Aluminium panthenolate and zinc panthenolate, their manufacture and use as topical medicaments are described.

SUMMARY OF THE INVENTION 
The present invention is concerned with panthenol derivatives. More 
particularly, the invention is concerned with novel salts of panthenol, 
namely aluminium D- or DL-panthenolate and zinc D- or DL-panthenolate. 
The invention is also concerned with the manufacture of these compounds and 
their use as topical medicaments for promoting the healing of wounds. 
DETAILED DESCRIPTION OF THE INVENTION 
The invention is concerned with panthenol derivatives. These compounds have 
the formula: 
D or DL 
##STR1## 
wherein Me is aluminium and n is the integer 3, or 
Me is zinc and n is the integer 2. 
The invention is also concerned with the manufacture of the compounds of 
formula I and their use as topical medicaments. 
The compounds of formula I can be manufactured by reacting D- or 
DL-panthenol of the formula 
##STR2## 
with a compound of the formula 
EQU (R).sub.3 Al III 
EQU (R).sub.2 AlH IV 
wherein 
R is a C.sub.1 -C.sub.12 -alkyl or C.sub.1 -C.sub.12 -alkoxy group, 
in the molar ratio 3:1 or with a compound of the formula 
EQU (R).sub.2 Zn V 
wherein 
R is as above, 
in the molar ration 2:1. 
In the specification the terms "alkyl" or "C.sub.1 -C.sub.12 alkyl" signify 
straight-chain and branched-chain alkyl groups containing 1 to 12 carbon 
atoms, preferably those containing 2-8 carbon atoms. Typical examples are 
ethyl, propyl, isopropyl, n-butyl, isobutyl, tert butyl, pentyl, hexyl 
etc. Triisobutylaluminium is an especially preferred alkylaluminium 
compound and diethylzinc is an especially preferred alkylzinc compound. 
The term "lower alkyl" signifies alkyl moieties containing 1-6 carbon 
atoms. 
The terms "alkoxy" or "C.sub.1 -C.sub.12 -alkoxy" signify alkoxy groups in 
which the alkyl residue has the significance given above. The compounds of 
formulae III-V in which R signifies alkoxy are alcoholates, there being 
preferred those which are derived from alcohols having a boiling point 
below 118.degree.-120.degree. C. at 10.sup.-2 Torr. Aluminium isopropylate 
and zinc isopropylate are preferred alcoholates. 
The reaction of D- or DL-panthenol with a compound of formulae III-V in 
which R signifies alkyl can conveniently be carried out in an aprotic 
anhydrous solvent and under a dry protective gas such as nitrogen or 
argon. Suitable solvents are, for example, aliphatic hydrocarbons such as 
hexane or heptane, aromatic hydrocarbons such as benzene or toluene, 
chlorinated hydrocarbons such as methylene chloride or chlorobenzene, 
ethers such as diethyl ether or anisole and the like. The reaction 
generally proceeds rapidly and quantitatively. Since the hydrocarbons and 
the hydrogen formed are either gases or low-boiling liquids, these can be 
separated readily. When pure starting materials are used, the reaction 
proceeds in one step directly to analytically pure products which do not 
require further purification. 
For the manufacture of aluminium D-panthenolate, D-panthenol is preferably 
reacted with triisobutylaluminium. For the manufacture of the DL-form, 
DL-panthenol is used as the starting material. In place of 
triisobutylaluminium there can also be used a bis(lower alkyl)aluminium 
hydride compound, preferably diisobutylaluminium hydride. 
For the manufacture of zinc D-panthenolate, D-panthenol is preferably 
reacted with diethylzinc. For the manufacture of the DL-form, DL-panthenol 
is used as the starting material. 
The reaction of D- or DL-panthenol with a compound of formulae III-V in 
which R signifies alkoxy comprises reacting an alcoholate of aluminium or 
of zinc with the panthenol. Thereby, such alcohol ROH is displaced by the 
panthenol and this proceeds especially well when the alcohol to be 
displaced has a boiling point lower than that of panthenol. In this 
process there can likewise be used the previously mentioned solvents, but 
it is advantageous to carry out the reaction in a solvent which forms an 
azeotrope with the alcohol ROH which is to be removed from the reaction 
mixture. When pure starting materials are used, analytically pure end 
products are obtained directly in this manner in one reaction step after 
separation of the alcohol ROH and the solvent. 
For the manufacture of aluminium D-panthenolate, D-panthenol is preferably 
reacted with aluminium isopropylate. For the manufacture of zinc 
D-panthenolate, D-panthenol is preferably reacted with zinc isopropylate. 
For the manufacture of the DL-forms DL-panthenol is used as the starting 
material. 
The starting materials used in the process provided by the invention are 
either known and, in part, can be purchased in sufficient purity or can be 
prepared in an analogous manner to the known compounds. 
The compounds of formula I provided by the invention, which have been found 
to have a very low toxicity in mice, come into consideration as topical 
medicaments. The compounds of formula I have been found to be practically 
non-irritating to the skin and to be non-allergic in guinea pigs, which is 
an extraordinarily favorable characteristic for a topical medicament to 
possess. 
The topical medicaments provided by the invention especially enhance the 
healing of soft tissue (e.g. skin, mucous membrane) wounds in mammals. The 
term "wounds" includes surgical incisions, abrasions, scratches, 
lacerations, cuts, punctures, ulcers, fissures, tears, sores, blisters, 
burns, ruptures and the like. 
More specifically, the inventive medicaments promote the healing and 
epithelization of wounds. For example, the medicaments are useful in 
treating burns, scratches and cuts, chronic ulcers, bedsores and anal 
fissures and for after-treatment following skin transplants and operative 
measures in the case of cervix erosions. The compounds provided by the 
invention are also suitable for the prophylaxis and therapy of 
anticipatable wounds such as cracked nipples, diaper or napkin rash and 
sunburn. Furthermore, it has been shown that the tensile strength of 
operation scars increases significantly when the compound provided by the 
invention are used. Quite generally, when the compounds provided by the 
invention are used a more rapid and better healing of wounds is achieved. 
It has also been established that the compounds provided by the invention 
have an inhibiting effect on the growth of suppurative organisms. That is, 
they have an antiseptic activity, and surprisingly at the same time they 
bring about an activation of the macrophages. 
Although the D- or DL-forms can be used in accordance with the invention, 
the D-isomers of the inventive compounds are preferred. 
In accordance with the invention, one or more compounds of formula I are 
applied topically to the soft tissue of a mammal at the site of the wound. 
The compounds of formula I are conveniently used in the form of 
pharmaceutical preparations or compositions which contain an effective 
amount of compound I and a pharmaceutically acceptable carrier material 
which is suitable for topical administration to the wound site. Topical 
dosage forms provided by the invention generally contain about 0.1 to 10 
weight percent, preferably 0.5 to 5 weight percent, of a compound of 
formula I, based on the total weight of the dosage form. However, higher 
or lower concentrations can also be present depending on the dosage form 
which is used. The inventive topical preparations can be applied to the 
wound site in an amount and under a time schedule varying withthe needs of 
the patient. For example, the preparations can be applied to the wound 
site once or twice a day or more often, if needed. 
The term "topical" as used in the present specification relates to the use 
of the active ingredient of formula I, which is processed with a suitable 
carrier material and which is applied to the skin or mucous membrane, so 
that it can display local activity. Accordingly, the topical medicaments 
embrace pharmaceutical dosage forms which are suitable for external use, 
so that a direct contact with the skin results. The topical dosage forms 
embrace gels, creams, lotions, salves, powders, aerosols and other 
conventional forms which are suitable for the direct application of 
medicaments to the skin or mucous membrane. These dosage forms can be 
manufactured by mixing compound of formula I with known pharmaceutical 
carrier materials which are suitable for topical use. 
Salves and creams contain oily, absorbent, water-soluble and/or emulsifying 
carrier materials such as vaseline, paraffin oil, propylene glycol, cetyl 
alcohol, glycerine monostearate, alkyl-branched fatty acids and the like. 
Lotions are liquid preparations and can vary from simple solutions to 
aqueous or aqueous/alcoholic preparations which contain the substances in 
finely divided form. The preparations contain suspending or dispersing 
substances such as, for example, sodium carboxymethylcellulose which 
suspend or disperse the active substance in a carrier prepared from water, 
alcohol, glycerine and the like. 
Gels are semi-solid preparations which are obtained by gelling a solution 
or suspension of the active substance in a carrier material. The carrier 
materials, which can be hydrophilic or hydrophobic, are gelled using a 
gelling agent such as Carbopol and the like. 
Aerosols are solutions or suspensions of the active substance in an inert 
carrier material which are applied using spray generators. Usually used 
carriers are trichloromonofluoromethane and trichlorodifluoromethane.

The following examples further illustrate the invention. Unless indicated 
otherwise, temperature is expressed in degrees Celsius (.degree.C.) and 
the examples were performed and compositions were prepared as written. 
Neo-PCL and Neo-PCL (water soluble) are preparations made by Dragoco 
located at Holzminden, Germany. Aerosil 200 is silicon dioxide 
manufactured by Degussa, Frankfurt, Germany. 
EXAMPLE 1 
72.8 g (354.7 mmol) of D-panthenol and 400 ml of absolute dichloromethane 
are added at room temperature under an inert gas to a 1 liter four-necked 
flask provided with a powerful stirrer, 250 ml dropping funnel with 
pressure balance and reflux condenser, as well as an apparatus for working 
under a protective gas. Since the D-panthenol dissolves poorly in 
dichloromethane, the mixture is stirred very vigorously and cooled to 
50.degree. C. in an ice-bath. To this emulsion there are added dropwise 
within 1 hour 23.46 g (30.0 ml, 118.2 mmol) of tri-isobutylaluminium 
dissolved in 150 ml of absolute toluene. A white stirrable mass is thereby 
obtained. After completion of the addition, the mixture is left to warm to 
room temperature, then warmed to 60.degree. C. (bath temperature) and the 
dichloromethane is distilled off. The mixture is then heated for 2 hours 
at the reflux temperature of the toluene. After cooling to about 
50.degree. C., the toluene is removed under a water-jet vacuum and the 
residue is dried up to constant weight under an oil pump vacuum. The 
residue is dried for 24 hours at 50.degree. C. in a vacuum drying oven 
under an oil pump vacuum, the product thereby gradually becoming solid. 
After cooling, the colourless amorphous mass can be pulverized in a mortar 
to a white powder which is slightly hydgroscopic. There are obtained 73.24 
g of aluminium D-panthenolate having a melting interval of 
78.degree.-82.degree. C. and a specific rotation of [.alpha.].sub.D.sup.20 
=+47.8.degree. (c=1 in dimethyl sulphoxide). 
EXAMPLE 2 
(a) 9.1 ml (7.1 g; about 118.3 mmol) of absolute isopropanol and 300 ml of 
absolute n-hexane are added to a 500 ml three-necked flask, provided with 
a dropping funnel, stirrer and apparatus for working under a protective 
gas, and the mixture is cooled to about 5.degree. C. A solution of 10 ml 
(7.82 g; about 39.4 mmol) of triisobutylaluminium in 60 ml of absolute 
n-hexane is added dropwise while stirring well. Thereafter, the cooling 
bath is removed and the temperature in the reaction flask is allowed to 
come to room temperature. The mixture is then warmed at 50.degree. C. for 
2 hours. In this manner there is obtained a clear solution of aluminium 
isopropylate in n-hexane. 
(b) 24.3 g (118.3 mmol) of D-panthenol are placed in a similar apparatus so 
that described in paragraph (a). Thereto there is added the aluminium 
isopropylate solution in n-hexane prepared as described in paragraph (a). 
The mixture is stirred at room temperature for 2 hours and heated under 
reflux for 4 hours. Thereafter, n-hexane and isopropanol are distilled off 
at normal pressure. From the dropping funnel there is added absolute 
n-hexane (about 300 ml) until isopropanol can no longer be detected by gas 
chromatography in the distillate. The remaining hexane is then removed 
during 2 hours, firstly under normal pressure and finally (at about 
65.degree. C. heating bath temperature) in an oil pump vacuum, there being 
obtained 25.2 g of aluminium D-panthenolate. 
EXAMPLE 3 
58.90 g (287 mmol) of D-panthenol and 600 ml of n-hexane (purest) are added 
at room temperature under an inert gas to a 1 liter four-necked flask, 
provided with a stirrer, 100 ml dropping funnel with pressure balance and 
reflux condenser as well as an apparatus for working under a protective 
gas, and the mixture is stirred vigorously. The D-panthenol is difficulty 
soluble in n-hexane. When the D-panthenol has emulsified to small 
droplets, there are added dropwise from the dropping funnel within 1 hour 
17.73 g (15.0 ml; 143.5 mmol) of diethylzinc diluted in 80 ml of n-hexane 
(purest). The reaction begins immediately and is recognizable by the 
escape of ethane; the batch warms slightly. After about a third of the 
diethylzinc solution has been added, the reaction flask contains a viscous 
difficultly stirrable mass. After cooling to 5.degree. C. in an ice-bath, 
the mass becomes solid and it is then pulverized to a fine powder. The 
mixture is left to come slowly to room temperature and the dropwise 
addition is continued. After completion of the addition, the mixture is 
warmed to reflux temperature, stirred at this temperature for 1 hour, 
again left to cool to room temperature and stirred overnight. Thereafter, 
250 ml of n-hexane are distilled off and the mixture remaining is cooled 
to 5.degree. C. in an ice-bath and left to stand without stirring for 2 
hours. The product solidifies and the n-hexane can be decanted off well. 
The remainder of the n-hexane is removed under a water-jet vacuum and then 
the residue is dried up to constant weight under an oil pump vacuum. Since 
the product is hygroscopic, it is stored with the exclusion of moisture. 
There are obtained 60.73 g of zinc D-panthenolate in the form of a white 
amorphous powder having a melting interval of 105.degree.-107.degree. C. 
and a specific rotation of [.alpha.].sub.D.sup.20 =+31.degree. (c=1% in 
dimethyl sulphoxide). 
EXAMPLE 4 
(a) A solution of 11.5 g (14.75 ml, about 191.4 mmol) of absolute 
isopropanol in 300 ml of absolute n-hexane is placed under argon in a 500 
ml four-necked flask, provided with stirrer, thermometer, dropping funnel, 
as well as a reflux condenser with an apparatus for working under a 
protective gas, and the mixture is cooled to 5.degree. C. Thereto there is 
slowly added dropwise a solution of 10 ml (11.82 g; about 95.7 mmol) of 
diethylzinc in 60 ml of absolute n-hexane. After completion of the 
addition, the mixture is warmed to 50.degree. C. for 2 hours. 
(b) 39.3 g (191.4 mmol) of D-panthenol are added at room temperature to the 
suspension of zinc isopropylate in n-hexane prepared as described in 
paragraph (a). n-Hexane and isopropanol are distilled off at normal 
pressure while stirring, fresh n-hexane (about 300 ml) being added until 
isopropanol can no longer be detected by gas chromatography in the 
distillate. The residual solvent is then removed, firstly in a water jet 
pump vacuum and then during 2 hours in an oil pump vacuum, and the residue 
is dried up to constant weight, there being obtained 42.9 g of zinc 
D-panthenolate. 
EXAMPLE A 
A wound gel in a neutral gel base having the following composition is 
manufactured in a manner known per se: 
Zinc D-panthenolate--5.0 g 
Glycofurol--9.0 g 
Isopropyl alcohol--11.0 g 
Neo-PCL--68.0 g 
Aerosil 200--7.0 g 
EXAMPLE B 
A wound gel in a neutral gel base having the following composition is 
manufactured in a manner known per se: 
Aluminium D-penthenolate--5.0 g 
Glycofurol --9.0 g 
Isopropyl alcohol--12.0 g 
Neo-PCL--68.0 g 
Aerosil 200--6.0 g 
EXAMPLE C 
A salve has the following composition: 
Aluminium D-panthenolate--1.0 g 
Glycofurol--9.0 g 
Miglyol gel--90.0 g 
A representative batch is manufactured as follows: 
1 g of aluminium D-panthenolate is dissolved in 9.0 g of glycofurol and the 
solution is mixed with 10.0 g of Miglyol gel (Miglyol gel is a 
pharmaceutical adjuvant consisting of a triglyceride mixture of saturated 
vegetable fatty acids). 
EXAMPLE D 
A gel has the following composition: 
Aluminium D-panthenolate--1.0 g 
Glycofurol--9.0 g 
Isopropyl alcohol--12.0 g 
Neo-PCL (water-soluble)--72.0 g 
Aerosil 200--6.0 g 
A representative batch is manufactured as follows: 
1 g of aluminium D-panthenolate is dissolved in 9.0 g of glycofurol and the 
solution is mixed with 12.0 g of isopropyl alcohol. This mixture is added 
to 72.0 g of Neo-PCL (water-soluble) and finally 6.0 g of Aerosil 200 are 
added under stirring. 
EXAMPLE E 
A powder has the following composition: 
Aluminium D-panthenolate--25.0 g 
Magnesium stearate--2.36 g 
Talc--64.75 g 
Zinc oxide 7.89 g 
A representative batch is manufactured as follows: 
25.0 g of aluminium D-panthenolate are sieved through a sieve (0.5 mm) 
together with 2.36 g of magnesium stearate, 64.75 g of talc and 7.89 g of 
zinc oxide and the mixture obtained is mixed for 15 minutes in a mixer. 
EXAMPLE F 
A powder has the following composition: 
Zinc D-panthenolate--5.0 g 
Magnesium stearate--3.0 g 
Talc--82.0 g 
Zinc oxide--10.0 g 
A representative batch is manufactured as follows: 
5 g of zinc D-panthenolate are sieved through a sieve (0.5 mm) together 
with 3.0 g of magnesium stearate, 82 g of talc and 10 g of zinc oxide and 
the mixture obtained is mixed for 15 minutes in a mixer.