CA1258231A - Topical pharmaceutical preparations, process for the manufacture thereof, and their application to promote granulation and epithelization of wounds - Google Patents
Topical pharmaceutical preparations, process for the manufacture thereof, and their application to promote granulation and epithelization of woundsInfo
- Publication number
- CA1258231A CA1258231A CA000480688A CA480688A CA1258231A CA 1258231 A CA1258231 A CA 1258231A CA 000480688 A CA000480688 A CA 000480688A CA 480688 A CA480688 A CA 480688A CA 1258231 A CA1258231 A CA 1258231A
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- CA
- Canada
- Prior art keywords
- pharmaceutical preparation
- ions
- preparation according
- calcium
- wounds
- 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
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/0066—Medicaments; Biocides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
- A61L26/0061—Use of materials characterised by their function or physical properties
- A61L26/008—Hydrogels or hydrocolloids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
- A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/412—Tissue-regenerating or healing or proliferative agents
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Dispersion Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
ABSTRACT
New topical preparations promoting the granulation and epithelization of wounds are disclosed. The preparations comprise a pharmacologically compatible carrier and an active component which increases the calcium-permeability of the plasma membrane.
The active component is either a mixture of ionizable calcium and potassium salts or a calcium ionophore and an ionizable calcium salt or a calcium-agonist and a mixture of ionizable calcium and potassium salts. The specification further discloses a process for manufacturing the preparations.
New topical preparations promoting the granulation and epithelization of wounds are disclosed. The preparations comprise a pharmacologically compatible carrier and an active component which increases the calcium-permeability of the plasma membrane.
The active component is either a mixture of ionizable calcium and potassium salts or a calcium ionophore and an ionizable calcium salt or a calcium-agonist and a mixture of ionizable calcium and potassium salts. The specification further discloses a process for manufacturing the preparations.
Description
~S~3Z3~L
D e s c r i p t i o n It is known from in vitro experiments on cell cultures that Ca2+ions exert an influence on the division of cells. (Proc.
Nat. Acad. Sci. 70, p. 675-679). It is also known that the depol-arization of the membrane potential may be realized by raising the extracellular K+-concentration. So far, however, there' have been no studies investigating the influences these effects exert on the granulation and epithelization of wounds. Extensive investiga-tions have shown that neither the Ca2+ concentrations established as being optimal for the growth of cell cultures, nor increased Ca~+ concentrations exert a promoting or inhibiting influence on the healing of wounds.
The addition of physiological amounts of potassium in the extracellular space also does not promote the healing of wounds, not even if at the same time there is provided an optimal extracellular Ca2+ concentration.
Surprisingly it has now first been found that Ca2~ and K+ ions together, in combination with quite specific concentration ratios, exert a surprisingly good, and in ideal molar ratios even highly potent, influence on the granulation and epithelization of wounds, and therefore represent a valuable agent for the promotion of wqund healing.
Accordingly, the present invention provides a topical pharmaceutical preparation for the promotion of granulation and epithelization of wounds, which preparation comprises a pharmaco-logically compatible carrier and . ~
,.~
, . , ~;~51~23~
~g785-1 a mixture of ioni~able pharmacoloyically compatible Ca2 and K
salts in the Ca2 :K molar ratio of about 1:3 to 4:1.
The specific concentration ratios can be achieved i~ we ensure that ~he wound surface comes into immedia~e contact wi~h an aqueous electrolyte which, in relation to ~he water contained in this electrolyte, contalns about 20 to 100 mM Ca2 ions and about 25 to 60 mM K ion~.
la ~'~58Z3~
The electrolyte itself may consist either of wound exudation and/or an aqueous preparation additionally applied to the wound.
In the former case physiologically compatible ioni~able Ca-and K-salts in a molar ratio of 1:3 to 4:1 and with a solid carrier are applied to the wound in a quantity that the Ca-and K-salts will form solutions in the wound e~udation which show the above concentrations. However, the amount o~ wound e~uda tion being variable and not exactly assessable, dry gels, powders, ion exchangers, fleeces, impregnated wound dressings, poly-saccharides or similar dry preparations will not always ensure that the concentrations according to the invention are achieved and can be maintained for a prolonged period of time.
More useful are such preparations which, though being mar-keted in dry form, require to be mixed with a relatively precisely determined amount of water before being used, and which will not be applied to the wound before the required amount of water has been incorporated, and following disso-ciation of the Ca2+ and K+salts. Examples of this group oE
preparations are dry gels according to DE-OS 28 49 570.
Possible would also be mixed forms in which dry carriers right from the start are wetted with water containing Ca2+
and K+ions in the desired ratio. Representatives of this group of forms are, e.g., ion exchangers, gels suitable for gel chromatography (molecular sieves), or simple solid, e.g., textile wound dressings which first are wetted and then are sealed in a sterile way.
The latter preparations are already typical aqueous prepara-tions per se. This would be preparations having mainly water as the carrier and containing Ca 2+ions and K+ions, if desired in addition to other excipients and/or active _ 3 ingredients, in a concentration of 20 to 100 mM, and 25 to 60 mM, respectively. In this case the range of preference would be between 25 and 35 mM Ca2+ions and 35 to 45 mM
K+ions. Particularly preferred is the ratio of 30 mM
Ca ions and 40 mM K ions.
As aqueous preparations may serve all pharmaceutical prepara-tions having a~atercontent which allows to adjust the molar ion concentration according to the invention. Besides simple aqueous solutions, lotions or oil-in-water emulsions these could also be viscous solutions, dispersed systems or foams.
Above mentioned gel-like preparations, such as e.g. poiy-acrylamide/agar gels are particularly well tolerated on wounds and therefore preferred.
Preferred is a process for the production of the above mentioned preparations to prc~Lote the oranulation and epithelization of w~unds, which is characterized by the fact that in a generally known manner Ca2+ and K+ ions forming pharmacologically compatible salts are added to an aqueous pharmaceutical carrier, optionally in addition to other excipients and/or active ingredients, and in relation to the water content up to a concentration of 20 to 100 (mMol) Ca2+ ions and 25 to 60 (mMol) K+ ions by uniformly distributing these ions in the aqueous phase.
Possible pharmacologically compatible salts are mainly chlorides and phosphates, but other inorganic or organic salts, such as e.g. citrates, maleates, succinates or similar salts may also be used if they are tolerated by the tissue and dissociable.
lZ~l~Z3~
~9785-15 In the case of aqueous preparations it is useful to isotonize the aqueous phase. In order to avoid having to use alien ions, isotonization may be brought about preferably by means of glucose. So far unresearched are the possible effects of cationic elec~rolytes added in additisn to Ca2 and K~. In many cases it would also be useful to add tensides to the aqueous phase which increase the permeability of the skin to electrolytes.
Since the effectiveness of the above preparations according to the invention exclusively depends on the claimed ratio of Ca2 to K ions in the extracellular space, of course also such preparations would be fully effective which contain said ions as the exclusive active ingredient. In some cases, however, the addition of further active lngredients will be desirable, such as e.g. antibiotic or fungistatic agents or surface anaesthetics.
By investigating the mechanism of the above mentioned preparations, it has been found that the positive effects for the promotion of wound granulation and epithelization does not only occur in the presence of Ca~+ and K ions but in all cases, where the calcium Permeabillt~ of the cell membrane is increased and thus Ca2 ~ions can flow into the cell.
This can not only be achieved as de~cribed above by uniformly distributing, possibly in addition to other active or auxlliary substances, 0.2 to 10% by weight of a mixture of active substances, consisting of pharmacologically tolerated ionizable Ca2 - and K -salts in the molar Ca2 :K ratio of 1:3 to 4:1, in a pharmacologically tolerated carrier (thus using K -ions for the opening of the so-called calcium channels in the plasma n.embrane), ~'~S~3~
but also by uniformly distributing a calcium-agonist at a concentra~ion of 10 5 ~o 10 9 M in the presence of K -ions at a concentration of 5 x 10 3 to 2 x 10 2 M and Ca at a concentration of 10 3 M to 3 x 10 2 M in a pharmacologically tolerated carrier.
Ca-a~onists act to increase the calcium permeability of the plasma membrane. The calcium channels are opened by them in the presence of potassium. With the use of Ca-agonists according to the lnvention, however, only very little potassium need be applied, so khat, especially in the case o~ wounds o~ large area, the potassium balance is not disturbed. This is an lmprovement compared with the above clescribed use of pure Ca and K ions.
The most effective concentration range of calclum agonists is 10 to 10 M. The required potassium concentration is in the ranye 5 x 10 3 to 2 x 10 2 M. The calcium concentration should be between 10 3 M and 3 x 10 2 M.
Such a calcium agonist is, for example, the suhstance Bay K 8644, of which it is alraady known that it stimulates calcium inflow into the cell [cf. e.g. Arzne:Lmittel~orschung/Drug Res. 33 (II) No. 9 (1983) and Biochem. and Biophys. Research Communic. l1984) 118, No. 3, p. 8~2-47]. It must be regarded as extremely surprising that within the cell calcium is an important factor for wound granulation. The calcium concentration in the extracellular spaGe has no effect whatsoever on wound healing without the agents for i.ncreasing the permeability according to the invention. Neither removal of calclum by the addition of a calcium chelator such as ethylene glycol bis-(~-aminoe~hyl)-,~
~S~323~
697~5-15 N~N,N',N'-tetraacetic acid (EGTA) nor increase of the calcium concentration to 20 times the physiological concentration in the extracellular space leads to any change in wound granulation.
From these data the experts could only conclude that calcium ions do not significantly participate in wound granulation.
The subject of the present invention is therefore a topical pharmaceutlcal preparation for the promotion of granulation and epithelization of wounds, containing a pharmacologically compatible carrier and an active substance which is characterized by the fact that the active suhstance which increases the calcium-permeahillty of the plasma membrane consists of a combination containing 0.2 to 10 percent in weight of an ionizable mixture of pharmacologically compatible Ca2 and K
salts in the Ca2 :K molar ratio of about 1:3 to 4:1.
A further subject of ~he present invention is a pxocess for the preparation of a topical pharmaceutical preparation for the promotion of wvund granulation and epithelization, which is characterized by the fact that within the pharmacologically compatible carrier, op~ionally in addition to other active substances and excipients, there is uniformly distributed the active substances.
The following ~igures illustrate the invention:
From Figure 1 it can be seen that the ~ormation of granulation tissue is essentially independent of the extracellular calcium concentration.
The tests ~orming the basis of Figure 1 were carried out as follows:
~S~Z3~ 69785-15 The skin of the backs of guinea-pigs was severed as far as the fascia~ A teflon ring of diameter 21 mm was sown into the wound. This was intended to prevent epithelial closure of the wound. An aqueous polyacrylamide agar gel containing the active substances in the stated concentrations was applied to the fascia of the back musculature, which was free from granulation tlssue at the time of the operation, for a period of 3 days. After 3 days, when the optimum stage of granulation had been attained, the entire granulation tissue was removed with a sharp spoon, weighed and examined histologically.
By carrying out process a~ compared with the controls, for which said gel was mixed with 0.9 percent in weight sodium chloride ~or isotonlc reasons, the volume of granulation tissue had significantly increased to up to about 180%.
The hlstologic controls showed a true proli~eration of cells, and not only an increase in the cellular volume.
The following examples serve to further lllustrate the invention.
.~
Example 1 Isotonic Solution 80 ml of purified water are introduced into a 100-ml vol-umetric flask. 20 mg benzalkonium chloride are added and dissolved while stirring with a magnetic stirrer. Then are added successively 0.3 g potassium chloride, 0.44 g calcium chloride ~both salts in conformity with Ph.Eur.I.) and
D e s c r i p t i o n It is known from in vitro experiments on cell cultures that Ca2+ions exert an influence on the division of cells. (Proc.
Nat. Acad. Sci. 70, p. 675-679). It is also known that the depol-arization of the membrane potential may be realized by raising the extracellular K+-concentration. So far, however, there' have been no studies investigating the influences these effects exert on the granulation and epithelization of wounds. Extensive investiga-tions have shown that neither the Ca2+ concentrations established as being optimal for the growth of cell cultures, nor increased Ca~+ concentrations exert a promoting or inhibiting influence on the healing of wounds.
The addition of physiological amounts of potassium in the extracellular space also does not promote the healing of wounds, not even if at the same time there is provided an optimal extracellular Ca2+ concentration.
Surprisingly it has now first been found that Ca2~ and K+ ions together, in combination with quite specific concentration ratios, exert a surprisingly good, and in ideal molar ratios even highly potent, influence on the granulation and epithelization of wounds, and therefore represent a valuable agent for the promotion of wqund healing.
Accordingly, the present invention provides a topical pharmaceutical preparation for the promotion of granulation and epithelization of wounds, which preparation comprises a pharmaco-logically compatible carrier and . ~
,.~
, . , ~;~51~23~
~g785-1 a mixture of ioni~able pharmacoloyically compatible Ca2 and K
salts in the Ca2 :K molar ratio of about 1:3 to 4:1.
The specific concentration ratios can be achieved i~ we ensure that ~he wound surface comes into immedia~e contact wi~h an aqueous electrolyte which, in relation to ~he water contained in this electrolyte, contalns about 20 to 100 mM Ca2 ions and about 25 to 60 mM K ion~.
la ~'~58Z3~
The electrolyte itself may consist either of wound exudation and/or an aqueous preparation additionally applied to the wound.
In the former case physiologically compatible ioni~able Ca-and K-salts in a molar ratio of 1:3 to 4:1 and with a solid carrier are applied to the wound in a quantity that the Ca-and K-salts will form solutions in the wound e~udation which show the above concentrations. However, the amount o~ wound e~uda tion being variable and not exactly assessable, dry gels, powders, ion exchangers, fleeces, impregnated wound dressings, poly-saccharides or similar dry preparations will not always ensure that the concentrations according to the invention are achieved and can be maintained for a prolonged period of time.
More useful are such preparations which, though being mar-keted in dry form, require to be mixed with a relatively precisely determined amount of water before being used, and which will not be applied to the wound before the required amount of water has been incorporated, and following disso-ciation of the Ca2+ and K+salts. Examples of this group oE
preparations are dry gels according to DE-OS 28 49 570.
Possible would also be mixed forms in which dry carriers right from the start are wetted with water containing Ca2+
and K+ions in the desired ratio. Representatives of this group of forms are, e.g., ion exchangers, gels suitable for gel chromatography (molecular sieves), or simple solid, e.g., textile wound dressings which first are wetted and then are sealed in a sterile way.
The latter preparations are already typical aqueous prepara-tions per se. This would be preparations having mainly water as the carrier and containing Ca 2+ions and K+ions, if desired in addition to other excipients and/or active _ 3 ingredients, in a concentration of 20 to 100 mM, and 25 to 60 mM, respectively. In this case the range of preference would be between 25 and 35 mM Ca2+ions and 35 to 45 mM
K+ions. Particularly preferred is the ratio of 30 mM
Ca ions and 40 mM K ions.
As aqueous preparations may serve all pharmaceutical prepara-tions having a~atercontent which allows to adjust the molar ion concentration according to the invention. Besides simple aqueous solutions, lotions or oil-in-water emulsions these could also be viscous solutions, dispersed systems or foams.
Above mentioned gel-like preparations, such as e.g. poiy-acrylamide/agar gels are particularly well tolerated on wounds and therefore preferred.
Preferred is a process for the production of the above mentioned preparations to prc~Lote the oranulation and epithelization of w~unds, which is characterized by the fact that in a generally known manner Ca2+ and K+ ions forming pharmacologically compatible salts are added to an aqueous pharmaceutical carrier, optionally in addition to other excipients and/or active ingredients, and in relation to the water content up to a concentration of 20 to 100 (mMol) Ca2+ ions and 25 to 60 (mMol) K+ ions by uniformly distributing these ions in the aqueous phase.
Possible pharmacologically compatible salts are mainly chlorides and phosphates, but other inorganic or organic salts, such as e.g. citrates, maleates, succinates or similar salts may also be used if they are tolerated by the tissue and dissociable.
lZ~l~Z3~
~9785-15 In the case of aqueous preparations it is useful to isotonize the aqueous phase. In order to avoid having to use alien ions, isotonization may be brought about preferably by means of glucose. So far unresearched are the possible effects of cationic elec~rolytes added in additisn to Ca2 and K~. In many cases it would also be useful to add tensides to the aqueous phase which increase the permeability of the skin to electrolytes.
Since the effectiveness of the above preparations according to the invention exclusively depends on the claimed ratio of Ca2 to K ions in the extracellular space, of course also such preparations would be fully effective which contain said ions as the exclusive active ingredient. In some cases, however, the addition of further active lngredients will be desirable, such as e.g. antibiotic or fungistatic agents or surface anaesthetics.
By investigating the mechanism of the above mentioned preparations, it has been found that the positive effects for the promotion of wound granulation and epithelization does not only occur in the presence of Ca~+ and K ions but in all cases, where the calcium Permeabillt~ of the cell membrane is increased and thus Ca2 ~ions can flow into the cell.
This can not only be achieved as de~cribed above by uniformly distributing, possibly in addition to other active or auxlliary substances, 0.2 to 10% by weight of a mixture of active substances, consisting of pharmacologically tolerated ionizable Ca2 - and K -salts in the molar Ca2 :K ratio of 1:3 to 4:1, in a pharmacologically tolerated carrier (thus using K -ions for the opening of the so-called calcium channels in the plasma n.embrane), ~'~S~3~
but also by uniformly distributing a calcium-agonist at a concentra~ion of 10 5 ~o 10 9 M in the presence of K -ions at a concentration of 5 x 10 3 to 2 x 10 2 M and Ca at a concentration of 10 3 M to 3 x 10 2 M in a pharmacologically tolerated carrier.
Ca-a~onists act to increase the calcium permeability of the plasma membrane. The calcium channels are opened by them in the presence of potassium. With the use of Ca-agonists according to the lnvention, however, only very little potassium need be applied, so khat, especially in the case o~ wounds o~ large area, the potassium balance is not disturbed. This is an lmprovement compared with the above clescribed use of pure Ca and K ions.
The most effective concentration range of calclum agonists is 10 to 10 M. The required potassium concentration is in the ranye 5 x 10 3 to 2 x 10 2 M. The calcium concentration should be between 10 3 M and 3 x 10 2 M.
Such a calcium agonist is, for example, the suhstance Bay K 8644, of which it is alraady known that it stimulates calcium inflow into the cell [cf. e.g. Arzne:Lmittel~orschung/Drug Res. 33 (II) No. 9 (1983) and Biochem. and Biophys. Research Communic. l1984) 118, No. 3, p. 8~2-47]. It must be regarded as extremely surprising that within the cell calcium is an important factor for wound granulation. The calcium concentration in the extracellular spaGe has no effect whatsoever on wound healing without the agents for i.ncreasing the permeability according to the invention. Neither removal of calclum by the addition of a calcium chelator such as ethylene glycol bis-(~-aminoe~hyl)-,~
~S~323~
697~5-15 N~N,N',N'-tetraacetic acid (EGTA) nor increase of the calcium concentration to 20 times the physiological concentration in the extracellular space leads to any change in wound granulation.
From these data the experts could only conclude that calcium ions do not significantly participate in wound granulation.
The subject of the present invention is therefore a topical pharmaceutlcal preparation for the promotion of granulation and epithelization of wounds, containing a pharmacologically compatible carrier and an active substance which is characterized by the fact that the active suhstance which increases the calcium-permeahillty of the plasma membrane consists of a combination containing 0.2 to 10 percent in weight of an ionizable mixture of pharmacologically compatible Ca2 and K
salts in the Ca2 :K molar ratio of about 1:3 to 4:1.
A further subject of ~he present invention is a pxocess for the preparation of a topical pharmaceutical preparation for the promotion of wvund granulation and epithelization, which is characterized by the fact that within the pharmacologically compatible carrier, op~ionally in addition to other active substances and excipients, there is uniformly distributed the active substances.
The following ~igures illustrate the invention:
From Figure 1 it can be seen that the ~ormation of granulation tissue is essentially independent of the extracellular calcium concentration.
The tests ~orming the basis of Figure 1 were carried out as follows:
~S~Z3~ 69785-15 The skin of the backs of guinea-pigs was severed as far as the fascia~ A teflon ring of diameter 21 mm was sown into the wound. This was intended to prevent epithelial closure of the wound. An aqueous polyacrylamide agar gel containing the active substances in the stated concentrations was applied to the fascia of the back musculature, which was free from granulation tlssue at the time of the operation, for a period of 3 days. After 3 days, when the optimum stage of granulation had been attained, the entire granulation tissue was removed with a sharp spoon, weighed and examined histologically.
By carrying out process a~ compared with the controls, for which said gel was mixed with 0.9 percent in weight sodium chloride ~or isotonlc reasons, the volume of granulation tissue had significantly increased to up to about 180%.
The hlstologic controls showed a true proli~eration of cells, and not only an increase in the cellular volume.
The following examples serve to further lllustrate the invention.
.~
Example 1 Isotonic Solution 80 ml of purified water are introduced into a 100-ml vol-umetric flask. 20 mg benzalkonium chloride are added and dissolved while stirring with a magnetic stirrer. Then are added successively 0.3 g potassium chloride, 0.44 g calcium chloride ~both salts in conformity with Ph.Eur.I.) and
2.62 g glucose monohydrate (Ph.Eur.II.). The temperature of the flask is adjusted to 20C in a water bath, and the flask then filled to volume with purified water which also has a temperature of 20C. Subsequently the solution is filtered sterile through a membrane filter of 0.2 ~m pore size and bottled sterileO
rO.29822 g KCl 40 mMol K+
0.44106 g CaC12 30 mMol Ca2+~
~Z~3Z3~
~..
Example 2 Oil-in-Water Emulsion In a first batch 7 g of a mixture consisting of saturated fatty acids, ~a~ty alcohols, lanolin, mineral oils and nonionogenic emulsifying agents are melted homogeneously together with 2.5 g polyethylene glycol glycerol fatty acid ester, 3 g monoglycerides of stearinic and palmitic acid, 0.3 g cetyl alcohol and 3.0 g isopropyl palmitate by heating to 70C in a water bath.
In a second batch 80 g purified water are mixed with 3 g propylene glycol while stirring and heated to 70C. The mixture so obtained is then mixed with 0.3 g potassium chloride, 0.44 g calcium chloride and 0.2 g of a preser-vative. The resultant clear solution is emulsified into the first batch while stirring at 70C. The resultant emulsion is cooled to 40C and the water loss from evaporation is made up. When cooled to 30C the emulsion is bottled.
5823~
~ . .
Example 3 Transparent Liquid Dressinq Material (Gel Disk) Batch A:
rO.29822 g KCl 40 mMol K+
0.44106 g CaC12 30 mMol Ca2+~
~Z~3Z3~
~..
Example 2 Oil-in-Water Emulsion In a first batch 7 g of a mixture consisting of saturated fatty acids, ~a~ty alcohols, lanolin, mineral oils and nonionogenic emulsifying agents are melted homogeneously together with 2.5 g polyethylene glycol glycerol fatty acid ester, 3 g monoglycerides of stearinic and palmitic acid, 0.3 g cetyl alcohol and 3.0 g isopropyl palmitate by heating to 70C in a water bath.
In a second batch 80 g purified water are mixed with 3 g propylene glycol while stirring and heated to 70C. The mixture so obtained is then mixed with 0.3 g potassium chloride, 0.44 g calcium chloride and 0.2 g of a preser-vative. The resultant clear solution is emulsified into the first batch while stirring at 70C. The resultant emulsion is cooled to 40C and the water loss from evaporation is made up. When cooled to 30C the emulsion is bottled.
5823~
~ . .
Example 3 Transparent Liquid Dressinq Material (Gel Disk) Batch A:
3.5 9 acrylamide and 0.091 9 bisacrylamide are dissolved in 100 ml purified water. The temperature of the solution is adjusted to 60C.
Batch B:
0.3 g potassium chloride and 0.44 9 calcium chloride are dissolved in 100 ml purified water and mixed with 0.2 g preservative. After adding 2 9 agar-agar (OAB9) the solution is heated to boiling while stirring with a magnetic stirrer, and afterwards cooled to 60C.
Subsequently batches A and B are mixed at 60C while stirring.
Then 0.045 9 ammonium peroxydisulfite and 0.0~5 9 (60 ~1) tetramethylene diamine are added. After a brief period of vigorous stirring the mixture is poured in~o Petri dishes previously heated to 60C in the heating cabinet. The filled Petri dishes are then placed into a heating cabinet set to 56C for 30 min. The temperature is then lowered to room temperature and the dishes with the transparent solidified disks placed into a cabinet set to a temperature of 4C for 24 hrs. for maturing. The disks so obtained may immediately be used to cover wounds.
S~123~
Example 4 Ready-to-Use Gel 94 g purified water are heated to 70C and-mixed with 0.3 g potassium chloride and 0O44 g calcium chloride. After adding 0.2 g preservative, 5 g methylhydroxyethylcellulose are dis-persed in the solution 50 obtained. Then the mixture is cooled while stirring. When cool the product is a highly viscous gel interspersed with air bubbles and of a viscosity of 90 Pa.s, which is ready to use on wounds.
~S8;~3~
Example_5 Textile Wound Dressin~
Sterile gauze pads, 4 x 4 cm large and 5 mm thick, are dipped into the sterile isotonic solution obtained according to Example 1 and then squeezed out only so much that the pads do no longer drip. The pads thus obtained are then sealed into polyethylene foils under sterile conditions.
:L~S8Z3~
Example 6 Spreadable ~el_with_~c K 8644 1000 g of purified water are heated to 70C and treated with 1.49 g of KCl, 3.3 g of CaC12 and 3.56 mg of Bay K 8644.
After the addition of 2 g of preservative 50 g of methyl hydroxy-ethylcellulose are dispersed into the solution obtalned and the mixture is worked up as descrlbed in Example 1.
F
Batch B:
0.3 g potassium chloride and 0.44 9 calcium chloride are dissolved in 100 ml purified water and mixed with 0.2 g preservative. After adding 2 9 agar-agar (OAB9) the solution is heated to boiling while stirring with a magnetic stirrer, and afterwards cooled to 60C.
Subsequently batches A and B are mixed at 60C while stirring.
Then 0.045 9 ammonium peroxydisulfite and 0.0~5 9 (60 ~1) tetramethylene diamine are added. After a brief period of vigorous stirring the mixture is poured in~o Petri dishes previously heated to 60C in the heating cabinet. The filled Petri dishes are then placed into a heating cabinet set to 56C for 30 min. The temperature is then lowered to room temperature and the dishes with the transparent solidified disks placed into a cabinet set to a temperature of 4C for 24 hrs. for maturing. The disks so obtained may immediately be used to cover wounds.
S~123~
Example 4 Ready-to-Use Gel 94 g purified water are heated to 70C and-mixed with 0.3 g potassium chloride and 0O44 g calcium chloride. After adding 0.2 g preservative, 5 g methylhydroxyethylcellulose are dis-persed in the solution 50 obtained. Then the mixture is cooled while stirring. When cool the product is a highly viscous gel interspersed with air bubbles and of a viscosity of 90 Pa.s, which is ready to use on wounds.
~S8;~3~
Example_5 Textile Wound Dressin~
Sterile gauze pads, 4 x 4 cm large and 5 mm thick, are dipped into the sterile isotonic solution obtained according to Example 1 and then squeezed out only so much that the pads do no longer drip. The pads thus obtained are then sealed into polyethylene foils under sterile conditions.
:L~S8Z3~
Example 6 Spreadable ~el_with_~c K 8644 1000 g of purified water are heated to 70C and treated with 1.49 g of KCl, 3.3 g of CaC12 and 3.56 mg of Bay K 8644.
After the addition of 2 g of preservative 50 g of methyl hydroxy-ethylcellulose are dispersed into the solution obtalned and the mixture is worked up as descrlbed in Example 1.
F
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A topical pharmaceutical preparation for the promotion of granulation and epithelization of wounds, which preparation comprises, in a pharmacologically compatible carrier, an ionizable pharmacologically compatible mixture of Ca2+ and K+ salts in the Ca2+:K+ molar ratio of about 1:3 to 4:1.
2. A pharmaceutical preparation according to claim 1 comprising an ionizable pharmacologically compatible mixture of from about 20 to 100 mM Ca2+ ions and from about 25 to 60 mM K+
ions.
ions.
3. A pharmaceutical preparation according to claim 1 wherein the carrier is aqueous.
4. A pharmaceutical preparation according to claim 1 or 2 wherein the carrier is a hydrated gel.
5. A pharmaceutical preparation according to claim 1 or 2 wherein the carrier is a dry gel.
6. A pharmaceutical preparation according to claim 1 or 2 wherein the carrier is aqueous and the mixture of Ca2+ and K+
salts is present in an amount from 0.2 to 10 percent by weight.
salts is present in an amount from 0.2 to 10 percent by weight.
7. A pharmaceutical preparation according to claim 1 or 2 which contains about 30 mM Ca2+ ions and about 40 mM K+ ions.
8. A pharmaceutical preparation according to claim 1, 2 or 3 wherein the K+ ions are supplied as potassium chloride, phosphate, citrate, maleate or succinate.
9. A pharmaceutical preparation according to claim 1, 2 or 3 wherein the Ca2+ ions are supplied as calcium chloride, phosphate, citrate, maleate or succinate.
10. A pharmaceutical preparation according to claim 1, 2 or 3 wherein a Ca2+-agonist which is the substance Bay K 8644 is also present in the preparation.
11. A pharmaceutical preparation according to claim 1, 2 or 3 which also contains an antibiotic, a fungistatic agent or a surface anaesthetic.
12. A pharmaceutical preparation according to claim 3 wherein the hydrated gel contains methylhydroxyethyl cellulose.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3416777A DE3416777C2 (en) | 1984-05-07 | 1984-05-07 | Topical pharmaceutical preparations |
| DEP3416777.3 | 1984-05-07 | ||
| DEP3435113.2 | 1984-09-25 | ||
| DE19843435113 DE3435113A1 (en) | 1984-05-07 | 1984-09-25 | PHARMACEUTICAL TOPICAL PREPARATIONS FOR PROMOTING WOUND GRANULATION AND EPITHELISATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1258231A true CA1258231A (en) | 1989-08-08 |
Family
ID=25820959
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000480688A Expired CA1258231A (en) | 1984-05-07 | 1985-05-03 | Topical pharmaceutical preparations, process for the manufacture thereof, and their application to promote granulation and epithelization of wounds |
Country Status (16)
| Country | Link |
|---|---|
| EP (1) | EP0165430B1 (en) |
| AU (1) | AU570558B2 (en) |
| CA (1) | CA1258231A (en) |
| CS (1) | CS257788B2 (en) |
| DD (1) | DD232819A5 (en) |
| DE (2) | DE3435113A1 (en) |
| DK (1) | DK201785A (en) |
| ES (1) | ES8607734A1 (en) |
| FI (1) | FI81260C (en) |
| GR (1) | GR851098B (en) |
| HU (1) | HU196902B (en) |
| IL (1) | IL74897A (en) |
| NO (1) | NO851793L (en) |
| NZ (1) | NZ211994A (en) |
| PH (1) | PH21464A (en) |
| YU (1) | YU44497B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3614095A1 (en) * | 1986-04-25 | 1987-10-29 | Goedecke Ag | OXYALKYLCELLULOSE CONTAINING GEL PREPARATION |
| FR2725901B1 (en) * | 1994-10-25 | 1997-06-27 | Thorel Jean Noel | USE OF CALCIUM IN COSMETOLOGY IN THE LOCAL TREATMENT OF IRRITATIVE PHENOMENA |
| FR2726187A1 (en) * | 1994-10-26 | 1996-05-03 | Jean Noel Thorel | Topical compsns. contg. calcium chloride |
| DE4447586C2 (en) * | 1994-11-07 | 1998-12-24 | Max Planck Gesellschaft | Use of ionophores as effectors of PTPases |
| DE4439662C2 (en) * | 1994-11-07 | 1997-10-02 | Max Planck Gesellschaft | Method for determining the activity of phosphotyrosine phosphatases and for identifying effectors thereof |
| US7404967B2 (en) | 1994-12-21 | 2008-07-29 | Cosmederm, Inc. | Topical product formulations containing strontium for reducing skin irritation |
| AU4690196A (en) * | 1994-12-21 | 1996-07-10 | Cosmederm Technologies | Formulations and methods for reducing skin irritation |
| AU5929499A (en) * | 1998-08-11 | 2000-03-06 | Susanna Elizabeth Chalmers | A wound treatment composition and a wound dressing containing it |
| DE102007002073A1 (en) | 2007-01-09 | 2008-07-10 | Matthias Habenicht | Medium for use during care and antimicrobial treatment of skin, for topical dermatological application, and for therapeutic skin and sore treatment, comprises benzalkonium chloride, which is basically exclusive pharmaceutically active |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2725261C2 (en) * | 1977-06-03 | 1986-10-09 | Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V., 3400 Göttingen | Transparent liquid dressing material, its manufacture and use |
-
1984
- 1984-09-25 DE DE19843435113 patent/DE3435113A1/en not_active Withdrawn
-
1985
- 1985-04-15 IL IL74897A patent/IL74897A/en unknown
- 1985-05-02 PH PH32222A patent/PH21464A/en unknown
- 1985-05-03 CA CA000480688A patent/CA1258231A/en not_active Expired
- 1985-05-03 FI FI851754A patent/FI81260C/en not_active IP Right Cessation
- 1985-05-05 CS CS853235A patent/CS257788B2/en unknown
- 1985-05-06 HU HU851703A patent/HU196902B/en not_active IP Right Cessation
- 1985-05-06 NO NO851793A patent/NO851793L/en unknown
- 1985-05-06 ES ES542846A patent/ES8607734A1/en not_active Expired
- 1985-05-06 NZ NZ211994A patent/NZ211994A/en unknown
- 1985-05-06 DD DD85276046A patent/DD232819A5/en not_active IP Right Cessation
- 1985-05-06 DK DK201785A patent/DK201785A/en not_active Application Discontinuation
- 1985-05-06 YU YU746/85A patent/YU44497B/en unknown
- 1985-05-07 EP EP85105587A patent/EP0165430B1/en not_active Expired
- 1985-05-07 DE DE8585105587T patent/DE3569197D1/en not_active Expired
- 1985-05-07 GR GR851098A patent/GR851098B/el unknown
- 1985-05-07 AU AU42041/85A patent/AU570558B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| DD232819A5 (en) | 1986-02-12 |
| YU74685A (en) | 1988-10-31 |
| CS257788B2 (en) | 1988-06-15 |
| GR851098B (en) | 1985-11-25 |
| DK201785D0 (en) | 1985-05-06 |
| DE3435113A1 (en) | 1986-04-03 |
| FI81260B (en) | 1990-06-29 |
| FI851754L (en) | 1985-11-08 |
| EP0165430A1 (en) | 1985-12-27 |
| PH21464A (en) | 1987-10-28 |
| CS323585A2 (en) | 1987-09-17 |
| AU4204185A (en) | 1985-11-14 |
| ES8607734A1 (en) | 1986-06-01 |
| FI81260C (en) | 1990-10-10 |
| HU196902B (en) | 1989-02-28 |
| YU44497B (en) | 1990-08-31 |
| DK201785A (en) | 1985-11-08 |
| EP0165430B1 (en) | 1989-04-05 |
| DE3569197D1 (en) | 1989-05-11 |
| NO851793L (en) | 1985-11-08 |
| IL74897A (en) | 1989-09-10 |
| IL74897A0 (en) | 1985-07-31 |
| HUT38247A (en) | 1986-05-28 |
| NZ211994A (en) | 1988-04-29 |
| FI851754A0 (en) | 1985-05-03 |
| AU570558B2 (en) | 1988-03-17 |
| ES542846A0 (en) | 1986-06-01 |
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| MKEX | Expiry |