CA1057662A

CA1057662A - Topical acne vulgaris compositions

Info

Publication number: CA1057662A
Application number: CA230,324A
Authority: CA
Inventors: Stephen N. Curtis
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1974-07-01
Filing date: 1975-06-27
Publication date: 1979-07-03
Also published as: DE2529149A1; FR2276815B1; FR2276815A1; JPS5129232A; ES439011A1; SE7506731L; GB1470355A; BE830830A; NL7507158A

Abstract

ABSTRACT OF THE DISCLOSURE
Topical acne compositions which comprise a bisguanide anti-acne agent and a skin penetrating agent. Also, included herein are methods of treating acne conditions in patients by administering the composition.

Description

~ 15347 ~5~766~ ~

This invention relates to new and useful pharma-ceutical formulations suitable for topical appl;cation in the treatment and control of acne. More particularly, the instant invention relates to anti-acne topical formulations comprising `~
a bis-biguanide anti-acne agent and a skin penetrating vehicle comprising a skin penetrating agent and a pharmaceutically ~ -- acceptable solvent suitable for topical application, to ~ ~;
`3' methods for preparing such formulations and to the method for topical treatment and control of acne employing such formu-lations.
~ Although the etiology of acne is still uncertain i there is mounting evidence that the disorder is the result of an interaction between physiological, bacteriological~ and chemical factors. It appears that the lipases produced by ; ~-,, Corynebaete~ia acn~s, the microorganism strongly implicated as an etiological agent in acne, in the anaerobic recesses of the ~ sebaceous follicle, split free fatty acids from sebum lipids.
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These substances are comedogenic, as well as, irritating, and they probably initiate the sequence of events, starting with follicular hyperkeratinization, which leads to comedone formation, follicular occlusion, and the subsequent disruption of the follicular wall, and ending in an inflammatory pustule.

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The literature teaches both topical and oral methods of treating acne. Topical foxmulations have been employed to prevent the blocking of the follicular duct or to re-open it once it becomes blocked, to penetrate into the follicle or the thickened sebum, whereby they are absorbed, or to obtain a successful combination of these actions. However, these formulations have disadvantages in their use in that they may be low in absorptive capacity, inherently toxic if absorbed into the body through the skin, suppoxtive to the growth of molds, bacteria and other micro-organisms, difficult to apply either alone or in a pharma-ceutical preparation, or cosmetically objectionable due to their odor, color etc. Currently, tetracycline, which ~:
has both antibacterial and anti-lipase activity, given orally is one of the most effective forms of therapy. How~
ever, the occurence of side effects, micxobial drug resist-ance and allergicreactions are some of the drawbacks en- `
countered in the use of antibiotics.
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It is an object o~ this invention to provide a formula~ion for topica~ treatment of acne which contains a bis-biguanide anti-acne agent and an agent which possesses skin penetrating activity.
: , It is a further object of this invention to soften the sebum plug to facilitate eventual removal.
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Another object of this invention is to provide an effective acne formulation comprising a low con~entration .. ~. .
;~ of the anti-acne agent. ~

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~ 153~7 1~'71662 Still another ob~ect of this invention is to provide a formulation which is capable of preventing the formation of comedones, retarding pustule development, and inhihiting the growth of corynebacteria. : :-In accordance with this invention, it i5 found that the formulation of this invention can be beneficially administered topically to patients suffering from mild to moderate acne conditions. It is believed that the s]cin acts as a res~rvoir by absorbing large amounts of the anti-acne com~ound and releases it slowly to the area being treated and that the skin penetrating agent enhances the penetration of the anti-acne agent into the skin.

As noted above, the anti-acne agents employed in the topical formulations of this invention are bis~
biguanide compounds. Applicant has ound that useful bis-biguanides are those selected from the group consisting of ~ 1,1'-hexametnylenebis-5-(hexyl)biguanide, l,l'-hexamethy-:
lenebis-5 (heptyl)biguanide, l,l'-hexamethylenebis-5~(n-octyl)biguanide, l,l'-~hexamethylenebis~-5-(2-ethyl hexyl) .
~0 biguanide, and l,l'-~hexamethylenebis 5-(non~rl)biguanide.
Also useful in the ormulations o this invention are the pharmaceutically acceptable acid addition salts o these ~.
'!' biguanides including, for example, the mono- and di-hyd~o-halide, sulfamate,saccharate, tartrate, acetate, sulfate, phthalate, succinate, citrate, lactate and nitrate salts.
These bis-biguanides are well-known compounds and are either available commercially or may be prepared by tech--niques alxeady fully described in the art (see, for example, . , .

~ - 3 -r ~ 1 5 3 ~! 7 ~057662 U.S. Pa-tent No. 3,46~,~98 wherein they are clescribed as :.
antibacterial agents).

The an-ti-acne agents herein are hiyhly substantive to the skin; are non-allergenic; }lave anti-lipase activity, tolerate reasonable amounts of soap and organic matterj re-sist the development of drug-resistant bacteria; are anti-mycotic, thus inhibiting overcJrowth o fungus on the skin;
are bactericidal at low concentratlons; have broad spectrum of anti-bacterial activity and are highly active in vitro ~ ;
- 10 against Corynebacterium acnes. ~ffective treatment and con~
trol of acne conditions susceptable to topical applications ~: is achieved with ~ormulations of this invention containing from 0.01 to 0.2~ by weight of the anti-acne ac;ent.
As an important aspect of the instant invention, applicant ha~ found that in order to ensure that an effect-ive amount of the anti-acne agent is adsorbed by topical . ~:
application, it is necessary to employ a vehicle which will `~ permit an efi~ient penetration o~ the ànti-acne agent into i~
i~ ~ the pilose-baceous canal. To achieve this result, applicant .~;
`:~ 20 incor~orated into the formulations of this invention a skin . .
~enetrating agent selected from the yroup consisting of lauryllactate, methyl pyrrolidone, mèthyl salicylate, allcl :

~ Vitamin A acid [3,7-dimethyl-9-(2,66--trimetllyl-1-cyclQhexen-yl)-2,4,6,8-nonatetraenoic acid] may be used to enhance the .

. 25 penetration of the anti-acne agent into the skin. The quan- .;~

, tity o~ skin penetrating agent required to achieve the de-! sired result, and at the same time avoid concentrations which ;i~ would be irritating in topical application, will vary widely ~,. depending upon the particular agent selected and must be . ~

critically controlled ~ -. ~ .
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: : - 4 -~ ~ 15347 7~2 in each case. Thus when methyl pyrrolidone is employed, it may constitute from 36 to 41~ by weight of the formulation;
when lauryl lactate i5 employed it may constitute from 10 to 20~ by weight of the formulation; when methyl salicylate is employed, it may constitute from 5 to 9~ ~y weiyht of the formulation; and when Vitamin A acid ~s employed, it may con-stitute from 0.05 to 0.1% by weight of t~e for~ulation.

The sol~ent employed is not a critical element of the ~ormulations of this invention. Any solvent for the anti-acne agent and the skin penetrating agent which is pharma-ceutically acceptable for topical application may be employed.
Typical solvents useful in the formulations of this invention include, for example, water, ethanol, isopropanol, 2-octyl dodecanol, diethylphthalate, propylene glycol, glycerine, dipropylene glycol and mixtures thereof~

In its compcsition aspect, therefore, the instant invention may be described as residing in the concept of new and useful pharmaceutical formulations suitable for topical application in the treatment and control of acne compri~ing a bis-biguanide anti-acne agent selected from the group consisting of 1,1'-hexamethylenebis-5-(hexyl) biguanide, l,l'hexamethylenebi 5- 5-(heptyl)biguanide, 1,1'-hexamethylenebis-5-(n-octyl)biguanide, l,l'-hexamethyl-enebis-5-(2-ethylhexyl ? biguanide, l,l'hexamathylenebis -5-(nonyl)biguanide and the pharmaceutically acceptable acid addition salts ~hereof; a skin penetrating agent selected from the group consisting of lauryl lactate methyl pyrrolidone, methyl salicylate and Vitamin A acid;

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~5766ff~ ~ ' and a pharmaceutically acceptable solvent suitable for topical application; wherein the bis biguanide constitutes from 0.01 to 0.2~ by weiyht of the fonmulation and wherein the lauryl lactate constitutes from 10 to 20% by weight of ` 5 the formulation, the methyl pyrrolidone constitutes from 36 to 41~ by weight of the formulation, the methyl salicy-late constitutes form 5 to 9~ by weight of the formulation, and the Vi~amin ~ acid constitutes from 0.05 to 0.1% by weight of the formulation. It is contemplated that dosage 10 units of such formulations will be applied topically in the treatment and control of acne con~itions.

Although not essential to the effeativeness of the formulations described above, optionally thera may be ;
included in the formulation an a~ti-oxidant as an inhibitor 15 to the ormation of new ~lack comedone heads. Suitable anti-oxidants include, for example, butylated hydroxy toluene, ascorbic acid, and butylated hydroxy anisole. ~ ;
When employed, the anti-oxidant usually constitutes from 0.01 to 0.15% by weight of the formulation. `~
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~'he compositions o this invention conveniently are prepared by agitating ~he anti-acne agent and a suitable ;
; solvent, such as descri~ed above, while adding thereto a solution which contains the skin penetrating agent and a minimum amount of such suitable solvent. The resulting mixture is aged (usually 10 to 30 minutes) with agitation, the remainder o~ the solvent is added and, finally, the resultiny mixtures are aged ~usually 10 to 3 a min.) with continuous agitation to assure uniformity~ Optionally, an anti~oxidant can be added prior to aging th~ mixture.

~ ~ 15347 ~L~)S7~Z

~lternatively, as one skilled in the art can readily appre-ciate, the anti-acne agent, skin penetrating a~ent and, optionally, the anti-oxidant can be combined in a minimum amount of solvent and stirred until the mixture is uniform.
After unifonmity is obtained the remainder of the solvent is added and the mixture again is aged to assure complete uniformity.

As disclosed al~ove, the topical formulations of this invention are efective in the treatment and control of acne conditions susceptible to topical therapy, especially mild to moderate acne conditions, and can be in any form suitable or topical application. Suitable topical dosage forms include r for example, lotions, fresheners, creams, ointments, jellies, salves and emulsions. A11 such dosage forms are readily prepared employing conventional formu--~ lating adjuvants and techniques well-~nown to those skilled in the art. It will be understood that the specific dose level for any particular patient will depend upon~pa~ a variety of factors including the activity of the specific active agents employed and the severity o the acne con-dition being treated. ~ective response usually is achieved by the topical application of the Eormulations of this invention 2 to 4 times daily to the area being treat- ~ ~-ed.
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The following examples illustrate the preparation of typical anti-acne formulations of this invention; no limitations~ however, being intended except as set forth in the appended claims.
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153~7 7~i62 EX~MPLE I -~
_ ~ b Weight Y , : ~
Ingredlents 1 2 3 4 5 1,1'-hexc~methylene-bis-5-(2-ethylhexyl)-biguanide-2~C1 0.01 0.1 0.01 0.1 0.1 0.2 Vitamin A acid 0.05 0.05 0.1 0.1 0.1 0.1 Isopropanol 35.0 25.0 45.0 35.0 50.0 35.0 Distilled water q.s. 100.0 lnn.0 100.0 100.0 100.0 100.0 . ~
To an ayitated mixture containing l,l'-hexamethylane~
bis-5-~2-ethylhex~l)biguanide dihydrochloride and a small ;~
~uantity of isopropanol at room temperature is added a solution of Vitamin ~ acid in isopropanol and a suficient amount o~ water to assure solution. The resulting solu-tion i5 then aged with agitation for about ten minutes while adding the remainder of water and agitation i5 continued for an additional ten minutes to assure uniformity. `-'`'~ '~ .
~ Other ~nti~acne agents such as l,l'-hexamethyl-,~ enebis-5-(hexyl)biguanide, 1,1'-hexamethylenebis~5-~heptyl)- ~`

biguanide, I,l'-hexamethylenebis-5-(n~octyl)biguanide, and l,l'-hexamethylenebis-5-~(nonyl)biguanide can be sub-~tituted for 1,1'-hexc~methylenebis-5-(2-ethylhexyl)biguanide.

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1 EXA~LE II

by Wei~ht In~e~ients 1_ 2 3 4 5 6 1,1'-hexc~methylene-bis-5-(2-ethylhexyl)-- biguanide-2~C1 0.01 0.05 0~1 0.2 0.1 0.2 Lauryl lactate 10.0 12.0 14.016.0 18.0 20.0 ~thanol q.s. 100.0 100.0 100.0100.0100.0100.0 . ; ~.
~ - 8 :. ., . .. , , . .... .. .. :. .

~ 153~7 )576G'~
To an agi~ated mixture containing l,l'~hexamethylene-bis-5-t2-ethylhexyl)biguanide dihydrochloride and a small amount of ethanol at room temperature is added a solution of lauryl lactate in a minimum amount of ethanol. With agitation this mixture is aged for about ten minutes;
the remainder amount o~ ethanol addad; and agitation con-tinued for an additional ten minutas to assure uniformity.
Other skin penetrating agents such as methylpyrroli done, methyl salicylate, or Vitamin ~ acid can he subs~ituted for lauryl lactate. Other solvents such as water, iso-propanol, 2-octyl dodecanol, diethylphthalate, propylene glycol, glycerine or dipropylene glycol can he suhstituted for the ethanol and other anti acne agents such as 1,1'-hexamethylenebis~5-(hexyl)biguanide, l,1'-hexamethylenebis-S~-(heptyl)biguanide, 1,1'-hexamethylenebis-5~-~n-octyl)-biguanide, and l,1'-hexamethylenebis-5-(nonyl)hiyuanide can be substituted ~or the l,l'-hexametllylenebis-5-(2--ethylhexyl)biguanide.

EX~MPLE lII

% b~ Weight Ingredients _ 1 2 3 4 5 6 l,l'-hexametl1ylene-bis-5-(2-ethylhexyl)-biguanide-2~ICl0.01 0.05 0.1 0.2 0.1 0.2 ; 25 Methyl pyrrolidone 36.5 36.0 36~0 36.0 40.5 41.0 i Methyl salicylate5.0 5~0 5.0 5.0 5. n 9. o Ethanol q.s. 100.0 100.0 100.0 100.0100.0 100.0 . .
To an agitated mixture containing l,l'-hexamethylene-bis-5-(2-ethyIhexyl)biguanide dihydrochloride, methyl .',, ~i :

,7 , .~

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pyrrolidone and methyl salicylate at room temperature is .
added approximately one~half the quantity of ethanol. The resulting mixtuxe i5 then agitated for about ten minutes, -.
the remainder of ethanol added and agitation continued for an additional ten minutes to assure uniformity. .~ ~
Other skin penetrating agents such as methylpyrroli- ~:
done, methyl salicylate, or Vitamin A acid can be substitu- -ted for methyl pyrrolidone and methyl salicylate. Other :~
solvents such as water, isopropanol, 2-octyl dodecanol, ~;.
.:, , diethylphthalate, propylene glycol, glycerine or dipropyl-ene glycol can be sukstituted for ethanol.
: EXA~LE IV ..
% by Weight In~redients 1 2 3 4 5 6 : 15 l,l'-hexamethy~
lene-bis-5-(2- .
ethylhexyl)- : ~
~: biguanide 2~1C1 0.01 G.l 0.2 0.1 0.2 0.1 ; .
Vitamin A Acid 0.05 0.07 0.1 0.1 0.1 0.1 :
20 : Butylated hy-drcxy toluene0.01 0.03 0.05 0.065 0.075 0.1 Isopropanol 35.0 25.0 45.0 35.0 50.035.0 `.
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Distilled . water ~.s. 100.0 100.0 100.0 100.0 100.0 100.0 ~; 25 To an agitated mixture containing l,l'-hexamethylene-~j -:~: bis 5-(2-ethylhexyl~)biyuanide dihydroch].oride and a small ; :
: quantity of isopropanol, at room temperature, is added a solution of Vitamin A acid and but~lated hydroxytoluene in isopropanol and a suffic..ent amount of water to assure , ~
solution. ~The resulting solution is then aged with agitation for about ten minutes while adding the remainder of water ~-.
~ and agitatLon is continued for an additional ten minutes 1 to assure uniformity:. ~ :

'. 1 ' ~ ' ~ 15347 l(~S7G~;~
Other anti-acne agents such as l,l'-hexamethylene-bis-5-(hexyl)biguanide, l,l'-hexamethylenebis-5-(heptyl)-biguanide, l,l'-hexamethylenebis-5-(n~octyl)bi~uanide, and l,l'-hexamethylenebis--5-(nonyl)higuanide can he substituted for 1,1'-hexamethylenebis-5--(2 ethylhexyl)-biguanide. :~
The subject matter ~hich applicant reyards as his `
invention is particularly pointed out and distinctly claimed as ollows.
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Claims

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. An anti-acne composition for topical adminis-tration comprising from about 0.01 to 0.2% by weight of an anti-acne agent selected from the group consisting of 1,1'-hexamethylenebis-5-(hexyl)biguanide, 1,1'-hexamethylenebis-5-(heptyl)biguanide, 1,1'-hexamethylenebis-5-(n-octyl)biguanide, 1,1'-hexamethylenebis-5-(2-ethylhexyl)biguanide, 1,1'-hexa-methylenebis-5-(nonyl)biguanide and the pharmaceutically acceptable acid addition salts thereof; a skin penetrating agent selected from the group consisting of lauryl lactate, methyl pyrrolidone, methyl salicylate and Vitamin A acid, wherein the lauryl lactate constitutes from 10 to 20% by weight of the formulation, the methyl pyrrolidone constitutes from 36 to 41% by weight of the formulation, the methyl salicylate constitutes from 5 to 9% by weight of the formulation, and the Vitamin A acid constitutes from 0.05 to 0.1% by weight of the formulation; and a pharmaceutically acceptable solvent suitable for topical application.

2. The composition of Claim 1, wherein the solvent is a member selected from the group consisting of water, ethanol, isopropanol, 2-octyl dodecanol, diethylphthalate, propylene glycol, glycerine, dipropylene glycol and mixtures thereof.

3. A composition of Claim 2, wherein the active agent is 1,1-hexamethylenebis-5-(2-ethylhexyl)biguanide.

4. A composition of Claim 3, wherein the skin penetrating agent is Vitamin A acid and the solvent is isopropanol and water.

5. A composition of Claim 3, wherein the skin penetrating agent is lauryl lactate and the solvent is ethanol.

6. A composition of Claim 3, wherein the formulation further comprises from 0.01 to 0.15% by weight of an anti-oxidant selected from the group consisting of butylated hydroxytoluene, butylated hydroxyanisole and ascorbic acid.

7. A composition of Claim 6, wherein the anti-oxidant is butylated hydroxytoluene.