CA1047924A

CA1047924A - Powdered emulsion product and method of production

Info

Publication number: CA1047924A
Application number: CA212,545A
Authority: CA
Inventors: Hitoshi Sezaki; Shozo Muranishi
Original assignee: Kyowa Hakko Kogyo Co Ltd
Current assignee: KH Neochem Co Ltd
Priority date: 1973-10-30
Filing date: 1974-10-29
Publication date: 1979-02-06
Also published as: FR2257267B1; FR2257267A1; DE2451568A1; GB1488522A

Abstract

ABSTRACT OF THE DISCLOSURE
Powdered products containing a drug or nutrient suitable for administering in emulsion form are prepared by dispersing (a) an oil; (b) a solution of a drug or nutriment in oil; or (c) an emulsion of an aqueous solution of a drug or nutriment in oil, in an aqueous solution containing a surface layer former, and, where appropriate, a drug or nutriment, and then spray-drying the dispersion.

Description

~047~24 BACKGROUND OF THE INVENTION
The present invention relates to a powdered product su;table for the preparat;on of emuls;ons~ and more specifi-cally, to a powdered product prepared by dispersing (a) an oil, (b) a solution of a drug or nutriment in oil; or (c) an emulsion of an aqueous solution of a drug or nutriment in oil, in an aqueous solution containing a surface layer former and, where appropriate a drug or nutriment, and then spray-drying the resulting dispersion. -Heretofore, there have been known water-in-oil emulsion products prepared by emulsifying an aqueous solution of a water-soluble drug in oil. Also, there have been reports of water-in-oil-in-water emulsion products obtained by further emulsifying the water-in-oil emulsion in water.
Such products have been ~requently.used.in the .
clinical administration of a drug or nutriment together with .
a suitable oil. For example, where an emulsion of an aqueous solution of an anti-cancer substance such as 5-fluorouracil, ;`~
bleomycln and mitomycin C, and an oil is administered, the drug has a lymphatic directivity due to the property of the co-existing oil. Therefore, the drug selectively reaches the lymph nodes at a high concentration. Such characteristic `
ls oF great ~mportance ~n administering an anti-cancer substance for the treatment of metastases of cancer to lymph n~des. In addltion, where an analgesic, an antibiotic or the like is incorporated into fine particles of an oil and such is administered by injection, where ~he size of the .
particle of oil is larger than a predetermined certain size~ the particle is maintained in the capillary vessels.
In this case, the active ingredient, i.e. the drug i$~"';. '' '

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gradllally permeates into the surrounding tissues. There-fore, the concentration of the drug in the specific tiscue can be maintained at a high level for a long period of time. This apparently results in an enhanced durability o~ the e~fect of -the drug. Moreover, it can easily be understood that such method would be effective to admini-ster an oil together with nutriments such as amino acids and glucose to a patient who has undergone a surgical operation. In addition, it is possible in such manner -to ~ `
administer an oil itself, as alnutriment, in the form of an emulsion.
From the ~oregoing, it will be understood that a double emulsion of a w~ter-in-oil emulsion in water or an ~;
oil-in-water emulsion is very useful. However, the ;
stability of the emulsion per se or that of drugs or nutriments is not at all satisfactory. More specifically when an emulsion once prepared is preserved for a long period of time, the emulsion structure is destroyed thus ~`
separating into oil and water. Moreover, -the drug or nutriment which is an active ingredient is not necessar-ily stable.
To illustrate, the stabili-ty of a oil-in-water emul- ^ ~i sion is examined. An emulsion is prepared by adding sesami oil to a solu-tion of mitomycin C in benzylalcohol and emulsifying the mixture in water in a ratio of 1:4.
The particle size distribution of the thus prepared oil-in-water emulsion is measured with a coal tar counter ;~
immediately after the preparation thereof and again after ;
three months of standing at room temperature. The results `
are shown in Fig. 1 wherein, the horizontal axis shows -the particle size (~ ) and the vertical axis shows -the ~ 3 -, ~

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particle size distribution t~). As is apparent t'rom Fig. 1, after -three months Or standing, the particle size becomes extreme~ly . ~ ., .: . ,:

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' ~llO47~4 unun1 form.
Further, the s~abili-ty of mitomycin C in an oil-in-water emulsion prepared in -the same manner as above is tested. The result$ are shown in Table 1 below.

~';.'~' Residual ratio (~
Period after preparation (days) ., - . .
Concentration 2 4 9 ~; 16 ~ _ 23-, 43 20 mg/lOOml 81.0 73.4 62.745.7 29.8 22.4 30 mg/lOOml 82.9 71.9 65.255.1 36.9 32.6 ~0 mg/lOOml 86.5 78.1 69.459.5 41.6 36.3 :~. '.,' As is apparent from the foregoing Table 1, mitmoycin C
rapidly decomposes.
In efforts to solve the problems exemplified by the ~, above, it has been proposed to prepare the emulsion just prior to administration. However, the prepraration~of an ;`, ' emulsion requires sophisticated equipment and is time con~
suming; and is thus impractical for general use. It has ~ "
also been proposed to prepare a solu-tion of a drug in oil or an emulsion of an aqueous solution of drugs in oils in-to microcapsules and -to emulsify the microcapsules in wa~r ~ust prior to administration. However -this proposal ~`
al~o ~uf-~era from various disadvantages. The preparation microcapsules also requires complicated steps and it is di~ficult to obtain microcapsules as small as several microns. Moreover, the use of microcapsules suffers from the disadvantage that the same do not readily decom-pose upon reaching the caplillary vessels.

~ ' " '' ~' ~ 79 Z ~

Therefore~ improvements are in great demand.
SUMMARY OF THE INVENTIO_ In accordance with the present inventionz ~t has been found that a powdered product, prepared by emulsify1ng (a) an oil, (b) a solution of a drug or a nutrimen~ in oil or (c) an emulsion of an aqueous solution of a drug or a nutriment in oil. in (d) water containing a surface layer former or (e) an aqueous solution o~ a drug or nutr;ment containing a surface layer former and thereafter spray-drying the resulting emulsion or double emulsion~ is very advantageous. The powdered product is characterized by a structure in which the surface of a small particle of oil, a solution of the drug or nutriment in oil or the water-in-oil emulsion of the drug or nutr;ment is coated with a th;n layer of a skin former. The product appears to be a powder or a small mass of powder.
Depending on the particular method of preparation, it is considered that the drug or nutriment in the aqueous solution is present mainly between the surface of the particle of oil and the thin layer of the surface layer former, combined with the oil. In certain applications it is also considered that some portion o~ the aqueous solution is incorporated as it is into the oil as fine particles.
The product of the present invention is, of course, stable ~n stru ~ure. In addition, the drug or nutriment ``~
;ncorporated therein is also very stable and can be preserved for a long period of t;me.
The product of the invention can easily be prepared into a oil-in-water emulsion or a double emulsion -of water-in-oil-in-water again by mixing with an ~'1 :`

79~4 appropriate amoun-t o:E` water and -the resulting emulsion is ~
ready for administra-tion. F`urthermore, when the product : :
of the inven-tion is used, an emulsion containing particles of a desired size in a range between one micron and sev~
eral hundred microns and at the same tirne having a small particle size dis-tribution can be prepared.
DESCRIPTION OF T~IE INVENTION
;. ~
In accordance with the present invention a powdered .:
..
product is prepared which is suitable for emulsifying on : . .
short notice and subsequent administration. ~. .
In one form of the invention, an aqueous solution ~ .
o:~ a drug or nu-triment to be employed is prepared. The concentra-tion is properly selected depending upon the .. ~ .
solubility o-f the specific drug or nutriment or the de~
sired dosage thereof. Where the water-solubility of the drug or nutriment is poor, it may be first dissolved in a water-miscible solvent and then the solu-tion may be mixed : ;
~ith water. For the preparation o~ the aqueous solution, ~ ;
buf~er solutions such as tris-buffer, etc. and physiolog~
ic~l sodium chloride solution may be used in addition to distllled water.
A surface layer former is then dissolved in the ~q~leou~ soluti4n. Any surface layer former may be used A~ l~ng as it can form a thin layer, is water-soluble And aausqs no incovenience upon administration. For ~xample, gela-tln, polyvinylpyrrolidone, methylcellulose, polyvinylalcohol, polyethylene glycol and fatty acid~
esters of sucrose are appropriate. The concentration of .
-the surface layer former is 0.5% ~ 10% by weight, pre-ferably, 1%-3% by weight based upon the weight of oil : ~
and water. ~: .

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Then, an oil is dispersed in the thus prepared aqueous solution to prepare an emulsion. Appropriate oils include peanut oil, olive oil, vitamin A oil and vitamin E oil bu-t the use of sesame oil is most prac-tical and is thus preferred. The mixing ratio of the : ., . ,:
oil to the aqueous solution is 1:1 - 1:40, preferably 1:4 -l:S. In preparing the emulsion, if desired, a `~
stabilizer for the drug or nu~riment to be employed may be added. Additionally, an emulsifier such as surfactants~
and other additives may also be added. Appropriate sur-factants include cationic surfacts such as benzethonium chloride, benzalkomium chloride, etc., anionic surfactants such as sodium laurylsulfate, etc.? and nonionic surfac~
tants such as polyoxyethylene fatty acid ester, polyoxy ethylene sorbitan fatty acid ester, etc. ~;
Emulsification may be carried out either by adding ;~
.
the oil to an aqueous solution containing the surface -layer former and the drug or nutrimen-t with vigorous .. . . .. .
s-tirring, or by adding the aqueous solution to the oil.
. , ; :
An emulsi~ier may be added either to the aqueous solu- -tion or to the oil. As an homogenizer, any of the aom-mercially available homogenizers may be employed. If neoessary, hea-ting or cooling ls applied during emulsi-~ic~tion to ob-tain a uniform emulsion. In this emulsifi-~Qtion to ob-tain a uniform emulsion. In this emulsifica-tion step, the particle size of the oil is adjusted by selec-ting the stirring conditions, temperature and kind or concentration of the surface layer former. The adjus-t-ment of particle size can be carried out in a conventlo~l manner known in the art. The thus~ obtained emulsion is ;~

then spray-dried. The conditions of spray-drying may be i;
selected depending upon the kind and concentration o~ the drug ~, ~ ~7 9 ~ ~
nutriment oil or the other raw materials to be employed or the size of particles in the emulsion. However, usually, the spray-drying step is carried out at an inlet~gas temperature of ~00-200C and an outlet-gas temperature of 70-100C.
Spray-drying is accomplished by means of commercial devices known to the art. For example, a cylinder spray drier or cyclone spray drier provided with an atomizer of pressure ::.;..
nozzle type, centrifugal disk type or two-fluid noz~le type ~; - -may be used. When a spray drier having a centri~ugal disk type-atomizer is used, spray-drying is carried out usually at a rotation of the atomizer of 10,000-25,000 r.p.m.
In another form of the invention, a powdered product o~ a double emulsion of a water-in-oil emulsion of an aqueous . . .
solution oF drugs or nutriments in oil in water is prepared in the following manner.
First, an aqueous solution of a drug or nutriment is prepared. The concentration is properly selected depending upon the solubility of the drug or nutriment to be employed or the deslred dosage thereof. It is to be understood that there is no restriction on the concentration of the drug or nutriment and such is variable depending upon the desired result. For the preparation of the aqueous solution, bufFer solutions such as tris-buffer, etc. and physiological sodium chloride solution may be used in addit~on to distilled water.
The aqueous solution prepared above is then dispersed and emulsified in oil, such as peanut oil, olive oil, vitamin A oil and vitamin E oil, preferably sesami oil. ;~
The mixing ratio of the oil to the aqueous solution oF the drug or nutriment is 1:10 - 1:1, preFerably 1:6 - 1:~. In preparing the water-in-oil emulsion, if desired, a stabilizer for the drug or nutriment to be employed may be added.

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Further, an emulsifier such as the above-described surfactants .
and other additives may also be added.
The water-in-oil emulsion prepared in this manner is then mixed with an aqueous solution containing a surface layer former and re-emulsified to prepare a water-in-oil-in-,:

79i~
water emulsion. To the mixing ratio ofithe water-in-oil ~, emulsion to the aqueous solution is 1:1 - 1:10, preferably ~;
1:2 -1:3. The surface layer ~ormer may be the same as those described above and the concentration of the sur- '~
. ~ , , .
face layer ~ormer is also the same as above. It is to be understood that such emulsifiers as surfactants, and other additives may, of~ course, be added when the re-emulsifica-tion is carried out and particle size is adjusted during the preparation of the double emulsion.
The emulsification to prepare the water-in-oil emul-sion and the double emulsion of water-in-oil-in-water is , carried out in the same manner as described above for the ~, preparation of the emulsion of oil in water. ~ , ` ! The emulsion thus prepared is a double emulsion, which has a structure characterized by small particles, each comprising a particle of an aqueous solut~on of a ;
drug or nutriment coated with oil, dispersed in an aqueous solution containing a surface layer former. ~ ~
By spray-drying the double emulsion, the desired '~ ' , powdered product is obtained. The spray-drying can be ' carried out under the same conditions as those for the , , preparation of -the powdered product described above.
The products of the present invention are very ~able and can be preserved ~or a long period of time.
~he produc-ts are readily prepared as an oil-in-water emulsion or water-in-oil-in-water emulsion again by '~
simply mixing the water. The emulsion is very stable and can be maintained for a long period of time. '~
~ or example,,a powder having an average particle size of 15 ~ and comprising sesami oil coa-ted with 20% by ' '~
:

_ g ._ ~479;29~

weight of gelatin based on the weight of sesami oil is physi-cally and chemically very stable. After stand;ng at room temperature for 18 months, the powder under~oes no change in appearance and in particle size distribution when dispersed in water. To disperse the powder in water 3 9 of the powder and 20 ml of water are placed in a 50 ml-centrifugal precipitation tube having an inner diameter of 3 cm closed with an air-tight ground stopper. Reciprocal shaking is applied at an amplitude of 4 cm and at a frequency of 280 times per min.; and the time required for complete restoration to an emulsion is measured.
The test is conducted immediately after the preparation of the powdered product and after 30 days, 12 months and 1~ months of preservation. The powder is restored to an emulsion within 2 minutes in each case.
The particle size distribution of the powder is ~
measured immediately after the preparation and after preser- ~;
vation for 18 months. The results are shown in Fig. 2 wherein the horizontal axis shows the particle size (~) and the verti-cal axis shows particle size distribution (%). As is apparent 2~ from Fig. 2, no substantial change appears in the particle size d~s~ribution.
To further exemplify the stability of a product pre- , pared in accordance with the present invention, a powdered product having an average particle size of 12 ~ and comprising a gelatin-coated sesami oil containing 2 mg/g of mltomycin C is stored under shaded conditions for one year and the content of , mitomycin C in the product is periodically measured. The ;~
results are shown in the following Table 2.

79;~
'I'ABLE 2 _ _ Content (mg/g) Sample No. Immediately after pre- Period of preservation (da paration 30 go 180 one ~_r 1 2.12 2.08 2.06 2.01 2.00 2 2.08 2.10 2.01 2.01 1.98 ~ `

3 2.03 2.02 2.00 1.98 1.96 As is apparent from Table 2, mitomycin C in the product is very stable.
In preparing a powdered product of the present in-vention, it is, of course, possible to employ the oil, drug and nutriment as a mixture of two or more constitu-ents. It is also possible within the scope of the present lnvention to prepare a product containing an oil-soluble drug and a water-soluble drug. Such product can be pre- ~
pared by dissolving an oil-soluble drug in oil and a `
water-solubleddrug in water; mixing and emulsifying the solution; dispersing the emulsion in water to prepare to double emulsion; and spray-drying the double emulsion.
When the product of the present invention is pre- ~ ~ `
p~red into an emulsion for administration, an aqueous solution containing nutriments such as glucose, amino acids, etc. and other drugs may be employed.
ln addition to the above, various modifications are ~os~lblo ~or the produc-tion and use of the produc-t of the presen-t inven-tion. Such modifications will be apparent -~o -those skilled in the art.
Practice of certain specific embodiments of -the invention is illustrated by the following representative examples.

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" E~;ample 1 2 ~ In this cx~mple 1.5 1. of sesami oil, 3 1. of distill~d water and 3 1. o~ an aqu~ous 10~ solution of

4 i~ gelatin are mix~d and emulsified with a supersonic s !~ apparatus under i~e-cooling. The resul~ing oil-in-water 6 ~! emulsion is subjected to spray-drying at an inlet-gas 7 ,I temperature of 150C and an outlet-gas temperature of 90C.
8 1l As a result, 1.2 kg of a fine powder having an average 9 j, particle size of 1~5 ~ is obtained. Upon mixing with lo 1l water, the powder is immediately restored ~o an emulsion.
1~ i!
~2 i~ Example 2 ll 1. ¦1 In this example, 1.5 1. of peanut oil, 3 1. of t~ ¦I distilled water and 3 1. of an aqueous 10% solution of 15 ,! polyvinylpyrrolidone are treated in the same manner as 16 1l described in Ex~mple 1. As a result, 1.3 kg of a fine ~7 j powder having an average p~rticle size of 2 ~ is obtained.

13 ij The product is readily restored to an emulsion by mixing j ~ ~`

9 ! with water. ~
!! ` . ~ `~ `
!I Example 3 ¦

In this example, 1-5 1. of sesami oil, 3 1- of t2 1~ distill~d water, 3 1. of an aqueous 10% solution of gelatin ana 60 g of Tween 80 ~trade mark of Atlas Chemical Industries t~ , Inc., U.S.~.) are treated in the same manner as described in Example 1. As a result, 1.3 kg of a fine powder having 26 ~' an average particle size of 2 ~ is obtained~ ~he powder 27 j is readily restored to an emulsion by mixing with water.

t8 Example 4 t9 In this example, 500 g of tocopherol is dissolvcd ~ ,' in 1.5 1. of sesami oil. Thc solution is mixed with 3 1.
31 ~ of distilled watcr, 3 1. of an aquecus 10~ solution of . . .

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gelatin and 60 g oE Tween~ ~0 ~nd -the mixture is emulsi-~ied with a supers~nic apparatus under ice-cooling. rrhe resulting oil-in-water emulsion is subjected to spray-drying at an inlet-gas temperature of 100C and an out-letgas -temperature of 80 C. As a result, 1.8 kg of a fine powder having an average particle size of 5~ is obtained. The product is readily restored to an emul-sion by mixing with water.
Example 5 In this example, the procedure described in Example 4 is repeated except for using olive oil in place of ses-ami oil and methylcellulose in place of gelatin. As a result, 1.8 k~ of a powdered product having an average particle size of 6~ is obtained. The product is readily restored to an emulsion upon mixing with water.
Example 6 In this example, 8.25 1 of sesami oil, 60 g of Span-80 ~trade mark of Atlas Chemical Industries, U.S.A.
and 15 g o~ HC0-60 (trade mark of nikko Chemical Co., Ltd.
Japan for a surfactant comprising polyoxyethyIene hydro-~enated caster oil) are mixed. To 21~ of -the mix-ture is ~dd~d 350 ml of an aqueous solution containing 175 mg. of ml~mycln C and the mixture i5 emulsi~ied with a super-sonla appara-tus at 50C. The 1 1. o~ the resulting water-in-oil emulslon i9 re-emulsified together with 1.6 1. of an aqueous 10~ solu-tion of gelatin wi-th a homogenizer at

5,000 r.p.m. for 15 min. The resulting double emulsion is sub;ected to spray-drying at an inlet-gas -temperature of 110 C and an outlet-gas temperature of 90 C. to obtain a powdered product having an average particle size of 20ll The product is restored to a water-in-oil-in-water emul-sion ,. ... . ~ . , .. , . ~ .. , ~0~7929,~
by mixing with water.
Example 7 In this example, a mixture consisting of 43.49~ ;
sesami oil, 40.21~ of an aqueous solution containing 0.5~;
mg!ml of 5-fluorouracil and 4.42% portions of benzylalco-hol, lecithin, sorbitan ~o~ooleate and sorbitan monostea-rate is emulsified into a water-in-oil emulsion using a ~ `~
supersonic apparatus. A mixture consisting of 37.25 emulsicnthus obtained, 5.75% Pulronic F~68 (trade mark of Wyandotte Chemicals Corporation, U.S.A.) and 57.0% dis tilled wa-ter is emulsified with a homogenizer at 7,000 ` -r.p.m. for 15 min. to prepare a double emulsion. The ~ `
resulting emulsion is then subjected to spr~y-drying at an inlet-gas temperature of 110 C and an outlet-gas Y`
temperature of 90 C to obtain a powdered product having ~; ;
an average particle size of 10H . `
Example 8.
In this example, the procedure described in Example ` ~;~
5 is repeated excep-t for using bleomycin`and mitomycin C, respectively, in place of 5-fluorouracil. As a result, powdered products containing the respective drugs are obtnlned.
xampl~ 9 In thi5 example, 300 ml of an aqueous solution oontainin$ 250 mg of mltomycin C, 300 ml of an aqueous lO~o solution of gelatin and 150 ml of sesami oil are mixed ~
and emulsified with a supersonci apparatus under ice-cool- ' ing. The resulting emulsion is subjected to spray-drying at an inlet-gas temperature of 160C and an outlet-gas temperature of 80 C. As a result, 120 g of a fine powder having an average particle size of 2~ lS obtained. The product is ;

792~
I I readily restor~d to an emulsion by mixing with water.
2 j, Example 10 In this example, 300 ml of an aqueous solution 4 ~, containing 6 g of 5-fluororuracil, 300 ml of an aqueous s l,l 5% solution of polyvinylpyrrolidone and lS0 ml o~ peanut

6 1¦ oil are treated in the same manner as described in Example

7 ll 9. As a result, 130 g of a powder having an average 9 ~I particle size of 5 ~ is obtained. The powder is readily 9 I restored to an emulsion by mixing with water. I
lo ! Example 11 ~ .
Il In this example, 500 ml of an aqueous solution 12 1I containing 10 g of chlorpromazine, 500 ml of an aqueous ~ 5~ solution of gelatin and 200 ml of sesami oil in which 14 ¦! 20 g o~ polyoxyethylene sorbitan monooleate is dissolved ~, I
!! are treated with a homogenizer at 10,000 r.p.m. fox lS min.
16 i! The resulting emulsion is subjected to spray-drying at an 17 j~ inlet-gas temperature of 105C and an outlet-gas temperature 18 !i o 93C. As a result, 200 g of a fine powder having an 19 ¦1 average diameter of 6 ~ is obtained. The product is 20 1! readily restored to an emulsion by mixing with water.
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Claims

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

1. A method of preparing a powdered product suitable for preparing an emulsion which comprises:
dispersing at least one substance selected from (a) a solution of a drug or nutriment in oil and (b) an emulsion of an aqueous solution of a drug or nutriment in oil in an aqueous solution containing 0.5 - 10.0% by weight of a water-soluble surface layer former based on the total weight of oil and water capable of forming a thin layer;
and thereafter spray-drying the dispersion at an inlet-gas temperature of 100° - 200°C and an outlet-gas temperature of 70° - 100°C, wherein said oil is selected from the group consisting of sesami oil, peanut oil, olive oil, vitamin A oil and vitamin E
oil; the ratio of the oil to the aqueous solution of the drug or nutriment is 1:10 to 1:1; and the ratio of water-in-oil emulsion to the aqueous solution is 1:1 to 1:10.

2. A method according to Claim 1, wherein the concentration of said surface layer former is from 1% to 3% by weight based upon the total weight of oil and water.

3. A method according to Claim 1, wherein said surface layer former is selected from the group consisting of gelatin, polyvinylpyrrolidone, methylcellulose, polyvinyl-alcohol, polyethylene glycol and fatty acid esters of sucrose.