1
0.50 Lucor (British Bureau) 7.2 Cetostearylua Liquid paraffin 6
,0 Lecoure (English Pharmacopoeia) S. OO (English Pharmacopoeia)
Beeswax substitutes 1.25 Setomak Mouth Gol 1000 (English Pharmacopoeia) 1.8 Arlacel 165 1.50 (Self-emulsifying mono white soft paraffin 15A0 stearin) Sodium dihydrogen phosphate tripropylene glycol 47.50 Um (trihydrate) 0.3 (European Pharmacopoeia) Add phosphoric acid and p
H4.8 Sodium citrate ~5.
2 (English Pharmacopoeia) 005 Chlorocresol 0.1 Chlorocresol 0. )75
(English Pharmacopoeia) (English Pharmacopoeia) Purified water Total amount
100 Purified water Total amount 100 Maximum vasoconstriction rate sample Experiment No. 3 Experiment No. 4 prescription A
80.8 78.3 Prescription B 58.3 51.7 Comparing A and B No. G value for 3 = 12.7
No. Compare A and B. G value for 4 = 21.1
In all four tests, the formulation was in contact with the skin for 6 hours under occlusion.

The above results were measured 24 hours after application and are expressed as the total possible vasoconstrictor rate.

Statistical analysis of the results was performed using the G or Record Likelihood Ratio test.

For the difference between the two formulations to be significant, G must be 5.9
91 (that is, probability P=O.OS, degree of freedom 2).

In all four tests, the G value was greater than 5.991, indicating that the vasoconstrictor nerve response of the substantially oil-free cream composition of the present invention was greater than that of the standard cream base of the prior art in each experiment. These experiments show that the substantially oil-free base of the present invention has a significantly better drug release rate than the conventional standard cream base, since the vasoconstrictive nerve response is an indicator of the amount of drug released. It can be concluded that the release of is greater and thus the bioavailability is also greater.

Embodiments of the present invention are listed below.

■． At least one wax is dispersed in an aqueous phase containing water together with at least one water-miscible hydroxyl solvent, the total amount of the wax or waxes being between 50 and 130%. and the amount of water is 7.
0 to 75 parts and the total amount of one or more hydroxyl solvents is 10 to 80 parts (such amount being in each case based on the total weight of the composition)
A substantially oil-free cream composition useful as a vehicle for anti-inflammatory steroid injections.

2. The composition according to item 1 above, wherein the hydroxyl solvent comprises at least one glycol.

3. The composition according to item 2 above, wherein the hydroxyl injection solvent comprises propanediol, diglopylene glycol and/or liquid polyethylene glycol.

4. The composition according to item 3 above, wherein the hydroxyl solvent comprises 1,2-propanediol and/or 1,3-propanediol.

5. 5. The composition according to items 1 to 4 above, wherein the hydroxyl solvent comprises at least one trihydroxyl alcohol.

6. The composition according to item 5 above, wherein the hydroxyl solvent comprises glycerol.

7. the hydroxyl solvent is present in an amount of 25 to 70 parts based on the total weight of the composition;
The composition according to item 6.

8. The hydroxyl solvent is at least one trivalent (
8. A composition according to paragraphs 1 to 7, wherein said alcohol is present in said composition in an amount of up to 40 parts based on the total weight of said composition.

9. The composition of claim 8, wherein said trihydric (trihydroxylic) alcohol is present in an amount of IO to 25 parts, based on the total weight of the composition.

10. 20 to 60, based on the total weight of the composition
10. A composition according to any one of the preceding paragraphs, wherein water is present in a corresponding amount.

11. 11. The composition according to items 1 to 10 above, wherein the wax comprises a waxy triglyceride, a waxy fatty alcohol, or a waxy saturated fatty acid.

12. 12. The composition of claim 11, wherein the wax consists of a saturated fatty alcohol containing 16 to 24 carbon atoms or an acetoglyceride.

13. 13. The composition of claim 12, wherein the wax comprises cetyl alcohol, stearyl alcohol, cetostearyl alcohol, or behenyl alcohol.

14. 14. A composition according to paragraphs 11 to 13, wherein the wax consists of a saturated fatty acid containing 14 to 26 carbon atoms.

15. the fourteenth said wax comprising stearic acid;
Compositions as described in Section.

16 Said Nos. 1 to 15 whose wax is made of beeswax
The composition according to section 17, based on the total weight of the composition, from 10 to 20
17. A composition according to paragraphs 1 to 16, wherein the wax is present in a corresponding amount.

18. The composition according to items 1 to 17 above, further comprising a surfactant.

19. 19. The composition according to item 18, wherein the surfactant comprises a nonionic surfactant.

20. 20. The composition according to item 19, wherein the surface active agent comprises one or more polyoxyethylene ethers or esters.

21. 21. The composition according to item 20, wherein the surfactant comprises polyoxyethylene stearate or a polyoxyethylene lanolin derivative.

22. The composition of claim 21, wherein the surfactant comprises polyoxyethylene 40 stearate, polyoxyethylene 25 lanolin or polyethylene glycol 1000 monocetyl ether.

23. 19. The composition according to item 18, wherein the active agent comprises an anionic surfactant.

24. The composition of item 23 above, wherein the surfactant comprises sodium lauryl sulfate or sodium dioctyl sulfosuccinate.

25. Items 18 to 2, wherein the surfactant is present in an amount of 0.1 to 10% based on the total weight of the composition.
Composition according to item 4.

26 The surfactant is 1% based on the total weight of the composition.
26. The composition of claim 25, wherein the composition is present in an amount of 5 to 5.

27. The composition according to items 1 to 26 above, further comprising one or more preservatives, wetting agents or lubricants.

28. 28. The composition of claim 27, containing up to 5.1 parts by weight of said lubricant.

29. 29. The composition according to item 28, which contains 1 to 2 parts by weight of the above lubricant.

30. 30. The composition according to items 1 to 29 above, wherein the wax comprises glycerol monoester of a long-chain fatty acid or waxy polyethylene glycol.

31. 31. The composition of item 30, wherein the wax comprises glycerol monostearate.

Claims (1)

[Claims] 1 Consisting of at least one wax dispersed in an aqueous phase containing water together with at least one water-miscible hydroxyl solvent, with a total amount of one or more waxes ranging from 5.0 to 30 q and the amount of water is 7
0 to 75 parts and the total amount of the hydroxyl solvent or solvents is 10 to 80 parts (such amount being in each case based on the total weight of the composition)
A substantially oil-free cream composition useful as a vehicle for anti-inflammatory steroids.