U.S. patent number RE39,181 [Application Number 09/955,274] was granted by the patent office on 2006-07-11 for aqueous risperidone formulations.
Invention is credited to Willy Maria Albert Carlo Dries, Marc Karel Jozef Francois.
United States Patent |
RE39,181 |
Francois , et al. |
July 11, 2006 |
Aqueous risperidone formulations
Abstract
The present invention is concerned with physicochemically stable
aqueous solutions of risperidone for oral and parenteral
administration; processes for preparing such formulations.
Inventors: |
Francois; Marc Karel Jozef
(Beerse, BE), Dries; Willy Maria Albert Carlo
(Beerse, BE) |
Family
ID: |
26955530 |
Appl.
No.: |
09/955,274 |
Filed: |
December 4, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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08272462 |
Jul 11, 1994 |
5453425 |
|
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Reissue of: |
08429435 |
Apr 26, 1995 |
05616587 |
Apr 1, 1997 |
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Current U.S.
Class: |
514/259.41;
514/340 |
Current CPC
Class: |
A61K
9/0095 (20130101); A61P 25/24 (20180101); A61K
31/519 (20130101); A61P 25/18 (20180101) |
Current International
Class: |
A61K
9/08 (20060101) |
Field of
Search: |
;514/258,340 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Page; Thurman K.
Assistant Examiner: Berko; Retford
Attorney, Agent or Firm: Woodrow; Hal B.
Parent Case Text
.Iadd.This application is a Continuation-In-Part of U.S.
application Ser. No. 08/272,462, filed Jul. 11, 1994, now issued as
U.S. Pat. No. 5,453,425..Iaddend.
Claims
We claim:
1. An aqueous solution suitable for oral and parenteral
administration comprising water, risperidone or a pharmaceutically
acceptable acid addition salt thereof, characterized in that said
solution comprises a buffer to maintain the pH in the range of 2 to
6 and is essentially free of sorbitol.
2. A solution according to claim 1 wherein said pH range is
obtained with a tartaric acid/sodium hydroxide buffer.
3. A solution according to claim 1 wherein the amount of
risperidone ranges from 0.01% to 1% by weight based on the total
volume of the solution.
4. A solution according to claim 1 having a pH ranging from 3 to 4
which is suitable for oral administration.
5. A solution according to claim 4 further comprising benzoic acid
as a preservative.
6. A solution according to claim 5 containing (a) 1 mg/ml
risperidone; (b) 2 mg/ml benzoic acid; (c) 7.5 mg/ml tartaric acid
and sufficient sodium hydroxide to adjust the pH in the range from
3 to 4; and (d) water q.s. ad 1 ml.
7. A solution according to claim 6 further comprising one or more
members selected from the group consisting of sweetening agents and
flavouring substances.
8. A solution according to claim 1 having a pH ranging from 5 to 6
which is suitable for parenteral administration.
9. A solution according to claim 4 further comprising sodium
chloride as an isotonizing agent.
10. A solution according to claim 9 containing (a) 1 mg/ml
risperidone; (b) 5 mg/ml sodium chloride; (c) 7.5 mg/ml tartaric
acid and sufficient sodium hydroxide to adjust the pH in the range
from 5 to 6; and (d) water q.s. ad 1 ml.
11. A process of preparing a solution according to claim 1
comprising the steps of (a) adding the acid component of the buffer
and the active ingredient risperidone to an amount of water, (b)
stirring the mixture until complete dissolution and cooling the
solution to room temperature, (c) adjusting the pH with the base
component of the buffer, and (d) further diluting the solution with
water to the required end-volume.
12. A process according to claim 11 for preparing an oral solution
as defined in claim 5 wherein step (a) is preceded by the steps of:
(a) dissolving the preservative in an amount of heated water, and
(b) diluting the solution with about an equal amount of water.
13. A process according to claim 11 for preparing an parenteral
solution as defined in claim 9 wherein step (d) is preceded
immediately by the step of rendering the solution about isotonic by
the addition of an appropriate amount of isotonizing agent, and is
followed by autoclaving.
Description
The present invention is concerned with physicochemically stable
aqueous solutions of risperidone for oral and parenteral
administration.
EP-0,196,132 (1984) discloses an unbuffered oral solution
containing a 1,2-benzisoxazol-3-yl derivative as an antipsychotic
ingredient, methylparaben, propylparaben, tartaric acid (ca. 1.37
eq of the active ingredient), sodium saccharin, raspberry and
gooseberry essence, the polyhydric alcohols sorbitol and glycerol
(1,2,3-propanetriol) and a relatively small amount water (<30%
v/v). It further discloses oral drops containing 10 mg/ml of a
1,2-benzisoxazol-3-yl derivative, lactic acid (5.5 eq.), sodium
saccharin, cocoa flavour and a very minor amount of water (5% v/v)
in polyethylene glycol. Also disclosed is an unbuffered aqueous
injectable solution comprising 4 mg/ml of a 1,2-benzisoxazol-3-yl
derivative, methylparaben, propylparaben, lactic acid and propylene
glycol. The aqueous risperidone formulations of the present
invention differ from these prior art formulations in that they are
buffered and do not contain sorbitol. Moreover, the present
formulations conform more readily to current regulatory
requirements.
Regulatory requirements for pharmaceutical preparations over the
years have become more stringent. For example, the use of
preservatives such as the parabens is nowadays being discouraged.
Also stability requirements during storage, when considerable
temperature changes may occur which may affect the integrity of the
pharmaceutical product, have become more prominent in the
regulatory approval phase, imposing new challenges to be faced, and
solved, during the development of present day pharmaceutical
products. Yet another concern uttered by the authorities relates to
the fact that the bioavailability of pharmaceutical products should
be predictable and reproducible. For example, this requirement
implies that the dissolution behaviour of the product upon oral
ingestion, as well as upon injection should be predictable and
reproducible.
The present invention relates to the finding that an aqueous
buffered solution wherein the benzisoxazole derivative is
risperidone has satisfactory oral bioavailability, can be preserved
without or with very little preservatives, and can easily be
diluted. It relates in particular to the fact that oral solutions
were found to have an unsatisfactory physicochemical stability when
sorbitol was comprised in the formula. Unexpectedly, sorbitol was
found to cause decomposition of risperidone upon storage of the
solution at elevated temperatures, i.e. under conditions which
imitate those of a long storage time. A similar observation
recently made with the polyhydric alcohol maltitol suggests that
risperidone may well be incompatible with other polyhydric
alcohols. A physico-chemically stable oral risperidone solution was
obtained after omitting the sorbitol constituent from the
composition. The advantages over the prior art compositions thus
are concerned with ease of dilution in other aqueous systems and
with improved physicochemical stability.
The present invention concerns an aqueous solution for oral and
parenteral administration comprising water, risperidone or a
pharmaceutically acceptable acid addition salt thereof,
characterized in that said solution comprises a buffer to maintain
the pH in the range of 2 to 6 and is essentially free of
sorbitol.
The subject compositions are characterized by their improved
physicochemical stability when compared to the art compositions.
The term "physicochemically stable" as herein defined refers to a
solution wherein, after storage for a period up to 4 weeks at a
temperature of 80.degree. C. or below, the residual amount of
risperidone is 80% or more of the initial risperidone
concentration. Several compositions of the subject invention are
characterized by an unchanged concentration of risperidone under
even more stringent conditions, in particular an extended storage
time at an elevated temperature.
Hereinafter, the amounts of each of the ingredients in the
compositions are expressed as percentages by weight based on the
total volume of the formulation (w/v), or as volume or weight per
ml of final solution. Ratios are intended to define
weight-by-weight ratios.
Risperidone is genetic to
3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethy1]-6,7,8,9-tet-
rahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. The preparation
and pharmacological activity thereof are described in EP-0,196,
132. The term risperidone as used herein comprises the free base
form and the pharmaceutically acceptable acid addition salts
thereof. The solubility of risperidone is increased upon the
formation of such salt forms, which can be obtained by reaction of
the base form with an appropriate acid. Appropriate acids comprise,
for example, inorganic acids such as hydrohalic acids, e.g.
hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and
the like acids; or organic acids such as, for example, acetic,
propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic,
succinic, maleic, fumaric, malic, tartaric, citric,
methanesulfonic, ethanesulfonic, benzenesulfonic,
p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic
and the like acids. The term addition salt as used hereinabove also
comprises the solvates which risperidone as well as the salts
thereof, are able to form. Such solvates are for example hydrates,
alcoholates and the like.
The solutions according to the present invention have a pH from 2
to 6, preferably from 3 to 5. Oral solutions most preferably have a
pH value from 3 to 4, parenteral solutions from 5 to 6. The pH of
the compositions is maintained by a buffer system. Buffer systems
comprise mixtures of appropriate amounts of an acid such as
phosphoric, succinic, tartaric, lactic, or citric acid, and a base,
in particular sodium hydroxide or disodium hydrogen phosphate.
Ideally, the buffer has sufficient capacity to remain in the
intended pH range upon dilution with a neutral, a slightly acidic
or a slightly basic beverage.
The desired pH range is most advantageously obtained using a
tartaric acid/sodium hydroxide buffer, particularly in view of the
fact that risperidone tartrate is the salt form that presently
would appear to have the best solubility in aqueous media, in
particular upon dilution. Thus, the solubility of risperidone
tartrate is about 80 mg/ml, or about 4 times that of risperidone
hydrochloride (19.6 mg/ml) at room temperature.
The amount (w/v) of risperidone in the present compositions ranges
from 0.01% to 1%, preferably from 0.02% to 0.5%, most preferably
from 0.05% to 0.25%, and in particular is 0.1% (1 mg/ml) in the
oral solutions and about 0.2% (2 mg/ml) in the parenteral
solutions.
In order to prevent the growth of micro-organisms such as bacteria,
yeasts and fungi in the oral compositions which are likely to be
used repeatedly, a preservative agent may be added. Suitable
preservatives should be physicochemically stable and effective in
the pH range mentioned above. They comprise benzoic acid, sorbic
acid, methylparaben, propylparaben, imidazolidinyl urea (=Germall
115.RTM.) and diazolidinyl urea (=Germall II.RTM.), phenoxetol,
benzyl alcohol, quaternary compounds, e.g. benzylalkonium chloride,
and the like. Some preservatives, such as benzoic acid, sorbic
acid, Germall 115.RTM., Germall II.RTM. and benzyl alcohol, have
the advantage that they yield clear, transparent solutions which do
not show any clouding upon storage. The concentration of the
preservatives may range from 0.05% to 1%, particularly from 0.1% to
0.5%, and most particularly is about 0.2%. The most preferred
preservative is benzoic acid used at about 2 mg/ml.
Parenteral solutions do not require the presence of any
preservatives. The parenteral solution is sterilized following
art-known procedures, e.g. it can be filtered aseptically through a
stainless-steel filter holder equipped with a 0.2 .mu.m
polyvinylidene difluoride filter into a suitable sterile glass
flask, filled into ampoules (e.g. 2 ml), and then sterilized by
autoclaving during 30 minutes at 121.degree.
C.(.sup.F10,121.gtoreq.15 min).
The oral compositions optionally may include additional ingredients
known in the art of formulation such as sweetening agents,
flavouring substances, solubility enhancers, viscosity regulating
agents and the like ingredients. For example, the aqueous
solubility of the active ingredient may be enhanced by the addition
to the solution of a pharmaceutically acceptable co-solvent, a
cyclodextrin or a derivative thereof.
The bitter taste of risperidone and the buffer, and the unpleasant
taste associated with the pH of some formulas optionally may be
masked by one or more intense sweetening agents such as saccharin,
sodium or potassium or calcium saccharin, acesulfame potassium or
sodium cyclamate. The concentration of the sweetening agent may
range from 0.04% to 0.15% and in particular is about 0.1%. Given
the incompatability of risperidone with sorbitol, it is believed
that the solution should not comprise polyhydric alcohols such as
mannitol, fructose, sucrose, maltose and the like sweetening
agents. The palatability of the subject solutions optionally may be
optimized further by the addition of one or more flavouring
substances. Suitable flavouring substances are fruit flavours such
as cherry, raspberry, black currant or strawberry flavour, or
stronger flavours, such as Caramel Chocolate flavour, Mint Cool
flavour, Fantasy flavour and the like. Combinations of flavours are
advantageously used. A combination of two cherry flavours was found
to yield very good taste masking results in the present
compositions. The total concentration of the flavouring substances
may range from 0.01% to 0.5%, preferably from 0.03% to 0.2% and
most preferably from 0.05% to 0.1%.
The buffered solutions according to the present invention are well
suited to dilution with water and beverages or drinking liquids
such as coffee, tea, soft drinks and the like. In general this
increases the palatability of the oral solution and, hence, patient
compliance to the medication.
A particular oral composition according to the present invention
comprises (a) 0.02% to 0.5% risperidone; (b) 0.1% to 0.5%
preservatives; (c) a suitable amount of buffer to adjust the pH in
the range from 2 to 6; and (d) water.
The most preferred oral composition according to the present
invention contains (a) 0.1% (1 mg/ml) risperidone; (b) 0.2% (2
mg/ml) benzoic acid; (c) 0.75% (7.5 mg/ml) tartaric acid and
sufficient sodium hydroxide 1 N to adjust the pH in the range from
2 to 6 (approx. 1 mg/ml); and (d) water q.s. ad 100% (1 ml).
Parenteral compositions according to the present invention
preferably comprise one or more isotonizing agents, in particular
sodium chloride, in amount sufficient to render the final solution
isotonic with the body fluid of the subject to be treated. The most
preferred parenteral composition according to the present invention
contains (a) 0.2% (2 mg/ml) risperidone; (b) 0.5% (5 mg/ml) sodium
chloride; (c) 0.75% (7.5 mg/ml) tartaric acid and sufficient sodium
hydroxide 1 N to adjust the pH in the range from 2 to 6 (approx.
3.5 mg/ml); and (d) water q.s. ad 100% (1 ml).
In a further aspect, the present invention relates to a process of
preparing solutions of risperidone as described hereinabove,
characterized by dissolving the active ingredient risperidone,
either the preservative or the isotonizing agent, and the acid and
base components of the buffer in water.
In particular, the process comprises the following steps: (a)
adding the acid component of the buffer and the active ingredient
risperidone to an amount of water which is preferably above room
temperature (b) stirring the mixture until complete dissolution and
cooling the solution to room temperature, (c) adjusting the pH with
the base component of the buffer and (d) further diluting the
solution with water to the required end-volume. In the preparation
of oral solutions, step (a) may be preceded by the steps of
dissolving the preservative in an amount of heated water and (b)
diluting the solution with about an equal amount of water.
Optionally, one or more sweetening agents and flavouring substances
may be added during any of the process steps. In the preparation of
parenteral solutions, step (d) may be preceded immediately by the
step of rendering the solution isotonic by the addition of an
appropriate amount of an isotonizing agent, and followed by
autoclaving.
The following examples are intended to illustrate the scope of the
present invention in all its aspects but not to limit it
thereto.
EXAMPLE 1
TABLE-US-00001 F1: oral solution (pH = 3 .+-. 1) Quantity,
Ingredient mg/ml oral solution risperidone 2 tartaric acid 7.5
benzoic acid 2 Cherry flavour 1 0.25 Cherry flavour 2 0.5 sodium
saccarin 1 sodium hydroxide ca. 1 (q.s. ad pH 3 .+-. 1) purified
water q.s. ad 1 ml
(1) 2 mg benzoic acid was dissolved in 0.5 ml water upon stirring
at 80.degree.-90.degree. C. 0.4 ml water was added to the solution
and 7.5 mg tartaric acid and 2 mg risperidone were dissolved in the
resulting mixture upon stirring.
(2) 1 mg sodium saccharin was dissolved in 0.05 ml water upon
stirring.
(3) fractions (1) and (2) were mixed upon stirring and the solution
was cooled to room temperature.
(4) 0.25 mg Cherry flavour 1 and 0.5 mg Cherry flavour 2 were added
to fraction (3) upon stirring.
(5) 1 mg sodium hydroxide was added to fraction (4) to adjust the
pH to about 3.
(6) fraction (5) was further diluted with water to 1 mL.
In a similar way there were prepared:
TABLE-US-00002 Quantity, Ingredient mg/ml oral solution F2: oral
solution (pH = 4 .+-. 1) risperidone 0.5 tartaric acid 7.5 benzoic
acid 2 Cherry flavour 1 0.25 Cherry flavour 2 0.5 sodium saccarin 1
sodium hydroxide q.s. ad pH = 4 .+-. 1 purified water q.s. ad 1 ml
F3: oral solution (pH = 3) risperidone 0.5 tartaric acid 7.5 sodium
chloride 5 sodium saccharin 1 sodium hydroxide q.s. ad pH = 3
purified water q.s. ad 1 ml F4: oral solution (pH = 5) risperidone
0.5 tartaric acid 7.5 sodium chloride 5 sodium saccharin 1 sodium
hydroxide q.s. ad pH = 5 purified water q.s. ad 1 ml F5: oral
solution (pH = 3) risperidone 1 tartaric acid 7.5 benzoic acid 2
sodium hydroxide ca. 1 (q.s. ad pH = 3) purified water q.s. ad 1 ml
F6 parenteral solution (pH = 5) risperidone 2 tartaric acid 7.5
sodium chloride 5 sodium hydroxide ca. 3.75 (q.s. ad pH = 5)
purified water q.s. ad 1 ml
EXAMPLE 2
The tables hereinbelow summarize the risperidone concentrations
measured after a particular storage time of the composition at a
particular temperature, expressed as the percentage of the initial
risperidone concentration.
TABLE-US-00003 F1 F2 4.degree. C. 12 months 98.2 25.degree. C. 1
month 100.4 101.1 3 months 102.1 99.1 6 months 100.9 9 months 99.5
12 months 98.7 30.degree. C. 3 months 102.1 98.8 6 months 100.3 12
months 98.9 40.degree. C. 1 month 102.1 101.1 3 months 100.9 99.4 6
months 100.5 12 months 98.3 60.degree. C. 1 month 100.1 100.3
EXAMPLE 3
TABLE-US-00004 TABLE 2 F3 F4 80.degree. C. 5 days 97.9 99.0 17 days
96.7 96.6 4 weeks 86.2 87.6
The data in the tables indicate that compositions F1-F4 satisfy the
criteria as set forth hereinbefore to qualify as a
"physiochemically stable" composition.
* * * * *