Note: Descriptions are shown in the official language in which they were submitted.
RAN _05]/23
Z~ 6
The present invention relat:es to topical pharmaceutical
compositions comprising lu,25-clihydroxycholecalciferol in
a suitable topical pharmaceutic:al carrier wherein said
topical compositions are emulsions having a pH of about 6.5
to about 7.5. Compositions of the invention include
10 aesthetically elegant vanishins~ creams. Compositions o~ the
invention have excellent stability at both room temperature
and elevated temperature6.
In the past, topical pharmaceutical compositions con-
taining 1~,25-dihydroxycholecalciferol ha~e had s~ability
problems due to the sensitive nature of the 1,25-di-
hydroxycholecalciferol. It has been unexpectedly found tha~
the stability of topical pharmaceutical compositions which
contain 1,25-dihydroxycholecalciferol and which are
20 emulsions can be improved by adjusting the pH the aqueous
phase so that the range of the pH of the topical compo-
sitions is about 6.5 to about 7.5, preferably about 6.B to
about 7.2. The most preferred p~ of the topical compo-
sitions is about 7Ø
As used herein emulsions include oil-in-water emulsions,
water-in-oil emulsions, and multiple emulsions.
As used herein a topical pharmaceutical carrier
30 compeises a mixture of a viscosity agent, a lipophilic
solubilizing agent, a hydrophilic solubilizing agent, an
emulsifier, an emollient, a preservative, an antio~idant, a
chelating agent, and a humectant.
35 Grn/25.10.90
,~
- 2 - ~ ~33'~
Compositions of the invention include skin creams,
vanishing skin creams, gels, and lotion6.
Skin creams may be oil-in-~ater emulsion6, water-in-oil
emulsions, or multiple emulsion6. Vanishing skin creams are
either oil-in-water or water-in-oil emulsions. Lotions are
usually oil-in-water emulsions.
The preferred compositions of the invention are
10 aesthetically elegant oil-in-water vanishing skin creams and
water-in-oil skin creams.
The pH of the compositions of the invention is in the
range of about 6.5 to about 7.5, preferably about ~.8 to
15 about 7.2. The most preferred pH of the compositions of the
invention is about 7Ø To achieve this pH, the a~ueous
phase of a composition of the invention is adjusted,
preferably buffered to a pH of about 7.0 to about ~Ø In
this manner the resulting pH of the final composition is in
the range of about 6.5 to about 7.5, preferably 7Ø
As used herein, the term "% (w/w)" or "~ (wt/wt)" refers
to % weight/weight. Thus, lO grams of ingredient A in lO0
grams of composition is present at lO ~ (w/w).
It is known that topical pharmaceutical composition6
containing la,25-dihydroxycholecalciferol can be utilized
in the treatment of skin conditions such as psoriasis. This
is disclosed, for example, in U.S. Patent 4,610,97~.
The topical pharmaceutical compositions of the present
invention comprise la,25-dihydroxycholecalciferol in
topical pharmaceutical carrier materials.
In particular, aesthetically elegant, vanishing skin
creams of the invention are buffered oil-in-water emulsion6
which comprise, la,25-dihydroxycholecalciferol, a
3 ~3~'Y;~:~
viscosity agent, a lipophilic solubilizing agent, a
hydrophilic solubilizing agent, an emulsifier, an emollient,
a preservative, an antioxidant, a chelating agent, a
humectant, and a buffering agent.
Topical pharmaceutical compositions of the present
invention may also contain conventional additives used in
topical pharmaceutical formulations. Such additives
include, for example, fragrances and substantive agents such
10 a~ polymers. (Substantive asents are agents which allow for
prolonged contact time between the topical pharmaceutical
composition and the skin.)
Viscosity agents are also referred to in this
15 specification as bodying agents. The viscosity agent may be
an alcohol selected from the group consisting of cetyl
alcohol, stearyl alcohol, ceteostearyl alcohol, and myristyl
alcohol. The viscosity agent may also be xanthan gum, a
magnesium aluminum silicate like veegum, carbomer, glyceryl
20 stearate, hydrogenated castor oil, cetyl palmitate, stearic
acid; a combination of synthetic and semisynthetic wax: a
combination of glyceryl stearate, cetearyl alcohol, cetyl
palmitate and cocoglycerides blend; or a combination of
glyceryl hydroxystearate, cetyl palmitate and
trihydroxystearin blend. The viscosity agent may also be
two or more of any of the viscosity agents mentioned above.
The viscosity agent is preferably a combination of cetyl and
stearyl alcohol.
The hydrophilic solubilizer can be dimethyl isosorbide
or transcutol: or an aliphatic alcohol selected from the
group consisting of ethyl alcohol, isopropyl alcohol,
polyethylene glycol, or more preferably propylene glycol.
The lipophilic solubilizer can be castor oil; isopropyl
myristate; an alcohol selected from the group consisting of
octyl dodecanol, isocetyl alcohol, oleyl alcohol, oleyl
3t~6
cetyl alcohol, or triglycerides of medium chain length
vegetable fatty acids such as Miglyols which are
mixtures of caprylic and capric triglyceride, propylene
glycol dicaprylate and dicaprate, or a mixture of caprylic
and capric triglyceride; or Neobee M-5. The lipophilic
solubilizer more preferably is mineral oil.
The emulsifier can be a polysorbate selected ~rom the
group consisting of Polysorbate 20, Polysorbate 40,
10 Polysorbate 60 and Polysorbate 80; a sorbitan selected from
the group consisting of sorbitan laurate, sorbitan oleate,
sorbitan palmitate, sorbitan stearate, sorbitan trioleate or
sorbitan tristearate. The emulsifier can also be glyceryl
monostearate, polyoxyethylene stearate, polyoxyethylene
lauryl ether, PEG-20 glyceryl stearate, ceteareth-12,
ceteareth-20, ceteareth-30, PPG-2-Ceteareth-9, polyethylene
glycol ethers of oleyl alcohol such as oleth-5, oleth-10, a
mixture of oleth-5 and oleth-10, sterols such as soya
sterol, PEG-5 soya sterol, PEG-10 sterol, PEG-16 soya
20 sterol, PEG-25 soya sterol, and also the emulsifier can be
sodium cetearyl sulfate, or PEG-40 hydrogenated castor oil.
The emulsifier is preferably a mixture of Span 60, which is
sorbitan monostearate, Arlacel 165 which is glyceryl
monostearate and polyoxyethylene stearate blend and Tween
60, which is polysorbate 60.
The emollient can be an ester such as oleyl oleate,
octyl stearate, myreth-3 myristate, hexyl lal.~rate, dibutyl
adipate, isocetyl stearate, octyldodecyl stearate,
30 PEG-7-glyceryl cocoate, oleyl erucate, a mixture o~
coco-caprylate and caprate, myristal myristate, cetearyl
isonanoate, decyl oleate. a mixture of caprylic and capric
triglyceride, PEG-5-Laureth-5, trihydroxymethoxy stearin,
and a mixture of propylene glycol dicaprylate and
35 dicaprate. The emollient can also be castor oil or dioctyl
cyclohexane or mineral oil. The emollient is preferably
- 5 ~ 3'726
mineral oil.
The preservative can be cis-1-(3-chloroethyl)-3,5,7-
tria~a-l-azoniaadamantane chloride: sorbic acid: potassium
sorbate: benzyl alcohol: benzalkonium chloride:
dichlorobenzyl alcohol; N-thydroxymethyl)-N-(1,3-dihydroxy-
methyl-2,5-dioxo-4-imidazolidinyl)-N-hydroxymethyl)urea;
boric acid: chlorobutanol: monothioglycerol: methyl paraben:
propyl paraben: or more preferably a mixture of methyl and
10 propyl parabens.
The anti-oxidant can be propyl gallate: butylated
hydroxytoluene: ascorbyl palmitate: sodium ascorbate:
a-tocopherol; or more preferably butylated hydroxyanisole.
The chelating agent can be dimercaprol: ascorbic acid:
diphenylthiocarbazone, versene acid, or more preferably
disodium edetate.
The humectant can be glycerin: elastin: hyaluronic acid;
or more preferably sorbitol.
The topical pharmaceutical carrier materials of the
; invention are slightly acidic. Accordingly, in order to
25 obtain a topical pharmaceutical composition within the
desired pH range of about 6.5 to about 7.5, it is necessary
that the aqueous phase be adjusted to that pH. Suitable
agents for adjusting the pH to the desired range are sodium
hydroxide or potassium hydroxide or buffering agents e.g. a
30 mixture of sodium citrate and citric acid a mixture of tris
(hydroxymethyl) aminomethane and tris(hydroxymethyl)
aminomethane hydrochloride; or disodium phosphate. Other
buffers which are compatible with topical pharmaceutical
compositions may also be used. The buffering agent is
35 preferably disodium phosphate. Determining the pH for the
aqueous phase, ~hich will be mixed with particular
pharmaceutical carrier materials, so that a final p~I between
-- 6
about 6.5 to about 7.5 is achieved, is within ~he skill of
the ordinary artisan. Ordinarily, when the pH of the
aqueous phase is in the range of about 7.0 to about 8.0 this
will result in a final topical pharmaceutical composition
whose pH is in the range of about 6.5 to about 7.5.
In the procedure for prepa,ring the topical
pharmaceutical compositions of the present invention, the
la,Z5-dihydroxy- cholecalciferol is dissolved i~ the oil
phase. The oil phase and the aqueous phase are then mixed
to form the final emulsion.
The topical pharmaceutical compositions of the present
invention contain from about 0.00001% (w/w) to about 0.1%
(w/w) preferably 0.0005 % (w/w) to about 0.005 % (w/w) of
la,25-dihydroxycholecalciferol. The topical
pharmaceutical compositions of the invention which are
oil-in-water emulsions can be prepared by incorporating
l,25-dihydroxycholecalciferol into carrier formulations,
20 by mixing in the following steps:
Step ~: la,25-dihydroxycholecalciferol is dissolved
in a hydrophilic solubilizer such as propylene glycol under
nitrogen. It is preferred to keep the resulting solution at
25 about room temperature until its use in Step 4 below so as
to avoid degradation of the la,25-dihydroxycholecalciferol.
Step 2: All hydrophilic ingredients are weighed out,
and added to water. The pH of the mixture is adjusted to
30 the range of about 7.0 to about 8Ø The resulting mixture
is heated with stirring until a maximum temperature of about
70C to about 75C is achieved. The resulting solution is
the aqueous phase of the final emulsion.
Step 3: ~ll lipophilic ingredients are mixed together,
and heated with stirring until a maximum temperature of
about 70C to about 75C is achieved. The resulting
- 7 - ~ 3'~
solution is the oil phase of final emulsion.
Step ~: Under nitrogen, the solution from Step 1 i6
then added to the oil phase of Step 3 while stirring iB
continued and the temperature is maintained at about 70 to
about 75C. Additional propylene glycol is used to wash the
vessel which contained the solution from Step 1. This wash
i5 added to the mixture of Step 4.
Step 5: Under nitrogen, the oil phase from Step 4 is
added to the aqueous phase from Step ~ using a homogenizer
to disperse the resulting emulsion. Homogenization is
continued until the droplet size of the oil droplets in the
emulsion is about 1 to about 20 microns. Then
homogeniæation is stop~ed, and gentle stirring is conducted
until the emulsion cools to room temperature.
The above procedure for prepaeing topical pharmaceutical
compositions of the invention is further exemplified in the
20 examples below.
The topical pharmaceutical compositions of the invention
are used by applying an effective amount to the areas to be
treated, for example, by rubbing the composition into the
2~ psoriatic skin or spreading the composition on the psoriatic
skin.
The following examples serve to illustrate in more
detail but are not intended to limit the invention.
- 8 ~ 2~
Example 1
1,25(OH12D3* Buffered Oil-in~Water
~opical Cream
CQmPonents Ran~es % (w/w)
1,25(OH)2D3 0.00001 - 0.1
Long Chain Alcohol/Viscosity Agent 0.1 - 20.0
Lipophilic Solubilizing Agent 0.2 - 40.0
Hydrophilic Solubilizing Agent 0.2 - 40.0
Emulsifiers 0.5 - 30.0
Emollient 1.0 - 20.0
Preservative Systems 0.001 - 10.0
10 Antioxidant 0.001 - 5.0
Chelating Agent O.001 - 5.0
Humectant 0.1 - 10.0
Water 50 - 95.0
Buf f ering Agent 2.0 - 12.0
pH pH 6.5 - 7.5
~ As used throughout the specification la,25(OH)2D3
refers to la,25-dihydroxycholecalciferol.
ExamPle 2
Oil-in-Water Cream
% (w/w)
la,25-dihydroxycholecalciferol O.O0001-O.l
Cetyl Alcohol 1.5
Stearyl Alcohol 2.5
Sorbitan Monostearate 2.0
Mineral Oil 4.0
25 Glyceryl Monostearate and Polyoxyethylene
Glycol Stearate Blend 4.0
Polysorbate 60 1.0
Propylene Glycol 5.0
Propylparaben 0.05
Butylated Hydroxyanisole (BHA) 0.05
Sorbitol Solution 2OO
Edetate Disodium 0.01
30 Methylparaben 0.18
~ater q. 6 . to 100.0
pH adjusted with Sodium Hydroxide Solution pH 6.5-7.5
The topical pharmaceutical compositions of the present
invention are preferably packaged for example, in
35 epoxy-lined aluminum tubes ~ealed with phenyloxy sealant.
Such packaging keeps oxygen and light ~rom contacting
the compositions. Alternatively, topical pharmaceutical
compositions of the invention may be packaged, for example,
in porcelain ointment jars or glaminate tube6.
:~ 25
3~7;~
-- 10 --
~ le 3
la,25(0H)2D3 0.0005 % ~w/w) Oil-in-Water Cream
Quantitative Com~osition
The left hand colum~ below gives the quantitative
composition of a topical phacmaceutical composition of the
invention that was made.
Also given in the center column o~ this example are
reasonable variations in amounts of the different com~onents
of this composition. Also given in the right hand column
are actual amounts of components for a batch of cream of
6,180 grams that was made.
Reasonable
VariationsTypical
Inqredients % (w/w) ~ (w~w)Batch, ~m
1,25(OH)zD3 0.00055** - 0.033
Purified Water, USP80.61945~**70-904,837.167
Methylparaben, USP 0.18 0.1~-O.Z2 10.8
Propylparaben, USP 0.05 0.04-0.06 3.0
Sorbitol Solution, USP 2.00 1-3 120.0
Edetate Disodium, USP 0.100.075-0.125 6.0
Cetyl Alcohol, USP/MF 1.50 0.5-2.5 go.o
Stearyl Alcohol, USP/NF 2.50 1.5-3.5 150.0
Glyceryl Monostearate and
Polyoxyethylene Stearate
Blend (Arlacel 165) 4.00 3-5 240.0
Sorbitan Monostearate
(Spunge) 2.00 1-3 120.0
Polysorbate 60 (Tween 60),
USP/NF 1.00 0.5-1.5 60.0
Mineral Oil, Light, USP 4.00 3-5 240.0
Propylene Glycol, USP 5.00 4-6 300.0
Butylated Hydroxyanisole
(BHA). USP O.05 0.03-0.07 3.0
TOTAL103.00 gm 6,180 gm
** Includes a 10% excess
*** Includes a 3% excess to compensate for water loss during
the manufacturing process.
.
,
.
- ' ~
.
- 11 - 2~33~
The aqueous phase of the above cream was adjusted to p~
7.5-8.0 using sodium hydroxide solution.
The Manufacturina Procedure:
l. The Cetyl Alcohol, Stearyl ~lcohol, Sorbitan
Monos~earate, Glyceryl Monostearate and Polyoxyethylene
Stearate Blend, Polysorbate 60, Mineral Oil and a
portion of Propylene Glycol were mixed in a suitable
container and were melted with a waterbath.
2. Butylated Hydroxyanisole and Propylparaben were added to
the material from step l, dissolved and maintained at
70-750C.
3. In a suitable container, the Edetate Disodium and
Methylparaben were dissolved in a preheated solution of
the Sorbitol Solution and Purified Water.
4. The la,25(0H)2D3 was dissolved in the balance of
the Propylene Glycol and added to the material from step
2.
Note: A nitrogen a~mosphere was maintained above the
product during this and subsequent steps.
5. The pH of the solution from Step 3 was adjusted to about
7.5-8Ø The oil phase from step 4 was added to the
aqueous phase from step 3 while emulsifying with a high
shear mixer.
6. The product was cooled to room temperature.
~33~
-- lZ --
Exam~le 4
oi 1- in-Water Buffered Cream
Inqredients % tW/W2
la,25(H)2D3 0.0005
Cetyl Alcohol 1.5
Stearyl ~lcahol z.5
Sorbitan Monostearate (Span 60j 2.0
Mineral Oil 4.0
Glyceryl Monostearate and Polyoxyethylene
Glycol Steaeate Blend (~rlacel 165) 4.0
10 Polysorbate 60 (Tween 60) l.O
Propylene Glycol 5.0
Propylparaben 0.05
Butylated Hydroxyanisole (BHA) O.05
Sorbitol Solution 2.0
Edetate Disodium 0.01
Methylparaben 0.18
1~ Water q.s. lOO.O
pH adjusted with disodium phosphate, pH 7.0
Manufacturin~ Procedure:
l. In a suitable container the Cetyl Alcohol, Stearyl
Alcohol, Sorbitan Monostearate, ~lyceryl Monosteara~e
and Polyoxyethylene Stearate Blend, Polysorbate 60,
Mineral Oil and a portion of Propylene Glycol were
melted in a waterbath.
2. Butylated Hydroxyanisole and Propylparaben were added to
the material from step l, dissolved and maintained at
70-75C.
3. In a suitable container the Edetate Disodium and
Methylparaben were dissolved in the preheated solution
of the Sorbitol Solution and Purified Water.
4. The la,25(0H)2D3 was dissolved in the balance of
the Propylene Glycol and added to the material from step
2.
~3~
- 13 -
Note: A nitrogen atmosphere was maintained above the
product
during this and subsequent steps.
5. The pH of the solution from Step 3 was adjusted ~o about
7.5-8Ø The oil phase from step 4 was added to the
aqueous phase from step 3 while emulsifying with a high
shear mixer.
6- The product was cooled to room temperature.
Example 4a
Oil-in-Water Buffered Cream
15 Inqredients (w/w~
la,25(OH)2D3 0.005
Cetyl Alcohol 1.5
Stearyl Alcohol 2.5
Sorbitan Monostearate (Span 60) 2.0
Mineral Oil 4,0
20 Glyceryl Monostearate and Polyoxye~hylene
Glycol Stearate Blend (Arlacel 165) 4.0
Polysorbate 60 (Tween 60) 1.0
Propylene Glycol 5.0
Propylparaben 0.05
Butylated Hydroxyanisole (BHA) 0.05
Sorbitol Solution z.o
25 Edetate Disodium 0.01
Methylparaben 0.18
Water q.s. 100 0
pH adjusted with disodium phosphate~ pH 7 0
The above cream can be made using a procedure analogous
to that of Example 4.
- 14 -
~xample 5
Oil-in-Water Buffered Cream
Inqredients % (w/w)
la, 25(OH)2D3 0.0005
Cetyl Alcohol l.5
Stearyl Alcohol 2.5
Sorbitan Monostearate (Span 60) 2.0
Mineral Oil 4.0
Glyceryl Monostearate and Polyoxyethylene
Glycol Stearate Blend (~rlacel 165) 4.0
10 Polysorbate 60 (Tween 60) l.O
Propylene Glycol 5.0
PLopylparaben 0.05
Butylated Hydroxyanisole (BHA) 0.05
Sorbitol Solution 2.0
Edetate Disodium O.Ol
Methylparaben 0.18
15 Water q.s. lOO.o
pH adjusted with Tris (hydroxymethyl)
aminomethane and Tris (hydroxymethyl)
aminomethane hydrochloride pH 7.4
The above cream was made using a procedure analogous to that of
Example 4.
Exam~le 6
Oil-in-Water Buffered Cream
Inqredient8 % (W/WL__
25 la,25(0H)zD3 0.0005
Cetyl Alcohol l.5
Stearyl Alcohol 2.5
Sorbitan ~onostearate (Span 60) ~.o
Mineral Oil 4.0
Glyceryl Monostearate and Polyoxyethylene
Glycol Stearate Blend (Arlacel 165) 4.0
30 Polysorbate 60 (Tween 60) l.O
Propylene Glycol 5.0
Propylparaben 0.05
Butylated Hydroxyanisole (BHA) 0.05
Sorbitol Solution 2.0
Edetate Disodium 0.01
Methylparaben 0.18
Water q.s. to lOO.O
pH adjus~ed with Sodium Hydroxide Solution pH 6.6
~)3~'7~26
- 15 -
The above cream was made using a procedure analogous to that of
Example 4.
_ample 7
Oil-in-Water Bu~fered Cream
. Inqredients % (w/w)
10 la,25(OH)2D3 0 005
Cetyl ~lcohol 1.5
Stearyl Alcohol 2.5
Sorbitan Monostearate (Span 60) 2.0
Mineral Oil 4.0
Glyceryl ~onostearate and Polyoxyethylene
Glycol Stearate Blend (Arlacel 165) 4.0
Polysorbate 60 (Tween 60) 1.0
15 Propylene Glycol 5.0
Propylparaben 0.05
Butylated Hydroxyanisole (BE~A) 0.05
Sorbitol Solution 2.0
Edetate Disodium 0.01
~ Methylparaben 0.18
: Water q.s. to 100.0
pH adjusted with Sodium Hydroxide Solution pH 7.1
The above cream was made using a procedure analogous to that of
Example 4.
33~7~2~
- 16 -
Example 8
Water-in=Oil Cream
Ranges
Inqredients % (w~w) _ % (w/wl _ Functions
1~,25(0H)2D3 0.00055-0.0055 0.00001-0.1 Active
Hydroxylated Lanolir 2.5 1.75-3.25 Emulsifier
~ineral Oil, and Lanolin
Alcohol 16.511.55-21.45 Emulsifier
Mineeal Oil Light 20.0 14.0-26.0 Emollient
Microcrystailine Wax
170-175~ m.p. 16.0 ll.Z-20.8 Thickener
Propylparaben 0.05 0.04-0.06 Preservative
Propylene Glycol 5.00 4.0-6.0 Solubilizer
Methylparaben 0.18 0.14-0.22 Preservative
Edetate Disodium 0.100.075-0.125 Chelating
Agent
15 Butylated Hydroxyanisole 0.05 0.03-0.07 Antioxidant
Water 39.6228.0-52.0 Vehicle
pH 6.5-7.0 - -
Manufacturinq Procedure:
1. In a suitable container melt the hydroxylated lanolin,
mineral oil and lanolin alcohol, light mineral oil,
microcrystalline wax and a portion of propylene glycol in a
waterbath at 70-75~C.
2. Add the butylated hydroxyanisole and propylparaben to the
mixture from step 1, dissolve and maintain at 70-75C.
3. In a suitable container dissolve the edetate disodium and
methylparaben in the preheated purified water.
4. Dissolve la,25(0H)2D3 in the balance of the propylene
glycol and add to the material from step 2.
Note: Maintain a nitrogen atmosphere above the product
during this and subsequent steps.
5. Adjust pH to about 7.5-8Ø The buffer used to adjust the
pH is disodium phosphate. Add the oil phase from step 4 to the
aqueous phase from step 3 while emulsifying with a high shear
mixer .
6. Cool the product to room temperature.
~. :
.. .
.. . . . . . .
~033i7r~
- 17 -
Example 9
Water-i.n-Oil Cream
Ranges
Inqredients % (w/w) % (w/w) Func~ions
1,25(0H)2D3 0.00055-0.0055 0.00001-0.1 Active
Petrolatum, Lanolin In.gredient
and Lanolin alcohol7.0 4.9-9.1 Emulsifier
Mineral Oil, Light12.0 8.4-15.6 Emollient
Microcrystalline Wax
170-175~ m.p. 9.0 6.3-11.7 Thickener
Sorbitan Sesquioleate 2.0 1.4-2.6 Emulsifier
Pro~ylparaben 0.05 0.04-0.06 Preservative
Butylated Hydroxyanisole 0.05 0.04-0.06 Sulubilizer
Propylene Glycol5.00 4.0-6.0 Solubilizer
Methylparaben 0.18 0.14-0.22 Preservative
15 Edetate Disodium0.10 0.075-0.125 Chelating
Agent
Water 64.62 45.0-84.0 Vehicle
pH 6.5-7.0
This cream i8 made in the same manner as the cream in
Example 8. The buffering agent is disodium phosphate.
The following data compare tha stability of la,25~
dihydroxycholecalciferol in unbuffered oil-in-water
vanishing creams and in buffered oil-in-water vanishing
creams of the invention. The data below, were obtained fro~
Z5 analyzing vanishing c~eams which were stored in 15g
epoxy-lined aluminum tubes with white polyethylene caps.
A 0.0005 % (w/w) vanishing cream made in the same manner
as described in Example 3 but without being buffered tpH
5.5-6.0) was stored for 12 months at Z5C and showed a loss
of potency of la,25-dihydroxycholecalciferol of 11%. By
contrast the 0.0005 % (w/w) vanishing cream of Example 3 (pH
6.5) when stored for 12 months at 25C showed a 106s of
potency of la,25-dihydroxycholecalciferol of only 2%.
~3~
- 18 -
A 0.005 % (w/w) vanishing cream made in the same manner
as described in Example 7 but without being buffered (pH
5.5-6.0) was stored for 6 months at 25C and showed a 10s6
of potency of 7%. By contrast a 0.005 % (w/w) vanishing
cream of Example 7 (pH 7.1) when stored for 6 months at Z5C
showed no loss of potency.
A 0.005 % (w/w) vanishing cream made in the same manner
as in Example 7 but without being buffered (pH 5.5-6.0) was
stored for 6 months at 37C and showed a loss of potency Oe
18%. By contrast a 0.005 ~ (w/w) vanishing cream of Examele
7 (pH 7.1) when stored for 6 months at 37C showed a 1068 of
potency of 4%.
The above data demonstrate that compositions of the
invention are more stable than compositions of the prior art.
-
