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Патент USA US3100182

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i'
1'
I I ite States atent O
1
3,100,177
Patented Aug. 6, 1963
1
2
3,100,177
room temperature, but also substances which are solid
at room temperature but which, when warmed to higher
Larry M. Wheeler, Grosse Pointe Farms, Mich, assignor
erties of ‘a liquid or semi-solid. A wide variety of ?ow
able vehicles are ‘suitable ‘for the invention, the main re
PENTCEHN COMPOSITION FOR PERICARDIAL
INTRODUCTION
to Parke, Davis & Company, Detroit, Mich, a ‘corpo
ration of Michigan
No Drawing. Fiied Jan. 5, 1961, Ser. No. 80,954
8 Claims. (Cl. 167-65)
temperature up to body temperature, have the ?uid prop
quirement being that such vehicles be compatible With,
and non-injurious to, the pericardial tissue while at the
same time being sterilizable and compatible with procaine
penicillin. Water is eminently suited for this purpose as
This invention relates to medicinal compositions 10 well as aqueous isotonic solutions. Water-in-oil and oil
adapted for pericardial introduction. More particularly,
‘in-water emulsions are also suitable. Examples of such
the invention relates to compositions comprising procaine
vehicles are natural butters such as dairy butter and cocoa
penicillin, which provide unexpected, bene?cial results fol
butter; gelatin, agar and acacia solutions, polyviuylpyr
lowing pericardial introduction into patients who have
rolid'one solutions; and the like. Optionally, the composi
undergone a coronary accident or 'who are suifering from 15 tions of the invention may contain one or more agents to
certain types of heart disease in which one of the symp
enhance stability, ?uidity, etc., and other agents such as
toms is pronounced local coronary pain associated with
isotonic agents, coloring agents, etc. For example, the '
circulatory impairment or coronary occlusion. Clinically,
compositions may contain a ?uid-izing agent such as man
this pain is a most distressing phenomenon that lasts day
and night for several days. It not only is of great con
cern to the physician because of the possibility of sec—
ondary spasms occurring, but also is a‘most fatiguing and
panicking symptom to the patient himself.
Heretofore, procaine penicillin in crystalline form has
nitol, sorbitol, sucrose and the like which advantageously
may provide isotonicity. For the purposes of the inven
tion each dosage unit comprises a su?icient volume of
vehicle to hold and suspend the procaine penicillin crys~
tals and other ingredients present, and to provide the bulk
necessary to substantially engross the pericardial cavity
been available for intramuscular injection by means of a 25 upon administration of the total dosage. In the case of
syringe and hollow needle particularly in those cases
water, for example, a convenient volume is 20 ml.
where a repository antibiotic effect is desired. The con
In addition to the large procaine penicillin crystals
ventional forms of procaine penicillin, however, are not
mentioned above, a preferred embodiment of the inven
suited and in fact are not intended for the treatment of the
tion \also includes procaine penicillin in micronized (the
type of heart disease which is relieved by the compositions 30 term “micronized” as used herein refers to crystals of
of the invention.
small size 90% of which are less than 10 microns in larg
According to the invention, there are provided composi
est dimension) form in an amount su?icient to maintain
tions in dosage form for pericardial introduction contain
the above-mentioned large crystals in a state of ?uidity
ing procaine penicillin preferably in suspended form in
when suspended in a vehicle, preferably from 10 to 20
a flowable vehicle. The procaine penicillin contained in 35 grams per unit dosage. The micronized procaine penicil
the compositions of the invention is characterized by a
lin serves conveniently as a carrier for (the large procaine
relatively large average crystal size. Each dosage unit
penicillin crystals and additionally protects the large
thereof contains a su?icient quantity of large crystals to
crystals against the solvent action of the vehicle and
afford on administration continous abrasion and stimula
thereby maintains the large crystals in substantially their
tion of the pericardial tissue, i.e., the tissue interphase 40 original condition over relatively long' periods of time.
between the heart muscle proper and the pericardium.
For this purpose each dosage unit contains, in accordance
with the invention, approximately 2 to 10, and prefer
ably 4 to 8 grams of procaine penicillin crystals exceed
. For enhanced stimulant laction, compositions of the in
vention may also contain an inert abrasive such as ?nely
divided asbestos powder.
The invention also contemplates dosage ‘forms in which
ing 420 microns in length. The crystals may be as large 45 the procaine penicillin is present in dry, crystalline form
as about 940 microns in length (i'.e., No. 16 mesh size)
or larger, but for practical purposes the upper limit of
crystal size is such that when suspended in a vehicle the
crystals can 'be administered by means of a syringe or
equivalent ?uid pumping device without undue blockage
if desired together with micronized procaine penicillin,
?uidizing agents, etc., to which, just prior to administra
tion, is added the desired liquid vehicle such ‘as water,
whereupon the resulting mixture is agitated to provide a
suspension of the procaine penicillin crystals, suitable for
of the ori?ce or chamber. Conveniently, the compositions - ‘ direct administration into the pericardium. Such dosage
of the invention contain procaine penicillin crystals rang
forms are advantageous in that during storage they have
ing in size from about 420 microns to over 860 microns
a relatively long shelf-life and for purposes of adminis
but less than 920 microns. A preferred composition con
tration the ?uidity thereof can be adjusted and controlled‘
tains per unit dosage about 3-3.2 ‘g. of crystals ranging
by the clinician not only by selecting any desired vehicle,
in length between 420-860 microns and 2.6-2.8 g. of - but also by varying the amount of vehicle to provide the
larger crystals ranging upward to 920 microns. In con
particular degree of fluidity required. A preferred dos
trast to the crystal sizes of procaine penicillin of the in
age form, in accordance with the invention, is a sealed
stant invention, the conventional ‘forms of procaine pen
receptacle of suitable volume, such as a syringe or cham
60
icillin used for intramuscular injection seldom if ever
ber insertable in a syringe, containing a unit dose, i.e.,
exceed 100 microns.
The large procaine penicillin crystals employed in the
; 2 about 2 to 10 grams, and prefer-ably 4 to 8 grams, of dry
procaine penicillin crystals to which can be added just
prior to use the desired vehicle for pericardial introduc
tion. The procaine penicillin content of such a preferred
equimolar amounts of procaine and a penicillin salt and 65 dosage form, in the amounts mentioned, is in the form
allowing the resulting solution to stand for a sufficient ‘ - of crystals exceeding 420 microns in length. The dosage
length of tune to permit the growth of a crystalline pre
may also include smaller crystals and preferably includes
compositions of the invention are conveniently prepared
by combining separate aqueous methanolic solutions of
cipitate. The precipitate is then recovered, dried and, if
desired, classi?ed ‘according to size.
approximately 10-20 g. of micronized procaine penicillin.
The compositions of the invention should be rendered
The term “?owable vehicle” as used herein refers not 70 sterile before use and preferably the ingredients, prior
only to substances which are normally liquid and flow at
to and during formulation, should be prepared and ban
3,100,177
4
The resulting crystalline procaine penicillin was col
dled under ‘aseptic conditions. Sterilization is accom
plished by conventional means such as heating, exposure
to ethylene [oxide gas, etc.
The compositions of the invention are administered
lected with suction on a medium sintered glass funnel and
washed with two 500 ml. portions of the ?ltered solvent.
After drying to constant weight (in vacuo, room tem
under sterile conditions by recognized medical techniques 5 perature) 489 gm. of product, M.P. 127-9” 0, was ob
tained.
into the pericardial chamber through a surgical incision.
The clusters of large crystals were broken up with a
In this connection, it is known that heart muscle under
mortar and pestle and pressed through a #16 screen.
duress does not, in many cases, mobilize pericardial fluid
as it should. Part of the loss of efficiency of the peri
Lot B
cardium is due ‘to the insulation generated by the ac 10
Dilute
methanol
was
prepared
by dissolving 16,540 ml.
cumulated ?uid which does not allow the pericardium to
of
methanol
in
su?icient
distilled
'water to make 23.5 1.
exert uniform pressure about the more vital muscles of
of solution.
the heart. Therefore, immediately prior to the adminis
2120 gm. (7.77 moles) of procaine hydrochloride was
tration of the instant compositions, it is desirable to re
move any accumulation of ?uid from ‘the pericardial 15 dissolved in 7 l. of the dilute methanol and ?ltered with
suction (medium sintered glass funnel), rinsing with 1500
chamber. Removal of the ?uid in this manner serves to
ml. of the solvent.
vA solution of 2896 gm. (7.77 moles) of potassium
cillin dosage. Such introduction is carried out con
penicillin
in 8.5 l. of the dilute methanol was prepared
veniently by means \of any suitable pumping device such
_ as a syringe containing the composition, to the ori?ce of 20 exactly as the procaine solution.
The penicillin solution was still slightly hazy. It was
which is attached a catheter or tube having inside dimen
clari?ed by ?ltering with suction through a #90‘ Alsop
sions sui‘?ciently large (e.g. 3 to 5 mm. or larger in diam
pad, rinsing with about 1 l. of the solvent.
eter) to permit the ?ow of the composition, the catheter
5.5 l. of the dilute methanol was ?ltered (suction, med.
being inserted through the incision directly into the peri
facilitate the introduction of the desired procaine peni
cardium. Administration is accomplished readily by
sintered glass funnel).
causing the composition to how, if necessary after pre
liminary warming of the composition to give it greater
bottom, open top glass tank, rinsing each container with
The solutions were transferred to a new 10 gal. round
1 l. of the ?ltered solvent.
The resulting solution was mixed thoroughly with a
the result of local intrapericardi-al motion. Following in 30 stirring rod. A few crystals had formed in the solution
after it stood a few minutes. The tank was sealed and
stillation, the dosage is allowed to remain inde?nitely in
allowed to stand undisturbed at room temperature.
the pericardium where it provides a continuing local
After standing 64 hrs. the crystalline product was col
stimulant and abrasive action. Such action favors the
?uidity, into the pericardial chamber, following which
the injected material becomes uniformly distributed as
lected with suction on a medium sintered glass funnel
establishment of collateral blood circulation to any areas
of the heart muscle where the circulation may be inade 35 and Washed with two 1750 ml. portions of the ?ltered
quate, thereby combatting anoxia or tissue asphyxiation.
methanol solution.
In addition to the ‘desired stimulant and abrasive action,
the compositions of the invention provide a repository
antibacterial eifeot and further importantly provide es
perature), 2247 gm. of the product, M.P. 127—9° C.,
After drying to constant weight (in vacuo, room tem—
was obtained.
sentially complete ‘and sustained alleviation of local pain 40
The clusters of very large crystals were broken up
within a short period following instillation. Ordinarily, a
by passing through a hand mill and ?nally pressed
single dosage provides subjective relief from pain for
several days, i.e. 3 to 4 ‘days, so that further therapy is
through a #16 screen.
Lots A and B were blended in a PK blender for about
unnecessary, at least until any later occurrence of another
40 minutes.
embodiment of the invention, illustrates in detail a proce
Percent (by weight)-—
45
The blended product had the following particle~size
coronary episode.
distribution:
The following description, exemplary of a preferred
dure used for the preparation of procaine penicillin crys
tals and the formulation thereof into a composition suit
able for pericardial introduction.
50
PREPARATION OF PROCAINE PENICILLIN
CRYSTALS
Lot A
Dilute methanol was prepared by dissolving 3598 ml. 55
Dimension (microns)
0 ________________________ __
33.7 ______________________ _.
37.4 ______________________ _.
13.2 _____________________ ..
4.8 _______________________ _.
1.9 _______________________ _.
7.7 _______________________ _.
Greater than
Above 860, to
Above 420, to
Above 250, to
Above 177, to
Above 149, to
940.
940.
860.
420.
250.
177.
Less than 149.
PREPARATION OF STERILE COMPOSITION FOR
of methanol in su?icien-t water to make 5140
of
PERICARDIAL INTRODUCTION
solution.
(A) Procaine penicillin G, micronized sterile
436 gm. (1.6 moles) of procaine hydrochloride was
bulk
___..._
_
gm _
1600
dissolved in 1300
of dilute methanol and ?ltered with 60
(B) Procaine penicillin, blended lots A
suction (medium sintered glass funnel) rinsing with 420
and B ____________________________ __gm__ 800.00
ml. of the solvent.
(C) Asbestos, puri?ed acid washed me
A solution of 596 gm. (1.6 moles) of potassium peni
dium ?ber
__ 0m _
30.00
cillin in 17 20 ml. of dilute methanol was prepared exactly
(D) D-sorbitol solution 70% aqueous_____cc__ 143.00
as the procaine solution.
65 (E) Water for injection U.S.P __________ __cc__ 1915
1700 ml. of dilute methanol was ?ltered (suction, me
dium sintered glass funnel).
Precautions: Mix the solution and powders and ?ll
The solutions were transferred to a 22 1. wide mouth,
tubes under aseptic conditions. Keep the suspension well
round bottom ?ask (free of scratches), rinsing each con
mixed during the ?lling procedure.
tainer with 350 ml. of the ?ltered methanol solution. 70
(1) Screen the asbestos through a #16 screen then
The resulting clear solution ‘was mixed by swirling. After
through a #30 screen.
standing a few minutes a crystal of procaine penicillin
(2)
Autoclave the screened asbestos for 30 minutes.
was added.
Place overnight in an oven at 105° C. to dry.
The ?ask was stoppered and the reaction mixture al
lowed to stand undisturbed for 88 hours at room tem 75 (3) Mix the dried asbestos and the procaine penicillins
in a 10 liter bottle. Ster-ilize with ethylene oxide.
perature.
3,100,177
5
6
(4) Dissolve the D-sorbitol solution 70% in the water
4. A composition according to claim 1 containing per
unit dosage about 3 to 3.2 grams of procaine penicillin
for injection and sterilize by ?ltration through an
02 Selas candle.
(5) Add the sterile sorbitol solution in divided portions
crystals ranging in length between 420 to 860 microns
‘and about 2.6 to 2.8 grams of larger procaine penicillin
to the sterile powders and mix until a smooth suspen
sion is formed.
crystals ranging in length upward ‘to 920 microns.
5. A composition according to claim 1 in which the
(6) Fill 45.30 gm. (vehicle content, 20 cc.) of the sus
pension into sterile, glass syringe tubes 1% x 4%
inches.
Analysis, by weight, per tube:
Percent
?owable vehicle is ?uid at body temperature.
6. A procaine penicillin dosage unit form adapted for
formulation with a vehicle, which comprises a sealed
10 receptacle containing approximately 2 to 10 grams of
__
2.21
procaine penicillin crystals exceeding 420 microns in
length, the contents of said receptacle being adapted for
pericardial introduction.
7. A procaine penicillin dosage unit form in accord
__
44.15
15 ance with claim 6 in which the receptacle also contains
Procaine penicillin G micronized ________ __ 35.32
Procaine penicillin
____
17.66
Asbestos
D-sorbitol
Water ___
0.66
__
__
An alternative preparation, in dry form for subsequent
reconstitution with an aqueous vehicle, is obtained by‘
blending the above dry ingredients A, B and C with
100 g. of D-sorbitol powder and ?lling the mixture in
25-gram amounts into sterile, glass syringe tubes.
What is claimed is:
approximately 10 to 20 grams of micronized procaine
penicillin crystals.
8. A procaine penicillin dosage unit form adapted for
formulation with a vehicle, which comprises a sealed
receptacle containing about 3 to 3.2 grams of procaine
penicillin crystals ranging in length between 420 to 860
microns, about 2.6 to 2.8 grams of larger crystal-s ranging
1. A procaine penicillin composition in dosage form
in length upward to 920 microns, and about 10 to '20
for pericardial introduction which comprises a suspension
grams of micronized procaine penicillin, the contents of
in a ?owable vehicle of procaine penicillin crystals, each 25 said receptacle being adapted for pericardial introduction.
dosage unit of said composition containing approximately
2 to 10 grams of procaine penicillin crystals exceeding
420 microns in length.
2. A composition according to claim 1 in which the
?owable vehicle contains water.
30
3. A composition according to claim 1 containing ap
proximately 10 to 20 grams of micronized procaine peni
cillin per unit dosage.
References Cited in the file of this patent
UNITED STATES PATENTS
2,507,193
2.741.573
Buckwalter ___________ __ May 9, 1950
Kirchmeyer __________ __ Apr. 10, 1956
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