CA1243948A - Stable, storable insulin product for the treatment of acne vulgaris - Google Patents
Stable, storable insulin product for the treatment of acne vulgarisInfo
- Publication number
- CA1243948A CA1243948A CA000479330A CA479330A CA1243948A CA 1243948 A CA1243948 A CA 1243948A CA 000479330 A CA000479330 A CA 000479330A CA 479330 A CA479330 A CA 479330A CA 1243948 A CA1243948 A CA 1243948A
- Authority
- CA
- Canada
- Prior art keywords
- insulin
- gel
- treatment
- product
- insulin product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/28—Insulins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Abstract
Abstract Acne vulgaris can be successfully treated by external use of insulin in the form of a gel; a stable, storable gel is formed by using a polyacrylic acid, the carboxyl groups of which are neutralized. An increase in the action, can be achieved by combining the insulin with the enzyme hyaluronidase or/and .alpha.-glucosidase. The product can be used both curatively and prophylactically, and as long term treatment, in order to prevent a renewed outbreak of the disease.
Description
3~4~
Stable, storable insulin product for the treatment of ~ ' .
Acne vulgaris is an inflammatory disorder which occurs frequently and fairly generalLy in middle to late youth It occurs in all races, but displays a milder course in certain oriental populationsn It is estimated that about 60% of adolescents are affected from puberty until about the age of 25; accordir-g to another es~ima-tion, about 100 million adolescents suffer from the dis-ease in the ~estern World (Western Europe and NorthAmerica).
Acne manifests itself clinically by the appear-ance of blackheads, papules, nodules and vesicles, which are distr;buted ;n a characteristic manner, in particular on the greasy sk;n of the face, with the exception of the periorbital region, and on the neck, chest and shoulders.
Damage in cases of acne is classified into damage of the inflammatory and non-;nflammatory type; non-inflammatory damage comprises open and closed blackheads. Bo~h sexes are affected, and in some cases the damage is more severe in males.
Numerous products have already been proposed and tried out for treating acne vulgaris, in particular var;
ous skin cleansers, sodium borate, sodium lauryl-sulfate, benzoyl peroxide, retinoic acid ~tretinoin, vitamin A
acid) and antibiotics, such as neomycin and tetracycline hydrochlor;de. All the products hitherto tested at best effect temporary impro~ement, but the action subsides after some time and side effects occasionally occur, which can sometimes be as se~ere as the acne itself.
Thus, uen~oyl peroxide tU.S~ Patent No. 4,387,107) can cause skin irritations~ which persist, and fur~her-more cauterization of the skin and scar formation~ which lead~to severe dermatoses. A side effect of benzoyl per-oxide which, although secondary~ is s~ill troublesome, isits ability to bleach textiles, ie. articles of clothing~
Retinoic ac1d can also cause intensive skin irritation;
- in addition, when this product was used for treatment, i.~
3~
it was difficult to ascertain unambiguous improvement.
Neomycin displays relatively good results in the infec~
tious phase of acne; however, after a short period of treatment, resistance develops~ so ~hat only little or no improvement is achieved in the long term. Tetracycline in turn can display an alleviating action on long-term treatmentf but it is known to produce a number of side effects, such as diarrhea, tiredness and headaches.
Overall, none of the products investigated have yet proved generally suitable in the treatment of the disease: the initially advantageous action of certain pro-ducts did not last or side effects occurred ~hich neces-sitated discontinuation of the treatment~ However, tem-porary successes and side effects are all the less accept-able since acne necessitates long-term treatment~ fre-quently even lasting years.
On the other hand, earlier publications have reported a certain improvement in the condition of non-diabetic patients who were suffering from acne and ~ere subjected to insulin treatment. The treatment consisted of a long-term series of insulin shocks in ~ psychotic, schizophrenic patients CJ. Wortis, J. Am. Med. Assoc.
108, 971 (1937)~, a series of parenteral insulin injec-tions two to three times per ~eek in 13 other patients ~H.C. Semon and F. Herrmann, ~rit. J. Derm. 52j 123 (1940)] and injectiGn of insuLin d;rectly into the acne pustules (papules) in some adolescents hospital;zed because of mental disorder ~R.W. Grover and N. Arikian, J. Invest. Derm. 40, 259 (1963)~
It should in itself be clear that insulln shock therapy or insulin injections for long-~erm treatment of ~- acne in otherwise healthy adolescen.s is entirely out of the quest;on. The abovementioned reports have therefore ~ ~ soon been forgotten and have given rise to no further - 35 investigations. The fear of a hypoglycemic reaction as a consequenre of the systemic effects of the insulin~
as pointed out by Grover and Arikian at the end of the;r report, also stopped other experiments being cons;dered.
It was thus all the more surprising ~hen it was ''' ' 3~
found tha~ insulin applied externally, in a phar~aceuti-cal form provided ad hoc, to the skin of adolescents suf~
fering from acne vulgaris was capable of healing the dis-ease or at least favorably influencing its course, with-out thereby displaying any side effects and, in particu-lar~ without systemic actions. The improvement s~arts after a short time: the inflammations and the swellings subside, the reddening o-f the parts of the body affected decrease and, as the infection subsides, the skin norm-alizes. Enclosed blackheads may flare up again, but areeasily healed by renewed treatment.
The action of the insulin must not be restricted to curative treatment of adolescents already suffering from acne, and the insulin can also be used prophylactic-ally with success. In particular, the earlier activetreatment of t~he acne is started, the better are the results and the fewer the complaints which occur. The treatment should be started if there is a disposition ~oward the disease and in any case at the slightest indi-cation of acne~ and, in order to counteract the infectionand to keep the d;sease under control, should be continued.
However, specific restrictions and requirements, which, ;n the case of acne vulgaris, result from the nature of the diseased skin itself~ are imposed an a stable, storable insulin product. Thus, no fats or fatty products should be used as the carrier material or exci-pient; the conventiona~ ointment bases are thus excluded from the start.
In addition~ insulin is known to be a particularly sensitive chemical compound which is easily decomposed by the most diverse external influences. For example, con-tact with glass can already suffice ~o initiate slow dec~m-position of the molecule. The temperature can also have an adverse effect on the stability on prolonged storage of an insulin product. Thus, insulin solutions, unless these are brought exactly to a neutral pH value, must be stored în a refrigerator; otherwise, decomposition can already be de~ected at temperatures of about 20C. The molecule behaves similarly toward most chemical substances.
:~4~
Inter alia, the use of water-soluble cellulose ethers as a gelling agent has facilitated the preparation of insulin-containing gels which were entirely satisfac-tory in respect of consistency and appearance. However, when the stability and storability in the long term were tested, it was found that the insulin had suffered par-tial decomposition. The same adverse results were in-evitably obtained later with other kno~n gelling agents.
Unexpectedly, ho~ever~ a gelling a~ent ideal for the intended purposes was found in a hi~h molecular weight polyacrylic acid~ the carboxyl groups of which are neut-ralized. In particuLar, water-containing, insulin-containing gels which are distinguished not only by the desired consistency and a satisfactory appearance but moreover also by an outstanding storability and stability of the insulin molecule can be prepared with th;s sub-stance~ T~e stability exper;ments at room temperature, which have now been running for more than 6 months, have shown no indication of decomposition of the active compound.
Of the acrylic acid polymers, also called poly-acrylic acids or carboxyvinyl polymers, those ~hich are obtainable under the trade names Carbopol, for example Carbopol 941~ Carbopol 934 or Carbopol 940 with an aver-age molecular weight of 1~250~000~ 3~000rûOû and 4,000,0ûOrespectively tmanufacturer: B.F. Goodr;ch Chemical Group, Cleveland~ OH/USA) can be used in part;cular.
- The acid ~roups of the polyacrylic ac;d must be neutralized by a water-soluble inorganic or organic base.
Particularly suitable inorganic bases are sodium hydroxide solution and potassium hydroxide solution; sodium hydrox-ide solution is preferably used, on the one hand because of the physiological role of the sodium ion~ and on the - other hand as a result of the ease of stoichiometric metering of dilute sodium hydroxide solution. Suitable organic bases are water-soluble amines. Such an amine can be, for example, methYlaminej dimethylamine, ethyl~
am;ne, diethylamine, propylamine, ;sopropylamine, diisopropylamine, cyclohexylamine, benzylamine, guanidine, "' ~3~
pyrrolidine, ~iperidine, morpholine, arginine, lysine, ethanolamine, diethanolamine, diisopropanolamine or tri-ethanolamine. The lower aliphatic amines which are liquid at room temperature, for example diisopropanolamine or diethylamine, are preferred.
The content of insulin in the gel can vary within a wide range, for example from about û.25 to 25 mg of insulin per ml of gel. The action of the product on acne can already be observed with such a minimum content as, for example, 0.25 mg of insulin/ml of gel; at higher con-centrations~ for example 0.50, 1, 2 or 5 mg of insulintml of gel, the efficacy of the treatment also increases.
The gel preferably contains 0.50 to 5 mg of insulin/ml.
The gel should have a physiologically acceptable pH value; it is advantageously brought to within a pH
range of 6.7 to 7.~, preferably to pH 6.8 to 7Ø To establish the p~ value, the required amount of the above-mentioned base or of a physiologically acceptable acid~
such as dilute phosphoric acid, hydrochloric acid, acetic acid, lactic acid or pyruvic acid, can be added.
It has furthermore been found that the addition of the enzyme hyaluronidase orland the enzyme ~-glucosi-dase is capable of impressively increasing the success of treatment. Hyaluronidase facilitates and improves the penetration of the gel into the skin, whilst ~-glucosidase is thought to assist the local action of the insulin on the carbohydrate metabolism in the skin.
A preservative, such as, for example, Nipagin ~
or methyl or ethyl 4-hydroxybenzoate, can furthermore be added to the product.
The investigations carried out w;th the gel des-cribed on voluntary acne patients of both sexes have now been running for more than 2 years; no side effects at all have been observed. In partirular, no 1ndication that the insulin would p~s ~hrough t~e skin and enter the blood stream was to be observed in any of the patients. In any case nothing at all of possible percutaneous absorption is to be found in the extensive literature on insulin; the compound is known to display its systemic actions on ,, ~3~
~ 6 --parenteral, usually intramuscular, administration.
The treatment of the acne should be started as early as possible, ie. as far as possible after the appearance of the first symptoms.
The treatment is in general carried out as fol lows. The affected areas of skin are carefully cleaned wi~h a suitable skin cleanser and then rinsed with luke-warm waterO After the skin has been dried, the insulin gel is spread in a thin layer over the affected areas.
1û Additional gel car, be appLied to more severely swollen regions and covered ~ith a pLaster during the night.
As a rule, such swellings disappear and clear improvement starts after about 8 hours.
The case of a 17-year old tnale suffering from dif-fuse acne vulgar;s on the face, back and shoulders sincethe age of about 12 years may be mentioned as an example.
He had already been treated with various products, each time with only little successO He was now treatecl daily for two ~eeks as follows: the affected areas of skin ~tere first w3shed with soap and water, in order to remove excess grease from the surface of the skin~ and were then rinsed thoroughly with water and dried carefully. The gel according to the follo~ting Example 1 tcontaining 0.50 mg of insulin per ml of gel) was distributed over ~hese areas of Z5 skin, and severely affected follicles were also coated with a thicker layer of gel and then covered with a plaster~
Improvement started after a short time, the reddening slowly decreased and as the infection subsided, the skin resumed its normal appearance.
~ The therapeutic successes ach;eved by the insulin, i.e.the new product,are of a symptomatic nature; the treatment should therefote be cc,ntinued for as long as the disease ;tself continues to exist. Needless to say, the durati~n of acne which proceeds uninfluenced and without any counter-measures cannot be estimated in advance; it is from some months to some years, and is in any case ent;rely individual~ The treatment will therefore be carried out, for example, once daily for 6 months~
, ,~
3~
discontinuation of the treatment is then attempted and~
if necessary, ie. on renewed appearance of the symptoms, is started again for another period of timeO
The following treatment plan is advisable, on the basis of the long period of treatment which frequently proves to b~ necessary for the acne finally to subside:
treatment is carried out once daily with about a.25 ~o 2 mg of insulin/ml of gel for several months, until the symptoms have disappeared completely.
~
- 5û mg of insulin are mixed with 10 ml of ~demineralized water, wi~h stirring: solution A
. 1.5 ~ of Carb ~ are m;xed with 20 ml of demineralized waterO the mixture is carefully neutral-ized by slowly adding dilute sodium hydroxide solution, with stirring~ stirring is continued until a homogeneous suspension is formed, solution A is slowly added and the mixture is stirred thoroughly: ~
Gel B is left to stand overnight.
Distilled water is slowly added, with thorough stirring, to make up to 100.0 ml:
Example_2
Stable, storable insulin product for the treatment of ~ ' .
Acne vulgaris is an inflammatory disorder which occurs frequently and fairly generalLy in middle to late youth It occurs in all races, but displays a milder course in certain oriental populationsn It is estimated that about 60% of adolescents are affected from puberty until about the age of 25; accordir-g to another es~ima-tion, about 100 million adolescents suffer from the dis-ease in the ~estern World (Western Europe and NorthAmerica).
Acne manifests itself clinically by the appear-ance of blackheads, papules, nodules and vesicles, which are distr;buted ;n a characteristic manner, in particular on the greasy sk;n of the face, with the exception of the periorbital region, and on the neck, chest and shoulders.
Damage in cases of acne is classified into damage of the inflammatory and non-;nflammatory type; non-inflammatory damage comprises open and closed blackheads. Bo~h sexes are affected, and in some cases the damage is more severe in males.
Numerous products have already been proposed and tried out for treating acne vulgaris, in particular var;
ous skin cleansers, sodium borate, sodium lauryl-sulfate, benzoyl peroxide, retinoic acid ~tretinoin, vitamin A
acid) and antibiotics, such as neomycin and tetracycline hydrochlor;de. All the products hitherto tested at best effect temporary impro~ement, but the action subsides after some time and side effects occasionally occur, which can sometimes be as se~ere as the acne itself.
Thus, uen~oyl peroxide tU.S~ Patent No. 4,387,107) can cause skin irritations~ which persist, and fur~her-more cauterization of the skin and scar formation~ which lead~to severe dermatoses. A side effect of benzoyl per-oxide which, although secondary~ is s~ill troublesome, isits ability to bleach textiles, ie. articles of clothing~
Retinoic ac1d can also cause intensive skin irritation;
- in addition, when this product was used for treatment, i.~
3~
it was difficult to ascertain unambiguous improvement.
Neomycin displays relatively good results in the infec~
tious phase of acne; however, after a short period of treatment, resistance develops~ so ~hat only little or no improvement is achieved in the long term. Tetracycline in turn can display an alleviating action on long-term treatmentf but it is known to produce a number of side effects, such as diarrhea, tiredness and headaches.
Overall, none of the products investigated have yet proved generally suitable in the treatment of the disease: the initially advantageous action of certain pro-ducts did not last or side effects occurred ~hich neces-sitated discontinuation of the treatment~ However, tem-porary successes and side effects are all the less accept-able since acne necessitates long-term treatment~ fre-quently even lasting years.
On the other hand, earlier publications have reported a certain improvement in the condition of non-diabetic patients who were suffering from acne and ~ere subjected to insulin treatment. The treatment consisted of a long-term series of insulin shocks in ~ psychotic, schizophrenic patients CJ. Wortis, J. Am. Med. Assoc.
108, 971 (1937)~, a series of parenteral insulin injec-tions two to three times per ~eek in 13 other patients ~H.C. Semon and F. Herrmann, ~rit. J. Derm. 52j 123 (1940)] and injectiGn of insuLin d;rectly into the acne pustules (papules) in some adolescents hospital;zed because of mental disorder ~R.W. Grover and N. Arikian, J. Invest. Derm. 40, 259 (1963)~
It should in itself be clear that insulln shock therapy or insulin injections for long-~erm treatment of ~- acne in otherwise healthy adolescen.s is entirely out of the quest;on. The abovementioned reports have therefore ~ ~ soon been forgotten and have given rise to no further - 35 investigations. The fear of a hypoglycemic reaction as a consequenre of the systemic effects of the insulin~
as pointed out by Grover and Arikian at the end of the;r report, also stopped other experiments being cons;dered.
It was thus all the more surprising ~hen it was ''' ' 3~
found tha~ insulin applied externally, in a phar~aceuti-cal form provided ad hoc, to the skin of adolescents suf~
fering from acne vulgaris was capable of healing the dis-ease or at least favorably influencing its course, with-out thereby displaying any side effects and, in particu-lar~ without systemic actions. The improvement s~arts after a short time: the inflammations and the swellings subside, the reddening o-f the parts of the body affected decrease and, as the infection subsides, the skin norm-alizes. Enclosed blackheads may flare up again, but areeasily healed by renewed treatment.
The action of the insulin must not be restricted to curative treatment of adolescents already suffering from acne, and the insulin can also be used prophylactic-ally with success. In particular, the earlier activetreatment of t~he acne is started, the better are the results and the fewer the complaints which occur. The treatment should be started if there is a disposition ~oward the disease and in any case at the slightest indi-cation of acne~ and, in order to counteract the infectionand to keep the d;sease under control, should be continued.
However, specific restrictions and requirements, which, ;n the case of acne vulgaris, result from the nature of the diseased skin itself~ are imposed an a stable, storable insulin product. Thus, no fats or fatty products should be used as the carrier material or exci-pient; the conventiona~ ointment bases are thus excluded from the start.
In addition~ insulin is known to be a particularly sensitive chemical compound which is easily decomposed by the most diverse external influences. For example, con-tact with glass can already suffice ~o initiate slow dec~m-position of the molecule. The temperature can also have an adverse effect on the stability on prolonged storage of an insulin product. Thus, insulin solutions, unless these are brought exactly to a neutral pH value, must be stored în a refrigerator; otherwise, decomposition can already be de~ected at temperatures of about 20C. The molecule behaves similarly toward most chemical substances.
:~4~
Inter alia, the use of water-soluble cellulose ethers as a gelling agent has facilitated the preparation of insulin-containing gels which were entirely satisfac-tory in respect of consistency and appearance. However, when the stability and storability in the long term were tested, it was found that the insulin had suffered par-tial decomposition. The same adverse results were in-evitably obtained later with other kno~n gelling agents.
Unexpectedly, ho~ever~ a gelling a~ent ideal for the intended purposes was found in a hi~h molecular weight polyacrylic acid~ the carboxyl groups of which are neut-ralized. In particuLar, water-containing, insulin-containing gels which are distinguished not only by the desired consistency and a satisfactory appearance but moreover also by an outstanding storability and stability of the insulin molecule can be prepared with th;s sub-stance~ T~e stability exper;ments at room temperature, which have now been running for more than 6 months, have shown no indication of decomposition of the active compound.
Of the acrylic acid polymers, also called poly-acrylic acids or carboxyvinyl polymers, those ~hich are obtainable under the trade names Carbopol, for example Carbopol 941~ Carbopol 934 or Carbopol 940 with an aver-age molecular weight of 1~250~000~ 3~000rûOû and 4,000,0ûOrespectively tmanufacturer: B.F. Goodr;ch Chemical Group, Cleveland~ OH/USA) can be used in part;cular.
- The acid ~roups of the polyacrylic ac;d must be neutralized by a water-soluble inorganic or organic base.
Particularly suitable inorganic bases are sodium hydroxide solution and potassium hydroxide solution; sodium hydrox-ide solution is preferably used, on the one hand because of the physiological role of the sodium ion~ and on the - other hand as a result of the ease of stoichiometric metering of dilute sodium hydroxide solution. Suitable organic bases are water-soluble amines. Such an amine can be, for example, methYlaminej dimethylamine, ethyl~
am;ne, diethylamine, propylamine, ;sopropylamine, diisopropylamine, cyclohexylamine, benzylamine, guanidine, "' ~3~
pyrrolidine, ~iperidine, morpholine, arginine, lysine, ethanolamine, diethanolamine, diisopropanolamine or tri-ethanolamine. The lower aliphatic amines which are liquid at room temperature, for example diisopropanolamine or diethylamine, are preferred.
The content of insulin in the gel can vary within a wide range, for example from about û.25 to 25 mg of insulin per ml of gel. The action of the product on acne can already be observed with such a minimum content as, for example, 0.25 mg of insulin/ml of gel; at higher con-centrations~ for example 0.50, 1, 2 or 5 mg of insulintml of gel, the efficacy of the treatment also increases.
The gel preferably contains 0.50 to 5 mg of insulin/ml.
The gel should have a physiologically acceptable pH value; it is advantageously brought to within a pH
range of 6.7 to 7.~, preferably to pH 6.8 to 7Ø To establish the p~ value, the required amount of the above-mentioned base or of a physiologically acceptable acid~
such as dilute phosphoric acid, hydrochloric acid, acetic acid, lactic acid or pyruvic acid, can be added.
It has furthermore been found that the addition of the enzyme hyaluronidase orland the enzyme ~-glucosi-dase is capable of impressively increasing the success of treatment. Hyaluronidase facilitates and improves the penetration of the gel into the skin, whilst ~-glucosidase is thought to assist the local action of the insulin on the carbohydrate metabolism in the skin.
A preservative, such as, for example, Nipagin ~
or methyl or ethyl 4-hydroxybenzoate, can furthermore be added to the product.
The investigations carried out w;th the gel des-cribed on voluntary acne patients of both sexes have now been running for more than 2 years; no side effects at all have been observed. In partirular, no 1ndication that the insulin would p~s ~hrough t~e skin and enter the blood stream was to be observed in any of the patients. In any case nothing at all of possible percutaneous absorption is to be found in the extensive literature on insulin; the compound is known to display its systemic actions on ,, ~3~
~ 6 --parenteral, usually intramuscular, administration.
The treatment of the acne should be started as early as possible, ie. as far as possible after the appearance of the first symptoms.
The treatment is in general carried out as fol lows. The affected areas of skin are carefully cleaned wi~h a suitable skin cleanser and then rinsed with luke-warm waterO After the skin has been dried, the insulin gel is spread in a thin layer over the affected areas.
1û Additional gel car, be appLied to more severely swollen regions and covered ~ith a pLaster during the night.
As a rule, such swellings disappear and clear improvement starts after about 8 hours.
The case of a 17-year old tnale suffering from dif-fuse acne vulgar;s on the face, back and shoulders sincethe age of about 12 years may be mentioned as an example.
He had already been treated with various products, each time with only little successO He was now treatecl daily for two ~eeks as follows: the affected areas of skin ~tere first w3shed with soap and water, in order to remove excess grease from the surface of the skin~ and were then rinsed thoroughly with water and dried carefully. The gel according to the follo~ting Example 1 tcontaining 0.50 mg of insulin per ml of gel) was distributed over ~hese areas of Z5 skin, and severely affected follicles were also coated with a thicker layer of gel and then covered with a plaster~
Improvement started after a short time, the reddening slowly decreased and as the infection subsided, the skin resumed its normal appearance.
~ The therapeutic successes ach;eved by the insulin, i.e.the new product,are of a symptomatic nature; the treatment should therefote be cc,ntinued for as long as the disease ;tself continues to exist. Needless to say, the durati~n of acne which proceeds uninfluenced and without any counter-measures cannot be estimated in advance; it is from some months to some years, and is in any case ent;rely individual~ The treatment will therefore be carried out, for example, once daily for 6 months~
, ,~
3~
discontinuation of the treatment is then attempted and~
if necessary, ie. on renewed appearance of the symptoms, is started again for another period of timeO
The following treatment plan is advisable, on the basis of the long period of treatment which frequently proves to b~ necessary for the acne finally to subside:
treatment is carried out once daily with about a.25 ~o 2 mg of insulin/ml of gel for several months, until the symptoms have disappeared completely.
~
- 5û mg of insulin are mixed with 10 ml of ~demineralized water, wi~h stirring: solution A
. 1.5 ~ of Carb ~ are m;xed with 20 ml of demineralized waterO the mixture is carefully neutral-ized by slowly adding dilute sodium hydroxide solution, with stirring~ stirring is continued until a homogeneous suspension is formed, solution A is slowly added and the mixture is stirred thoroughly: ~
Gel B is left to stand overnight.
Distilled water is slowly added, with thorough stirring, to make up to 100.0 ml:
Example_2
2 9 of Carbopol ~ 941 are mixed with 30 ml o~
demineralized ~ater, the mixture is carefully neutralized by slowly adding dilute sodium hydroxide solution, with stirring, and a homogeneous suspension is prepared there-fro~, by continued stirring: ~
500 mg of ;nsulin are dissolved ;n 20 ml of demineralized water, with stirring: solution B
,, .
Solut;on B is slowly added to gel A and the mix-ture is stirred thoroughly: ~
Gel C is left to stand overn;ght amd is finally ~ made up to a volume of 1Q0 ml by addition of demineral;zed ; uater: ~
Example 3 ;~ 3 g of Carbo ~ are mixed with 20 ml of dem;neralized water, the mixture is carefully neutral-ized by slowly adding a solution of 3 g of diisopropanolam~ne in 10 ml of demineralized water, with stirring, and a homo~eneous suspension is prepared ~2a~3 therefrom by continued stirring: gel A
lO0 mg of insulin are dissolved in 20 ml of demineralized water~ with stirring: s'ol'ut'ion B
100 International Units of hyaluronidase are dissolved in lO ml of demineralized water, wi.th stirrin~:
_olution C
Solution C is slowly added to solution B and the mixture is stirred thoroughly:''solu'tion D
Solution D is slowly added to gel A and the mixture is stirred thoroughly: gel E
Gel E ist left to stand overnight and is finally made up to a volume of lO0 ml by addition of : demineralized water: ~
Example_4 2 g of Carbopol 941 are mixed with 20 ml of demineralized water, the mixture is carefully : neutralized by slowly adding a solution of 2 g of diethanolamine in lO ml of demineralized water, with 20: stirring, and a homogeneous suspension is prepared ; therefrom by continued stirring:' g'el A
200 mg of insulin are dissolved in 25 ml of demineralized water, with stirring:' _olution B
5 ml of Spritamylase SAN (liquid preparation 25 of ~-glucosidase, manufactured by Novo Industrie GmbH, Mainz FRG) are added to 5 ml to water, with stirring-solu'ti'on C
; : SoIution C is slowly added to solution B
and the mixture is stlrred thoroughly: so'lution D
: :Solution D is slowly added to gel A and the mixture is stirred thoroughly:'gel' E
Gel E is left to:stand overnight and is finally brought to a volume Qf 100 ml by addition of demineralized water: ~
~- :
.
~3g~$~
Examples 5 to 8 Component ~ le No.
l. insulin3 crystalline40 mg 80 mg 120 mg 160 mg 2. zinc 2000 ~g 4000 ~g 6000 ~g8000 ~g
demineralized ~ater, the mixture is carefully neutralized by slowly adding dilute sodium hydroxide solution, with stirring, and a homogeneous suspension is prepared there-fro~, by continued stirring: ~
500 mg of ;nsulin are dissolved ;n 20 ml of demineralized water, with stirring: solution B
,, .
Solut;on B is slowly added to gel A and the mix-ture is stirred thoroughly: ~
Gel C is left to stand overn;ght amd is finally ~ made up to a volume of 1Q0 ml by addition of demineral;zed ; uater: ~
Example 3 ;~ 3 g of Carbo ~ are mixed with 20 ml of dem;neralized water, the mixture is carefully neutral-ized by slowly adding a solution of 3 g of diisopropanolam~ne in 10 ml of demineralized water, with stirring, and a homo~eneous suspension is prepared ~2a~3 therefrom by continued stirring: gel A
lO0 mg of insulin are dissolved in 20 ml of demineralized water~ with stirring: s'ol'ut'ion B
100 International Units of hyaluronidase are dissolved in lO ml of demineralized water, wi.th stirrin~:
_olution C
Solution C is slowly added to solution B and the mixture is stirred thoroughly:''solu'tion D
Solution D is slowly added to gel A and the mixture is stirred thoroughly: gel E
Gel E ist left to stand overnight and is finally made up to a volume of lO0 ml by addition of : demineralized water: ~
Example_4 2 g of Carbopol 941 are mixed with 20 ml of demineralized water, the mixture is carefully : neutralized by slowly adding a solution of 2 g of diethanolamine in lO ml of demineralized water, with 20: stirring, and a homogeneous suspension is prepared ; therefrom by continued stirring:' g'el A
200 mg of insulin are dissolved in 25 ml of demineralized water, with stirring:' _olution B
5 ml of Spritamylase SAN (liquid preparation 25 of ~-glucosidase, manufactured by Novo Industrie GmbH, Mainz FRG) are added to 5 ml to water, with stirring-solu'ti'on C
; : SoIution C is slowly added to solution B
and the mixture is stlrred thoroughly: so'lution D
: :Solution D is slowly added to gel A and the mixture is stirred thoroughly:'gel' E
Gel E is left to:stand overnight and is finally brought to a volume Qf 100 ml by addition of demineralized water: ~
~- :
.
~3g~$~
Examples 5 to 8 Component ~ le No.
l. insulin3 crystalline40 mg 80 mg 120 mg 160 mg 2. zinc 2000 ~g 4000 ~g 6000 ~g8000 ~g
3. protamines 40 ~g 80 ~g 120 ~g 160 ~g
4. methyl parahydroxyben~oate25 mg 50 mg 75 mg lO0 mg
5. Carbopol gel 50 g 50 g 50 g 50 g
6. sodium hydroxide -sufficient to provide a pH of 7.3-The Carbopol gel used as component 5 was Carbopol 934phg~
a pharmaceutical grade.
The gels were formed by mixing the Carbopol gel #5 with components 1, 2, 3, 4, and 6 to provide a homonegous gel.
a pharmaceutical grade.
The gels were formed by mixing the Carbopol gel #5 with components 1, 2, 3, 4, and 6 to provide a homonegous gel.
Claims (8)
PROPERTY OF PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A stable, storable insulin product for prophylactic and curative treatment of acne vulgaris by external use, which con-sists of a water-containing gel which - in addition to insulin itself - contains, as the gelling agent, a high molecular weight polyacrylic acid, the carboxyl groups of which are in the form of a salt with a water-soluble inorganic or organic base.
2. An insulin product as claimed in claim 1, wherein a poly-acrylic acid with a molecular weight of about 1 million to about 4 million is used.
3. An insulin product as claimed in claim 1, wherein the carboxyl groups of the polyacrylic acid are in the form of the sodium salt, the ammonium salt or the calcium salt.
4. An insulin product as claimed in claim 1, which contains 0.25 to 25 mg of insulin per ml of gel.
5. An insulin product as claimed in claim 4, which contains 0.50 to 5 mg of insulin per ml of gel.
6. An insulin product as claimed in any one of claims 1, 2 or 3 which also contains hyaluronidase.
7. An insulin product as claimed in any one of claims 1, 2 or 3 which also contains .alpha.-glucosidase.
8. An insulin product as claimed in any one of claims 1, 2 or 3 which also contains hyaluronidase and .alpha.-glucosidase.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH199684 | 1984-04-18 | ||
| CH1996/84 | 1984-04-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1243948A true CA1243948A (en) | 1988-11-01 |
Family
ID=4223461
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000479330A Expired CA1243948A (en) | 1984-04-18 | 1985-04-17 | Stable, storable insulin product for the treatment of acne vulgaris |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0162007A1 (en) |
| JP (1) | JPS60233018A (en) |
| CA (1) | CA1243948A (en) |
| DK (1) | DK173085A (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009134380A3 (en) * | 2008-04-28 | 2009-12-30 | Halozyme, Inc. | Super fast-acting insulin compositions |
| US7829081B2 (en) | 2005-02-23 | 2010-11-09 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases |
| US8202517B2 (en) | 2003-03-05 | 2012-06-19 | Halozyme, Inc. | Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof |
| WO2012174478A3 (en) * | 2011-06-17 | 2013-04-11 | Halozyme, Inc. | Stable formulations of a hyaluronan-degrading enzyme |
| US8557770B2 (en) | 2000-11-29 | 2013-10-15 | Pharmecosse Ltd. | Method of preventing or reducing scarring of human skin |
| AU2013201842B2 (en) * | 2008-04-28 | 2014-10-16 | Halozyme, Inc. | Super fast-acting insulin compositions |
| US9993529B2 (en) | 2011-06-17 | 2018-06-12 | Halozyme, Inc. | Stable formulations of a hyaluronan-degrading enzyme |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63174924A (en) * | 1987-01-14 | 1988-07-19 | Toko Yakuhin Kogyo Kk | Ointment base and ointment |
| IL127209A0 (en) * | 1998-11-23 | 1999-09-22 | Bio Silk Ltd | Composition and method for treatment of hypertrophic skin accumulations and their prevention |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5138412A (en) * | 1974-09-24 | 1976-03-31 | Nippon Kayaku Kk | Kokoseizai no seiho |
-
1985
- 1985-04-15 EP EP85810165A patent/EP0162007A1/en not_active Withdrawn
- 1985-04-17 DK DK173085A patent/DK173085A/en not_active IP Right Cessation
- 1985-04-17 CA CA000479330A patent/CA1243948A/en not_active Expired
- 1985-04-18 JP JP60083588A patent/JPS60233018A/en active Pending
Cited By (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9308240B2 (en) | 2000-11-29 | 2016-04-12 | Pharmecosse Limited | Method of preventing or reducing scarring of human skin |
| US8557770B2 (en) | 2000-11-29 | 2013-10-15 | Pharmecosse Ltd. | Method of preventing or reducing scarring of human skin |
| US8431380B2 (en) | 2003-03-05 | 2013-04-30 | Halozyme, Inc. | Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof |
| US9677061B2 (en) | 2003-03-05 | 2017-06-13 | Halozyme, Inc. | Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof |
| US8202517B2 (en) | 2003-03-05 | 2012-06-19 | Halozyme, Inc. | Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof |
| US10898551B2 (en) | 2003-03-05 | 2021-01-26 | Halozyme, Inc. | Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof |
| US10286044B2 (en) | 2003-03-05 | 2019-05-14 | Halozyme, Inc. | Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof |
| US8431124B2 (en) | 2003-03-05 | 2013-04-30 | Halozyme, Inc. | Methods for treating a disease characterized by an excess of hyaluronan by administering a soluble hyaluronidase glycoprotein (sHASEGP) |
| US8772246B2 (en) | 2003-03-05 | 2014-07-08 | Halozyme, Inc. | Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof |
| US11723959B2 (en) | 2003-03-05 | 2023-08-15 | Halozyme, Inc. | Preparation of mammalian oocyte for fertilization via a soluble human PH20 hyaluronidase polypeptide |
| US8450470B2 (en) | 2003-03-05 | 2013-05-28 | Halozyme, Inc. | Soluble hyaluronidase glycoprotein (sHASEGP), process for preparing the same, uses and pharmaceutical compositions comprising thereof |
| US8765685B2 (en) | 2003-03-05 | 2014-07-01 | Halozyme, Inc. | Methods for treating edema by administering a Soluble Hyaluronidase Glycoprotein (sHASEGP) |
| US9677062B2 (en) | 2003-03-05 | 2017-06-13 | Halozyme, Inc. | Hyaluronidase and factor VIII compositions |
| US9562223B2 (en) | 2003-03-05 | 2017-02-07 | Halozyme, Inc. | Methods for reducing intraocular pressure by administering a soluble hyaluronidase glycoprotein (sHASEGP) |
| US7829081B2 (en) | 2005-02-23 | 2010-11-09 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases |
| US7846431B2 (en) | 2005-02-23 | 2010-12-07 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases |
| US8568713B2 (en) | 2008-04-28 | 2013-10-29 | Halozyme, Inc. | Super fast-acting insulin compositions |
| US9034323B2 (en) | 2008-04-28 | 2015-05-19 | Halozyme, Inc. | Method for control of post-prandial glucose |
| AU2013201842B2 (en) * | 2008-04-28 | 2014-10-16 | Halozyme, Inc. | Super fast-acting insulin compositions |
| EP2705850A3 (en) * | 2008-04-28 | 2014-04-02 | Halozyme, Inc. | Super fast-acting insulin compositions |
| WO2009134380A3 (en) * | 2008-04-28 | 2009-12-30 | Halozyme, Inc. | Super fast-acting insulin compositions |
| AU2009241795B2 (en) * | 2008-04-28 | 2013-05-09 | Halozyme, Inc. | Super fast-acting insulin compositions |
| EA029502B1 (en) * | 2008-04-28 | 2018-04-30 | Галозим, Инк. | Super fast-acting insulin compositions |
| US8318154B2 (en) | 2008-04-28 | 2012-11-27 | Halozyme, Inc. | Super fast-acting insulin compositions |
| JP2011523940A (en) * | 2008-04-28 | 2011-08-25 | ハロザイム インコーポレイテッド | Super fast acting insulin composition |
| US9993529B2 (en) | 2011-06-17 | 2018-06-12 | Halozyme, Inc. | Stable formulations of a hyaluronan-degrading enzyme |
| WO2012174478A3 (en) * | 2011-06-17 | 2013-04-11 | Halozyme, Inc. | Stable formulations of a hyaluronan-degrading enzyme |
Also Published As
| Publication number | Publication date |
|---|---|
| DK173085A (en) | 1985-10-19 |
| EP0162007A1 (en) | 1985-11-21 |
| JPS60233018A (en) | 1985-11-19 |
| DK173085D0 (en) | 1985-04-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10085966B2 (en) | Compositions and methods for skin care | |
| CA2142530C (en) | Topical compositions containing benzoyl peroxide and clindamycin and method of use thereof | |
| BRPI0611713A2 (en) | topical skin care compositions | |
| KR20010013712A (en) | Pharmaceutical preparation containing hydrosoluble ketoprofen salts and their application | |
| JPH08208488A (en) | Skin preparation for external use | |
| CA1243948A (en) | Stable, storable insulin product for the treatment of acne vulgaris | |
| FR2710840B1 (en) | Viscoelastic compositions highly concentrated in fluorinated compounds, their preparation and their uses in the medical and cosmetic fields. | |
| KR20100101123A (en) | Compositions containing at least one naphthoic acid derivative, benzoyl peroxide and at least one film-forming agent | |
| KR20050089740A (en) | Topical formulation for treatment of rosacea | |
| EP2197417A1 (en) | Pharmaceutical composition comprising s-nitrosoglutathione and polysaccharide | |
| EP0338291A1 (en) | Antiinflammatory Gel | |
| BRPI0111142B1 (en) | USE OF BIGUANIDE DERIVATIVES OR ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF FOR MANUFACTURE OF A MEDICINAL PRODUCT HAVING A HEALING EFFECT | |
| US20070154546A1 (en) | Sustained release pharmaceutical compositions | |
| US8404266B2 (en) | Method for stabilization of S-nitrosoglutathione and composition prepared by the same | |
| KR100894364B1 (en) | Amino-acid-based compositions, suitable in therapy for the healing and/or mending of wounds and lesions, in particular for application in the ophthalmic field | |
| EP0881904B1 (en) | Topical pharmaceutical composition containing heparin | |
| US3230143A (en) | Antihypertensive injection methods using acid addition salts of alkyl esters of alpha-methyl-3, 4-dihy-droxyphenylalanine | |
| CA2046412A1 (en) | Treatment of inflammatory diseases with polyoxyethylenesorbitan mono-higher-fatty acid esters | |
| KR100543558B1 (en) | Semisolid pharmaceutical formulation containing dexketoprofen trometamol | |
| JPH03120230A (en) | Percutaneous absorbefacient of drug active ingredient and percutaneous absorption type pharmaceutical | |
| US5696099A (en) | Topical preparations for the treatment of acne and acneiform dermatitis | |
| CA2896038C (en) | Polymer matrix compositions comprising a high concentration of bio-fermented sodium hyaluronate and uses thereof | |
| US20230320984A1 (en) | Tofacitinib-containing anhydrous elastomer-based gel formulations | |
| EA018384B1 (en) | Topical formulation of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate | |
| US5693623A (en) | Topical preparations for the treatment of acne and acneiform dermatitis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |