CA1069823A - Solution of a oxazepine for oral or parenteral administration - Google Patents
Solution of a oxazepine for oral or parenteral administrationInfo
- Publication number
- CA1069823A CA1069823A CA256,154A CA256154A CA1069823A CA 1069823 A CA1069823 A CA 1069823A CA 256154 A CA256154 A CA 256154A CA 1069823 A CA1069823 A CA 1069823A
- Authority
- CA
- Canada
- Prior art keywords
- oxazepine
- chloro
- solution
- dibenz
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
Abstract
SOLUTION OF A OXAZEPINE FOR ORAL OR
PARENTERAL ADMINISTRATION
ABSTRACT OF THE DISCLOSURE
Stable, soluble solutions of 2-chloro-11-(4-methyl-l-piperazinyl)-dibenz[b,f][1,4]oxazepine are described, some of which are suitable for oral and others for parenteral administration.
PARENTERAL ADMINISTRATION
ABSTRACT OF THE DISCLOSURE
Stable, soluble solutions of 2-chloro-11-(4-methyl-l-piperazinyl)-dibenz[b,f][1,4]oxazepine are described, some of which are suitable for oral and others for parenteral administration.
Description
?5, ~It(3 ,s :~
,~ .
9~3Z3 B/~CK(;ROUrll) 01;'~, Il`l'`rE;r~ O~ .
The compound 2~ch10ro~ meth~Jl-l-piperazinyl)- . :
dibenz[b,r][l,ll]oxazeplne is a Icnown compound havlng thera-peutic effects on the central nervous system. U S. Patent No. 3,5l~6,226 specifically discloses 2-chloro-11-(4-methyl-l-pipera~inyl)-dibenz[b,f][1,4]oxazepine, its nontoxic pharmaceutically acceptable acid addition salts, their parenteral administration and their utility as central nerv-ous system.agents U.S. Patent 3,66~,696 discloses a parenteral solution composed of 2-chloro-11-(1-piperazinyl)-dibenz[b,f][l,4]oxazepine and certain acid addition sa.lts thereof, -ln a mixture of propylene glycol, water and ascorbic acid U.S. Patent ~,412,193 discloses the oral administratiGn of 2-chloro-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]-oxazepine in propylene ~lycol for the purpose of testing anti fertility efficacy.
Problems have existed with preparations containin~ ~;
: 2-chloro-11-(4-methyl-1.-piperazinyl)-dibenz[b,f][1,4]oxaze-pine. .Due to the.compound's low solubility in water, it is . difficult to.formulate in conventional pharmaceutical forms such as parenteral and oral liquid preparations employing, for example, water for in~ection. Another problem which makes the compound difficuIt to prepare in liquid dosage forms is its low solubility in liquids having a basic or ~ 25 .near neutral.pH. A still further problem associated with the compound is that one of.its hydrolysis products, namely, : 2-chloro-dibenz[b,f][1,4]oxazepin-ll(lOH)-one, is extremely insoluble in water, Aqueous solutlons Or 2-chloro-11-(4-methyl-l-piperazinyl)-dlbenz[b,fJ[1,4Joxazeplne have proven ~0 unstable and unsuitabIe prlmarily because of the precipltatlon of the above hydroly~i~ product whlch forms ln trace amounts long before the potency Or the solutlon has dropped below acceptable levels Although the hydrolysis product ls non-, . ~ .
~6~t;98Z3 toxic, i~s preclpit{lt:l.oll is, of courl3c, unacceptable ln .~n inJectable soluti.on of the nct~ve oxazepine. ~11 Or the above problems can be overcome by the 'application of the instant invention.
The oxazepine of this invention and its acid addition salts can be prepared as illustrated in U.S. '.
Patent No. ~,66~,696.
. ~ SU~Y OF THE INVENTION . '' This inven~ion is concerned with sta~le oral concentrates and parenteral solutions of 2-chloro ll- .
(4.-methyl-l-piperazinyl)diben~[b,f][1,4~oxazépine base and its non-toxic pharmaceutically acceptable acid addition salts.
The invention is specifically concerned with an improved solubilizedJ stabilized solution comprising as the main active ingredient.2-chloro-11-(4-methyl-l-pipera-zinyl)-`; dibenz[b,f][lJ4]oxazepine base or pharmaceutically acceptable acid addition salts thereof dissolved in about 5~ to about 80~o (preferab.ly about 70~ v/V) aqueous solution o~ propylene glycol having a pH of from about 5.0 to about 7.0 (préferably about 6,0), and, optionallyJ containing from about:2~ to .about lO~ (preferably about 5t~o) polysorbate 80. The invention is specifically concerned with parenteral solution's and oral concentrates in accordance with the~above.
. The invention is.further specifically concerned 2S with a method of solubilizing and stabilizing 2-chloro~
(4-methyl-l-piperazinyl)-dibenz[bJf][1,4]oxazepine which ~ '~
comprises dissolving the compound in about 50~ to oO~O (pre- : :
' ferably 70~0 v/v) aqueous solutlons Or propylene glycol, ad-' Justing the pH to about 5.0 to about 7.0 (prere.rably about : ~0 6.0 p~I) wlth a dilute mlneral acid such as dilute hydrochloric or sulfuric Rcid (e.g., lO~); optionally, adding rrom about
,~ .
9~3Z3 B/~CK(;ROUrll) 01;'~, Il`l'`rE;r~ O~ .
The compound 2~ch10ro~ meth~Jl-l-piperazinyl)- . :
dibenz[b,r][l,ll]oxazeplne is a Icnown compound havlng thera-peutic effects on the central nervous system. U S. Patent No. 3,5l~6,226 specifically discloses 2-chloro-11-(4-methyl-l-pipera~inyl)-dibenz[b,f][1,4]oxazepine, its nontoxic pharmaceutically acceptable acid addition salts, their parenteral administration and their utility as central nerv-ous system.agents U.S. Patent 3,66~,696 discloses a parenteral solution composed of 2-chloro-11-(1-piperazinyl)-dibenz[b,f][l,4]oxazepine and certain acid addition sa.lts thereof, -ln a mixture of propylene glycol, water and ascorbic acid U.S. Patent ~,412,193 discloses the oral administratiGn of 2-chloro-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]-oxazepine in propylene ~lycol for the purpose of testing anti fertility efficacy.
Problems have existed with preparations containin~ ~;
: 2-chloro-11-(4-methyl-1.-piperazinyl)-dibenz[b,f][1,4]oxaze-pine. .Due to the.compound's low solubility in water, it is . difficult to.formulate in conventional pharmaceutical forms such as parenteral and oral liquid preparations employing, for example, water for in~ection. Another problem which makes the compound difficuIt to prepare in liquid dosage forms is its low solubility in liquids having a basic or ~ 25 .near neutral.pH. A still further problem associated with the compound is that one of.its hydrolysis products, namely, : 2-chloro-dibenz[b,f][1,4]oxazepin-ll(lOH)-one, is extremely insoluble in water, Aqueous solutlons Or 2-chloro-11-(4-methyl-l-piperazinyl)-dlbenz[b,fJ[1,4Joxazeplne have proven ~0 unstable and unsuitabIe prlmarily because of the precipltatlon of the above hydroly~i~ product whlch forms ln trace amounts long before the potency Or the solutlon has dropped below acceptable levels Although the hydrolysis product ls non-, . ~ .
~6~t;98Z3 toxic, i~s preclpit{lt:l.oll is, of courl3c, unacceptable ln .~n inJectable soluti.on of the nct~ve oxazepine. ~11 Or the above problems can be overcome by the 'application of the instant invention.
The oxazepine of this invention and its acid addition salts can be prepared as illustrated in U.S. '.
Patent No. ~,66~,696.
. ~ SU~Y OF THE INVENTION . '' This inven~ion is concerned with sta~le oral concentrates and parenteral solutions of 2-chloro ll- .
(4.-methyl-l-piperazinyl)diben~[b,f][1,4~oxazépine base and its non-toxic pharmaceutically acceptable acid addition salts.
The invention is specifically concerned with an improved solubilizedJ stabilized solution comprising as the main active ingredient.2-chloro-11-(4-methyl-l-pipera-zinyl)-`; dibenz[b,f][lJ4]oxazepine base or pharmaceutically acceptable acid addition salts thereof dissolved in about 5~ to about 80~o (preferab.ly about 70~ v/V) aqueous solution o~ propylene glycol having a pH of from about 5.0 to about 7.0 (préferably about 6,0), and, optionallyJ containing from about:2~ to .about lO~ (preferably about 5t~o) polysorbate 80. The invention is specifically concerned with parenteral solution's and oral concentrates in accordance with the~above.
. The invention is.further specifically concerned 2S with a method of solubilizing and stabilizing 2-chloro~
(4-methyl-l-piperazinyl)-dibenz[bJf][1,4]oxazepine which ~ '~
comprises dissolving the compound in about 50~ to oO~O (pre- : :
' ferably 70~0 v/v) aqueous solutlons Or propylene glycol, ad-' Justing the pH to about 5.0 to about 7.0 (prere.rably about : ~0 6.0 p~I) wlth a dilute mlneral acid such as dilute hydrochloric or sulfuric Rcid (e.g., lO~); optionally, adding rrom about
- 2% to about l~, (pre~erably about 5(,~) polysorbnte 80; and ~ adding water to the'desired ~olume (water ror in~ection in : - 2 -; . ~
38~;~
the case of p~renterals). Such ~ procedure h~s the ~d vantages of providin~ a stable, pharmaceut-lcally acceptable solution of the active oxazepine, wherein: solution is eomplete and remains so for prolonged periods; the p~l is conduc-tive to malntainlng solution and is not incompatible for either oral or parenteral a.dminis.tration; the stability is good; and traces of the noted hydrolysis product remain in solution.
' The addition of Polysorbate 80 at a level of about 2% to about 10~, although not absolutely necessary,-provides an additional advantage for both the parente~al solution and oral concentrate. Because 2-chloro-11-(4-' ' methyl-l-piperazinyl)-dibenz[b~f][l~4~oxazepine crystallizes-from~neutral or basic media, the oxazepine exhibits a tendency :
to crystallize when parenterally a.dministered to body fluids - . (pH about 7.0). The a.ddition of Polysorbate 80 raises the ~.
solubility level of the oxazepine in the 7~,~ aqueous propylene glycol an'd eliminates the crystallization during intramuscular admi'nistration, The addition of Polysorba.te 80 to the oral eoncentrate is advantageous ~hen it is desi.red to add the ' '- concentrate to non-acidic foods or beverages because the oxazepine precipitates on dilution with such foods unless polysorbaté 80 is present.
The compound 2-chloro~ methyI-l-piperazinyl) dibenz b,f 1,4 oxazepine may be.employed in the solutions of this invention either.in the form o~ its free base or its non-toxic, pharmaceutically acceptable acid addi~ion salts, pre~erably the succinate salt. O~her non-to~ie .
~; pharmaceutically acceptable acid addition salts deeme'd suitable
38~;~
the case of p~renterals). Such ~ procedure h~s the ~d vantages of providin~ a stable, pharmaceut-lcally acceptable solution of the active oxazepine, wherein: solution is eomplete and remains so for prolonged periods; the p~l is conduc-tive to malntainlng solution and is not incompatible for either oral or parenteral a.dminis.tration; the stability is good; and traces of the noted hydrolysis product remain in solution.
' The addition of Polysorbate 80 at a level of about 2% to about 10~, although not absolutely necessary,-provides an additional advantage for both the parente~al solution and oral concentrate. Because 2-chloro-11-(4-' ' methyl-l-piperazinyl)-dibenz[b~f][l~4~oxazepine crystallizes-from~neutral or basic media, the oxazepine exhibits a tendency :
to crystallize when parenterally a.dministered to body fluids - . (pH about 7.0). The a.ddition of Polysorbate 80 raises the ~.
solubility level of the oxazepine in the 7~,~ aqueous propylene glycol an'd eliminates the crystallization during intramuscular admi'nistration, The addition of Polysorba.te 80 to the oral eoncentrate is advantageous ~hen it is desi.red to add the ' '- concentrate to non-acidic foods or beverages because the oxazepine precipitates on dilution with such foods unless polysorbaté 80 is present.
The compound 2-chloro~ methyI-l-piperazinyl) dibenz b,f 1,4 oxazepine may be.employed in the solutions of this invention either.in the form o~ its free base or its non-toxic, pharmaceutically acceptable acid addi~ion salts, pre~erably the succinate salt. O~her non-to~ie .
~; pharmaceutically acceptable acid addition salts deeme'd suitable
3 in addition to the succinate included the hylrochloride, sulfote, .
~0 ~9 ~'~ 3 phosphate, ci~rate, ~artrate, male~te, fumarate, heptanoate, pamoate, etc.
D~TA~L~D DI~SCRIPT~ON OF T~-IL~ INVl~l'rION
A parenteral solution Or the invention may be prepared as follows: The concentrations of ingredients are based on the final volume unless otherwise defined. 2-Chloro-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepine in an amount sufficient to provide a final weight percent/volume of O.5~0 to 5~ (5 mg/cc to 50 m~/cc) is dissolved in 5~,~ to 80~ v/v of propylene glycol U S.P The solution is adjusted to pH 5.0 to 7.0 with a dilute mineral acid, dilu~ed to 100~
with water for injection U.S.P. and then sterile filtered. ~ ~ -If desired, Polysorbate 80 U.S.P. at 2~ to 10~ may be added to the propylene glycol solution before diluting to final ` 15 volume with water for injection.
A oral concentrate of the invention may be pre-pared in the same manner as above except that sterilization is not needed and distilled water may be substituted for water~for injection. ~ -The oral concentrate can be added to foods for the purpose of producing a palatable form of the oxazepine or for concealing its presence, e.g., ~or administration to patients ~ho may reject the drug if aware of it Such pat-ients include mentally disturbed persons, as in mental hos-~ pitals; children; senile persons; etc. Although a varlety of foods can be used for these purposes, liquid foods are especially adaptable and particularly fruit juices, such as orange juice and related beverage~. Oral conc~ntratcs con-taining about 10~50 m~ of drug per ml of concentrate may be used with about 25 mg/ml being preferred. The oral concentrate may be added to foods in amount3 Or up to 2 ml of concen-: .
trate per ounce of food with about 0,5-1,0 ml~ounce being preferred. The total amount of concentrate will of course .- _ 1~ ~
9~Z3 depend on the na~ure o~ the lllnes~ and on ~he pat~ent, but, in g~neral, f'rom one ha].f ~o G ml Or conc~n~rate, con~aining for example 25 me/ml, m.~Y be used per day, wi~h a preferred range of 2 to ll ml, Such amount may be given in one dose or divided into 2, ~ or 4 doses which are glven at appropriate intervals Preparation of Parentcral Solution of 2-Chloro~ (4-methyl -l-piperazinyl)-dibenz[b,fl[1,4]oxazepi.ne Base A 6~ 0 gm portion o~ 2-chloro-11~(4-methyl-1-`piperazinyl)-dibenz[b,f]-[1,4]oxazepine base is added to 2100 ml of propylene glycol U.S.P. grade and mixed. An 800 ml portion of water for in~ection is added and mixed. The pH
. is adjusted to 6.2'with 10~ hydrochloric acid, mixed and heated to 60C for 30 minutes The pH is adjusted to 6 0 with 10~ hydrochloric acid (making the total volume of hydro-chloric'acid used 51 ml). The mixture is diulted to ~000 ml with water for injection and sterile filtered through a -29~ mm Selas filter'or its equivalent having-a 0 22u membrane `20 The final solution has a potency of 2.0~ active ingredient The formulation is filled into ampoules o~ vials each containing 2.0 ml (representing 40 mg'of drug), ', ' ' ' ", Preparation of Parenteral Solution of 2-Chloro-11-4-methyl--l-piperazinyl)~dibenz[b,f][1,_41oxazepine Base ~ A 105.6~ gm portion of 2-chloro-11-(4-methyl-1 piperazinyl)-dibenz[b,f~[1,4Joxa7epine ~ase i5 adde'd to a ~' mixture of 1l~00 ml of proyylcne glycol U.S.P. and 400 ml Or water for in~ection and mixed, The p~l ls ~dJusted to 6.0 with 10~ hydroch].orlc acld, ~ 100 gm portlon of Polysorbate 80 U.S.P. Ls added, The p~l i8 read~usted to 6,0 with 10~
hydrochloric acid and the solution is diluted to 2000 ml with ~' ' 10~i9~
water for injection. The solution is filtered through a Millipore* AP20 pad and then Selas* 0.2u silver membrane or lts equivalent. The final solution has a potency of 5.0~ active inyredient.
The formulation is filled into ampoules or vials each containing 2.Om. (representing 100 mg of drug).
Preparation of an Oral Concentrate of 2-Chloro-11-(4-methyl--l-piperazinyl)-dibenz[b~f][1~4]oxazepine Base A 12,600 ml portion of propylene glycol U.S.P. is placed in a 25 liter stainless steel pot. A 4 liter portion of water is added and mixed. A 474 gm portion of 2-chloro--11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepin~
base is added and mixed. The pH o the solution is adjusted to 6.0 with 10% hydrochloric acid. This solution is diluted to 18,000 ml with water; mixed, the pH is readjusted to 6.0 and then filtered through a Millipore* AP 20 pad and 0.45 to 1.2 micron solvent resistant membrane. The potency of the final solution is 2.5~ as active ingredient.
Use of Oral Concentrate of 2-Chloro-11-(4-methyl-1-piperaziny]
dibenz[b,f][l,4]oxazepine Base An oral concentrate containing 2.5% w/v 2-chloro-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepine base in 70% aqueous propylene glycol, prepared as in Example 3, was added to grapefruit, orange, or pineapple juice, adding 1 ml of concentrate per ounce o juice (0.83 mg of drug per ml of drink). The taste, appearance~ and pH of the drinks were ac-ceptable and the stability was satisfactory for at least 24 hours in the juices named.
*Trademarks - 6 -. ~
.
lO~j9~Z3 ~XAMPL~
Typical rormulations are:
Parenteral Percent ~/ v 2-chloro-11-(4-methyl.-1-piperazlnyl)-dibenz[b,f~[l,4]oxazeplne base 5.25 Polysorbate 80 VSP Food ~.dditive Grade 5.0 Hydrochloric Acid - Reagent q.s. pH 6.0 q.s.
Propylene Glycol USP 70.0 (v) Water for injection USP ~.s. ad 100.0 (v) Oral 2-chloro-11-(4-methyl-1-piperaziny~)-dibenz[bJf][1,4.~oxazepine base 2~63 .Hydrochloric Acid - Reagent q.s. pH 6.0 q.s.
Propylene Glycol USP 70 0 (v) Water (Distilled) 100.0 ~v~
Other ingredients which do not adversel~J affect the parenteral solution or ora.l concentrate may also be add-ed thereto such as buffers, preservatives, flavors, dyes, : sweetening agents, suspending agents, and the like. Also, minor amounts.of other active ingredients may be added as : .long as they do not adversely affect the solution or concen-trate.
The efficacy of thë solutions of 2-chloro-il-(4-methyl-l-piperazinyl~-dibenz[b,f][1,4]oxazepine, prepared in accordance with the present invention, may be illustrated by a comparison of their potency with the encapsulated form of - this compound. For such a tes.t, ma~e Wistar strain rats are used, Capsule contents comprising 2-chloro~ 1(4-methyl-1-..
piperazinyl)-dibenz[b,f][1,4]oxazepine succinate and convent-lonal excipients is suspended in a 2,~ starch vehicle and administered to rats by gavage at the rate of 0.5 ml per 100 gm of body ~leight. Nlne dose levels ran~ing rrom O.OG to 12.0 .. mg/kg are used with 10 to 15 rats per dose A parenteral . 30 solution comprising 2-chloro-11-(4-methyl-1-plperazinyl)-dibenz-~b,~1,4]oxazepine base at a concentration of 20 ~g/
.:
ml in 70~ propylene glycol is lnJected into rats un~iluted, intramuscularly in ~icro liter volumes. Eight dose levels i~ - 7 -~ , ,,. ~
~ 6~ 3 rane~lng from 0.12 to 12,0 rng/kg are used wlth 10 to llO rats per dose, Each rat is testcd for catalcpsy, a measure of the neuroleptic activity of' the dru~, at varlous times up to 6 hours after drug administration, The criterion for catalepsy is maintenance of paw posltion on four corks for longer than 10 seconds. The median effective doses, those at which 50~ of the animals showed catalepsy, is calculated at various intervals of time after drug administration.
The results appear in Table I.
, .
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_ O ~
,~ ~ ~ ~ r ~ ~
~ .o~ . . . . .
o . ,, o o o o . O ~ o r~
~n i~ ~ ~D ~r ~ ~ ~ ., tn ,. ~ ~ o o o o o ~r~ ~ _ _ _ y _ _ _ I` O
~rl ~ O ~ a~In ~ ' ~1 ~ ~ . . .. . . .
C ~ ,~ ~ o o o o o .
~a ~
.,, C . , .
~, _....__ ...__ . .
_J
~ . .
. o ~
a"' ~ .
Hl a o~ .
~1 ~ c ~ ~ ~ ~ ~
.~ O ^ ~ r o ~ ~ 1 ~ ~ ~
t~ tn ~~r . . . . , . O O O O O .
.
. ~~ ' I I~D O ~ ~ 'r~
1~~r~)(~1 ~1 0 G
~: U~ U~~1 0 0 0 0 G
a _ y~_ y .
a ~a ~ O ~
~ ~ . . . . . . .
:~: - u ~ o o o o o _ _ - ' ', .
,i ` O .
h ~ .
S~
~:S ~ In U~
u) ~ In r` o ~n o c ~` . U~
O O o ~ ,~
. ~'~ . .
- , _ .
'`
_ 9 _ , 10698'h3 The above results show that there are no real differences in potency b~tween the oral (capsule) and parenteral (i.ntramuscular) forms at any time period up to 6 hours.after drug administration. ~ :
The favorable stabllity of the oral and parenteral solutions of this invention have been established in numerous tests. The criterion of stability being the lack of precipi- ~ -tation of the hydroylsis product 2-chloro-dibenz[b,f][1,4]-oxa.zepin-ll(10~l)-one In general, crystallizatlon of this hydrolysis product does.not occur at concentra.tions below 500 mcg/ml in these new solutions. Three such studies follow:
In.the first study a number of 10 mg/ml solutions of 2-chloro~ -methyl-l-piperazinyl)-dibenæ~b,f][1,4]oxaze-. pine base are prepared in 50.~., 60,~ and 70~ aqueous propylene glycol at pH 6Ø A 15 month stability study produced the . composite resu}ts shown in Table II.
-. .
. . .
. 20 .' ~'~ .' .
. ' . ' " ' ~
' ' ' , ' ~:, :
.' . ' , ~ ' , -` - . - 10 -.. . .
~ ' ' ~0t;98Z3 . `
aJ .
E.
C
~P. .
~-, ~ ~ In O I . . .
. ~ ~ r CO CO C10 . ~ r c~
~C .
~ U .
. ,po~: ~ .
~ .. . . .' ' 1~.~ .
H ::~ E o o o .
~ 0~ ~ ~ o ~ I 1~
_ ~ C . . .
~:: I dP c P ~
a) I o o o C L~
.~ . oR, . .
' ' . ~ . .
'~ . , _ ~ ' . .
%3 All of the solutl.ons rctaln acceptable potency levels and none show preclpitation Or thc hydrolysis product.
In the second stu~y a parenteral solutlon of 2-chlQro-11~(4-methyl-1-piperazinyl)-dibenz~b,f][l,li]oY~azepine is prepared at a concentration of 15 mg/ml in 70% v/v propylene glycol in water for inJection U.S.P. at a pH Or 6.0 A stability study is carried out at various temperatures and for varying lengths of time, as indicated in Table III, to measure the retained potency of the active component as well as the increase in concentration of the hydrolysis product.
, '' -'' .
.: 30 -: , ~ ~f~ .
9~
_ .... ._ ..... ~_ ~0l ~, a) .
~. ~
,~ h ~1 0 ~
C~ ~ ~r1 ,~ ,~ ::: ::: U:
~ ~) ~
._ . ~ ., .
. ~
. ~ r o ~r ~ o ~ o o o r-.~ ~ d' ~ . , ~ .
. ~ _ . -,î
.
HH ~ .
~~_ .
~ o ~ o u~ O In o 3 .~1 .' .~ .
. .-. . .
.
~ U~, ~ O ~
O
: ~ ~ ~ ~ ~o ~ ~ ,, ~o ~ ~0 a) u~ ~ ,"~, ~,, ,~, ,_ O E~ o o o o ~n .e ~
-.
~0~8 In the third te~t a pQrcnteral ~olutlt~n t~' l;h~
active ingredient at a concentration Or 20 rng/ml was prepared as described ln the second stability study. The results appear in Tab le IVo ~'-15 ~ ~
, ' " , ~ ~.
,~ .
~ ' ' , . .
3~ 3 __ _ _ o .
h a ,~
,~ ~ Q,: , U t) t) `~ . ~
E _ ~
.~ .' :' ~ . ' ~ `.
P~ o ~_ Ul ~) ~ C3 ~D O ~ O ~ r N O ~
O r~ D
. ~ . , : .
H _ ~ E ~ ~J ~1 oo r~ u:l In co u~ ~ o, ~o ~ , t) ~ ~ ~ o o o o ~ o o ~ o a~ o o .
~ ~ ~ t`J ~ ~.~ ~ N ~ 1 O, .
. ' .
O ~ , ~ U)~
. ~ , ~ O
~ ~ . ` .
O N ~ ~D H t~ C~ -1 N d' ~ N r-J N
.C E3 0 u) a) O u a) ~ E~ ~ o o O - ~ D O
, - U~ F~
,'` . _ _ ,. .
:`
~S
~ 8 Z 3 As can be seen rrorn khe second nn~ khlrd stability studies, the solutions of thls inventlon show excellent stabi.lity even under accelerated condlt~ons.
~, ! ~ :
, . ' , ',, : 15 "- .
'~
; 20 ' ' ~.
`. 25 ~'' ''' ' .
'' ., ' ' , ,: , '- ' ' ' .
~0 ~9 ~'~ 3 phosphate, ci~rate, ~artrate, male~te, fumarate, heptanoate, pamoate, etc.
D~TA~L~D DI~SCRIPT~ON OF T~-IL~ INVl~l'rION
A parenteral solution Or the invention may be prepared as follows: The concentrations of ingredients are based on the final volume unless otherwise defined. 2-Chloro-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepine in an amount sufficient to provide a final weight percent/volume of O.5~0 to 5~ (5 mg/cc to 50 m~/cc) is dissolved in 5~,~ to 80~ v/v of propylene glycol U S.P The solution is adjusted to pH 5.0 to 7.0 with a dilute mineral acid, dilu~ed to 100~
with water for injection U.S.P. and then sterile filtered. ~ ~ -If desired, Polysorbate 80 U.S.P. at 2~ to 10~ may be added to the propylene glycol solution before diluting to final ` 15 volume with water for injection.
A oral concentrate of the invention may be pre-pared in the same manner as above except that sterilization is not needed and distilled water may be substituted for water~for injection. ~ -The oral concentrate can be added to foods for the purpose of producing a palatable form of the oxazepine or for concealing its presence, e.g., ~or administration to patients ~ho may reject the drug if aware of it Such pat-ients include mentally disturbed persons, as in mental hos-~ pitals; children; senile persons; etc. Although a varlety of foods can be used for these purposes, liquid foods are especially adaptable and particularly fruit juices, such as orange juice and related beverage~. Oral conc~ntratcs con-taining about 10~50 m~ of drug per ml of concentrate may be used with about 25 mg/ml being preferred. The oral concentrate may be added to foods in amount3 Or up to 2 ml of concen-: .
trate per ounce of food with about 0,5-1,0 ml~ounce being preferred. The total amount of concentrate will of course .- _ 1~ ~
9~Z3 depend on the na~ure o~ the lllnes~ and on ~he pat~ent, but, in g~neral, f'rom one ha].f ~o G ml Or conc~n~rate, con~aining for example 25 me/ml, m.~Y be used per day, wi~h a preferred range of 2 to ll ml, Such amount may be given in one dose or divided into 2, ~ or 4 doses which are glven at appropriate intervals Preparation of Parentcral Solution of 2-Chloro~ (4-methyl -l-piperazinyl)-dibenz[b,fl[1,4]oxazepi.ne Base A 6~ 0 gm portion o~ 2-chloro-11~(4-methyl-1-`piperazinyl)-dibenz[b,f]-[1,4]oxazepine base is added to 2100 ml of propylene glycol U.S.P. grade and mixed. An 800 ml portion of water for in~ection is added and mixed. The pH
. is adjusted to 6.2'with 10~ hydrochloric acid, mixed and heated to 60C for 30 minutes The pH is adjusted to 6 0 with 10~ hydrochloric acid (making the total volume of hydro-chloric'acid used 51 ml). The mixture is diulted to ~000 ml with water for injection and sterile filtered through a -29~ mm Selas filter'or its equivalent having-a 0 22u membrane `20 The final solution has a potency of 2.0~ active ingredient The formulation is filled into ampoules o~ vials each containing 2.0 ml (representing 40 mg'of drug), ', ' ' ' ", Preparation of Parenteral Solution of 2-Chloro-11-4-methyl--l-piperazinyl)~dibenz[b,f][1,_41oxazepine Base ~ A 105.6~ gm portion of 2-chloro-11-(4-methyl-1 piperazinyl)-dibenz[b,f~[1,4Joxa7epine ~ase i5 adde'd to a ~' mixture of 1l~00 ml of proyylcne glycol U.S.P. and 400 ml Or water for in~ection and mixed, The p~l ls ~dJusted to 6.0 with 10~ hydroch].orlc acld, ~ 100 gm portlon of Polysorbate 80 U.S.P. Ls added, The p~l i8 read~usted to 6,0 with 10~
hydrochloric acid and the solution is diluted to 2000 ml with ~' ' 10~i9~
water for injection. The solution is filtered through a Millipore* AP20 pad and then Selas* 0.2u silver membrane or lts equivalent. The final solution has a potency of 5.0~ active inyredient.
The formulation is filled into ampoules or vials each containing 2.Om. (representing 100 mg of drug).
Preparation of an Oral Concentrate of 2-Chloro-11-(4-methyl--l-piperazinyl)-dibenz[b~f][1~4]oxazepine Base A 12,600 ml portion of propylene glycol U.S.P. is placed in a 25 liter stainless steel pot. A 4 liter portion of water is added and mixed. A 474 gm portion of 2-chloro--11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepin~
base is added and mixed. The pH o the solution is adjusted to 6.0 with 10% hydrochloric acid. This solution is diluted to 18,000 ml with water; mixed, the pH is readjusted to 6.0 and then filtered through a Millipore* AP 20 pad and 0.45 to 1.2 micron solvent resistant membrane. The potency of the final solution is 2.5~ as active ingredient.
Use of Oral Concentrate of 2-Chloro-11-(4-methyl-1-piperaziny]
dibenz[b,f][l,4]oxazepine Base An oral concentrate containing 2.5% w/v 2-chloro-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxazepine base in 70% aqueous propylene glycol, prepared as in Example 3, was added to grapefruit, orange, or pineapple juice, adding 1 ml of concentrate per ounce o juice (0.83 mg of drug per ml of drink). The taste, appearance~ and pH of the drinks were ac-ceptable and the stability was satisfactory for at least 24 hours in the juices named.
*Trademarks - 6 -. ~
.
lO~j9~Z3 ~XAMPL~
Typical rormulations are:
Parenteral Percent ~/ v 2-chloro-11-(4-methyl.-1-piperazlnyl)-dibenz[b,f~[l,4]oxazeplne base 5.25 Polysorbate 80 VSP Food ~.dditive Grade 5.0 Hydrochloric Acid - Reagent q.s. pH 6.0 q.s.
Propylene Glycol USP 70.0 (v) Water for injection USP ~.s. ad 100.0 (v) Oral 2-chloro-11-(4-methyl-1-piperaziny~)-dibenz[bJf][1,4.~oxazepine base 2~63 .Hydrochloric Acid - Reagent q.s. pH 6.0 q.s.
Propylene Glycol USP 70 0 (v) Water (Distilled) 100.0 ~v~
Other ingredients which do not adversel~J affect the parenteral solution or ora.l concentrate may also be add-ed thereto such as buffers, preservatives, flavors, dyes, : sweetening agents, suspending agents, and the like. Also, minor amounts.of other active ingredients may be added as : .long as they do not adversely affect the solution or concen-trate.
The efficacy of thë solutions of 2-chloro-il-(4-methyl-l-piperazinyl~-dibenz[b,f][1,4]oxazepine, prepared in accordance with the present invention, may be illustrated by a comparison of their potency with the encapsulated form of - this compound. For such a tes.t, ma~e Wistar strain rats are used, Capsule contents comprising 2-chloro~ 1(4-methyl-1-..
piperazinyl)-dibenz[b,f][1,4]oxazepine succinate and convent-lonal excipients is suspended in a 2,~ starch vehicle and administered to rats by gavage at the rate of 0.5 ml per 100 gm of body ~leight. Nlne dose levels ran~ing rrom O.OG to 12.0 .. mg/kg are used with 10 to 15 rats per dose A parenteral . 30 solution comprising 2-chloro-11-(4-methyl-1-plperazinyl)-dibenz-~b,~1,4]oxazepine base at a concentration of 20 ~g/
.:
ml in 70~ propylene glycol is lnJected into rats un~iluted, intramuscularly in ~icro liter volumes. Eight dose levels i~ - 7 -~ , ,,. ~
~ 6~ 3 rane~lng from 0.12 to 12,0 rng/kg are used wlth 10 to llO rats per dose, Each rat is testcd for catalcpsy, a measure of the neuroleptic activity of' the dru~, at varlous times up to 6 hours after drug administration, The criterion for catalepsy is maintenance of paw posltion on four corks for longer than 10 seconds. The median effective doses, those at which 50~ of the animals showed catalepsy, is calculated at various intervals of time after drug administration.
The results appear in Table I.
, .
, ~P~98'h~
_ O ~
,~ ~ ~ ~ r ~ ~
~ .o~ . . . . .
o . ,, o o o o . O ~ o r~
~n i~ ~ ~D ~r ~ ~ ~ ., tn ,. ~ ~ o o o o o ~r~ ~ _ _ _ y _ _ _ I` O
~rl ~ O ~ a~In ~ ' ~1 ~ ~ . . .. . . .
C ~ ,~ ~ o o o o o .
~a ~
.,, C . , .
~, _....__ ...__ . .
_J
~ . .
. o ~
a"' ~ .
Hl a o~ .
~1 ~ c ~ ~ ~ ~ ~
.~ O ^ ~ r o ~ ~ 1 ~ ~ ~
t~ tn ~~r . . . . , . O O O O O .
.
. ~~ ' I I~D O ~ ~ 'r~
1~~r~)(~1 ~1 0 G
~: U~ U~~1 0 0 0 0 G
a _ y~_ y .
a ~a ~ O ~
~ ~ . . . . . . .
:~: - u ~ o o o o o _ _ - ' ', .
,i ` O .
h ~ .
S~
~:S ~ In U~
u) ~ In r` o ~n o c ~` . U~
O O o ~ ,~
. ~'~ . .
- , _ .
'`
_ 9 _ , 10698'h3 The above results show that there are no real differences in potency b~tween the oral (capsule) and parenteral (i.ntramuscular) forms at any time period up to 6 hours.after drug administration. ~ :
The favorable stabllity of the oral and parenteral solutions of this invention have been established in numerous tests. The criterion of stability being the lack of precipi- ~ -tation of the hydroylsis product 2-chloro-dibenz[b,f][1,4]-oxa.zepin-ll(10~l)-one In general, crystallizatlon of this hydrolysis product does.not occur at concentra.tions below 500 mcg/ml in these new solutions. Three such studies follow:
In.the first study a number of 10 mg/ml solutions of 2-chloro~ -methyl-l-piperazinyl)-dibenæ~b,f][1,4]oxaze-. pine base are prepared in 50.~., 60,~ and 70~ aqueous propylene glycol at pH 6Ø A 15 month stability study produced the . composite resu}ts shown in Table II.
-. .
. . .
. 20 .' ~'~ .' .
. ' . ' " ' ~
' ' ' , ' ~:, :
.' . ' , ~ ' , -` - . - 10 -.. . .
~ ' ' ~0t;98Z3 . `
aJ .
E.
C
~P. .
~-, ~ ~ In O I . . .
. ~ ~ r CO CO C10 . ~ r c~
~C .
~ U .
. ,po~: ~ .
~ .. . . .' ' 1~.~ .
H ::~ E o o o .
~ 0~ ~ ~ o ~ I 1~
_ ~ C . . .
~:: I dP c P ~
a) I o o o C L~
.~ . oR, . .
' ' . ~ . .
'~ . , _ ~ ' . .
%3 All of the solutl.ons rctaln acceptable potency levels and none show preclpitation Or thc hydrolysis product.
In the second stu~y a parenteral solutlon of 2-chlQro-11~(4-methyl-1-piperazinyl)-dibenz~b,f][l,li]oY~azepine is prepared at a concentration of 15 mg/ml in 70% v/v propylene glycol in water for inJection U.S.P. at a pH Or 6.0 A stability study is carried out at various temperatures and for varying lengths of time, as indicated in Table III, to measure the retained potency of the active component as well as the increase in concentration of the hydrolysis product.
, '' -'' .
.: 30 -: , ~ ~f~ .
9~
_ .... ._ ..... ~_ ~0l ~, a) .
~. ~
,~ h ~1 0 ~
C~ ~ ~r1 ,~ ,~ ::: ::: U:
~ ~) ~
._ . ~ ., .
. ~
. ~ r o ~r ~ o ~ o o o r-.~ ~ d' ~ . , ~ .
. ~ _ . -,î
.
HH ~ .
~~_ .
~ o ~ o u~ O In o 3 .~1 .' .~ .
. .-. . .
.
~ U~, ~ O ~
O
: ~ ~ ~ ~ ~o ~ ~ ,, ~o ~ ~0 a) u~ ~ ,"~, ~,, ,~, ,_ O E~ o o o o ~n .e ~
-.
~0~8 In the third te~t a pQrcnteral ~olutlt~n t~' l;h~
active ingredient at a concentration Or 20 rng/ml was prepared as described ln the second stability study. The results appear in Tab le IVo ~'-15 ~ ~
, ' " , ~ ~.
,~ .
~ ' ' , . .
3~ 3 __ _ _ o .
h a ,~
,~ ~ Q,: , U t) t) `~ . ~
E _ ~
.~ .' :' ~ . ' ~ `.
P~ o ~_ Ul ~) ~ C3 ~D O ~ O ~ r N O ~
O r~ D
. ~ . , : .
H _ ~ E ~ ~J ~1 oo r~ u:l In co u~ ~ o, ~o ~ , t) ~ ~ ~ o o o o ~ o o ~ o a~ o o .
~ ~ ~ t`J ~ ~.~ ~ N ~ 1 O, .
. ' .
O ~ , ~ U)~
. ~ , ~ O
~ ~ . ` .
O N ~ ~D H t~ C~ -1 N d' ~ N r-J N
.C E3 0 u) a) O u a) ~ E~ ~ o o O - ~ D O
, - U~ F~
,'` . _ _ ,. .
:`
~S
~ 8 Z 3 As can be seen rrorn khe second nn~ khlrd stability studies, the solutions of thls inventlon show excellent stabi.lity even under accelerated condlt~ons.
~, ! ~ :
, . ' , ',, : 15 "- .
'~
; 20 ' ' ~.
`. 25 ~'' ''' ' .
'' ., ' ' , ,: , '- ' ' ' .
Claims (3)
1. A method of preparing a solubilized and stabi-lized solution containing 2-chloro-11-(4-methyl-1-pipera-zinyl)-dibenz[b,f][1,4]oxazepine, or a pharmaceutically ac-ceptable salt thereof, which comprises dissolving said oxa-zepine or salt thereof in about 50% to about 80% v/v aqueous solution of propylene glycol; adjusting the pH to about 5.0 to about 7.0 with a dilute mineral acid; and adding water to the desired volume.
2. A method according to Claim 1, which involves the additional step of adding from about 2% to about 10%
polysorbate 80.
polysorbate 80.
3. A solubilized and stabilized solution comprising 2-chloro-11-(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]oxaze-pine, or a pharmaceutically acceptable acid-addition salt thereof, in about 50% to about 80% v/v aqueous solution of propylene glycol having a pH of from about 5.0 to about 7.0 whenever prepared by the process of Claim 1 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US60233175A | 1975-08-06 | 1975-08-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1069823A true CA1069823A (en) | 1980-01-15 |
Family
ID=24410918
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA256,154A Expired CA1069823A (en) | 1975-08-06 | 1976-07-02 | Solution of a oxazepine for oral or parenteral administration |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS5221313A (en) |
| AR (1) | AR210501A1 (en) |
| AT (1) | AT345464B (en) |
| AU (1) | AU500641B2 (en) |
| BE (1) | BE844903A (en) |
| CA (1) | CA1069823A (en) |
| DE (1) | DE2633943A1 (en) |
| DK (1) | DK147727C (en) |
| EG (1) | EG12425A (en) |
| ES (1) | ES450520A1 (en) |
| FI (1) | FI762171A (en) |
| FR (1) | FR2320102A1 (en) |
| GB (1) | GB1546933A (en) |
| IL (1) | IL49996A (en) |
| NL (1) | NL7608575A (en) |
| NO (1) | NO146457C (en) |
| PT (1) | PT65400B (en) |
| SE (1) | SE431716B (en) |
| ZA (1) | ZA764052B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8404735B2 (en) | 2009-03-18 | 2013-03-26 | Omnipharm Limited | Parasiticidal formulation |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2739255B1 (en) | 1995-09-29 | 1998-09-04 | Rhone Merieux | PEST CONTROL COMPOSITION FOR THE TREATMENT AND PROTECTION OF PETS |
| FR2739254B1 (en) * | 1995-09-29 | 1997-12-19 | Rhone Merieux | PEST CONTROL COMPOSITION FOR THE TREATMENT AND PROTECTION OF PETS |
| IE80657B1 (en) * | 1996-03-29 | 1998-11-04 | Merial Sas | Insecticidal combination to control mammal fleas in particular fleas on cats and dogs |
-
1976
- 1976-07-02 CA CA256,154A patent/CA1069823A/en not_active Expired
- 1976-07-07 ZA ZA764052A patent/ZA764052B/en unknown
- 1976-07-08 IL IL49996A patent/IL49996A/en unknown
- 1976-07-09 AU AU15775/76A patent/AU500641B2/en not_active Expired
- 1976-07-09 GB GB28752/76A patent/GB1546933A/en not_active Expired
- 1976-07-13 AR AR263933A patent/AR210501A1/en active
- 1976-07-22 PT PT65400A patent/PT65400B/en unknown
- 1976-07-28 DE DE19762633943 patent/DE2633943A1/en not_active Withdrawn
- 1976-07-29 FI FI762171A patent/FI762171A/fi not_active Application Discontinuation
- 1976-08-02 NL NL7608575A patent/NL7608575A/en not_active Application Discontinuation
- 1976-08-04 EG EG475/76A patent/EG12425A/en active
- 1976-08-05 AT AT581376A patent/AT345464B/en not_active IP Right Cessation
- 1976-08-05 SE SE7608810A patent/SE431716B/en unknown
- 1976-08-05 DK DK354076A patent/DK147727C/en not_active IP Right Cessation
- 1976-08-05 FR FR7623990A patent/FR2320102A1/en not_active Withdrawn
- 1976-08-05 NO NO762713A patent/NO146457C/en unknown
- 1976-08-05 BE BE169573A patent/BE844903A/en not_active IP Right Cessation
- 1976-08-06 ES ES450520A patent/ES450520A1/en not_active Expired
- 1976-08-06 JP JP51093257A patent/JPS5221313A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8404735B2 (en) | 2009-03-18 | 2013-03-26 | Omnipharm Limited | Parasiticidal formulation |
| US8580837B2 (en) | 2009-03-18 | 2013-11-12 | Fidopharm, Inc. | Parasiticidal formulation |
| US8829038B2 (en) | 2009-03-18 | 2014-09-09 | Velcera, Inc. | Parasiticidal formulation |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2320102A1 (en) | 1977-03-04 |
| JPS5221313A (en) | 1977-02-17 |
| NL7608575A (en) | 1977-02-08 |
| GB1546933A (en) | 1979-05-31 |
| DK147727B (en) | 1984-11-26 |
| FI762171A (en) | 1977-02-07 |
| IL49996A0 (en) | 1976-09-30 |
| SE7608810L (en) | 1977-02-07 |
| ZA764052B (en) | 1977-06-29 |
| DE2633943A1 (en) | 1977-02-17 |
| DK147727C (en) | 1985-06-17 |
| ES450520A1 (en) | 1978-05-01 |
| NO146457B (en) | 1982-06-28 |
| AU500641B2 (en) | 1979-05-31 |
| AU1577576A (en) | 1978-01-12 |
| EG12425A (en) | 1979-06-30 |
| AT345464B (en) | 1978-09-25 |
| NO146457C (en) | 1982-10-06 |
| DK354076A (en) | 1977-02-07 |
| NO762713L (en) | 1977-02-08 |
| SE431716B (en) | 1984-02-27 |
| BE844903A (en) | 1977-02-07 |
| PT65400A (en) | 1976-08-01 |
| IL49996A (en) | 1981-01-30 |
| AR210501A1 (en) | 1977-08-15 |
| PT65400B (en) | 1978-01-27 |
| ATA581376A (en) | 1978-01-15 |
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