CA2015657A1

CA2015657A1 - Pharmaceutical composition

Info

Publication number: CA2015657A1
Application number: CA 2015657
Authority: CA
Inventors: Peter G. Hicks; John R. Howard
Original assignee: Fisons Ltd
Current assignee: Fisons Ltd
Priority date: 1989-04-29
Filing date: 1990-04-27
Publication date: 1990-10-29
Also published as: PT93897A; WO1990013284A1

Abstract

Abstract Pharmaceutical composition A pharmaceutical solution comprising 0.1 to 6.0% w/w sodium cromoglycate, 0.1 to 2.0% w/w carbomer, and sufficient quantity of an inorganic base to confer on the solution a pH of from 5.0 to 6.8, the solution containing no amino acids possesses advantageous properties, particularly for ophthalmic use.
The solution preferably contains less than 1.5%, more preferably less than 1.0%, and more than 0.6%, eg about 0.8% w/w carbomer.
The solution preferably contains more than 1.0%, eg 2% w/w, and more preferably more than 3%, eg 4% w/w, of sodium cromoglycate. The concentration of sodium cromoglycate in the solution is preferably less than 5% w/w.
The preferred inorganic base is sodium hydroxide at a concentration of 0.15 to 0.3% w/w.
Also described are processes for the preparation of the solution and methods of treatment involving its use.

Description

2 ~ 7 Pharmaceutical Composition This invention relates to pharmaceutical compositions, processes for their preparation, and methods of treatment -involving their use.
Sodium cromoglycate, the disodium salt of 1,3-bis(2-carboxychromon-5-yloxy)propan-2-ol, has been known for many years for the treatment of conditions in which allerqy plays at least a contributory part. Aqueous ~ ~
solutions containing about 2% w/w sodium cromoglycate are ~ ;
also known, eg from US Patent No 4053628, for administration to the eye. Such solutions are effective but suffer from the disadvantage that they have to be applied frequently, eg every four hours, for maximum Pffect. In an attempt to overcome this problem, viscous solutions containing 2% w/w sodium cromoglycate and hydroxypropyl methylcellulose (HPMC) as viscosity-modifying agent have been prepared (see, for example British Patent Application No 2167300A).
A drawback of viscous ophthalmic solutions is that if the viscosity is too great the user may suffer some discomfort after administration of the solution. By increasing the concentration of the active ingredient it may be possible to reduce the viscosity necessary to achieve improved duration of action. However, sodium 25 cromoglycate solutions containing HPMC have been found to :
'-.

-2~5~7 be unstable when the concentration of the active ingredient is increased to more than about 3% w/w.
We have now surprisingly found that viscous 4% w/w sodium cromoglycate solutions are stable when a carbomer is used as the viscosity-modifying agent and an inorganic base is incorporated as neutralising agent. Furthermore, recent teaching in the art (see European Patent Application No 0275054) suggests that carbomer-based formulations exhibit low storage stability unless adjusted to a pH of 10 ~
10 or higher. Such a pH is however physiologically ~;
unacceptable. EP-A 0275054 teaches that this problem may be overcome by the inclusion of an amino acid in the formulation. Contrary to this teaching, we have found that, in the case of carbomer-based sodium cromoglycate formulations, the stability of the solution is satisfactory at pH values physiologically acceptable to the eye and is actually greater when the solution does not contain an amino acid.
Thus, according to the invention there is provided a pharmaceutical solution comprising 0.1 to 6.0% w/w sodium cromoglycate, 0.1 to 2.0% w/w carbomer, and sufficient quantity of an inorganic base to confer on the solution a pH of from 5.0 to 6.8, the solution containing no amino acids.

25 The solutions according to the present invention are -. - .. ~ - . :, - ~ . , - :

... .

- ` ~ Q ~ 7 advantageous in that they are longer acting, more acceptable to the patient, give rise to higher concentrations of active ingredient in target tissues, give rise to effective concentrations of active ingredient in target tissues for a longer time or are more stable, eg in terms of their viscosity, pH or colour, than known similar ;
formulations. This may enable reduced frequency of administration and improved patient compliance. Also, the tendency of the solutions to discolour on storage is less than is the case where an amino acid is included in the solution, as is the dependence of the viscosity on pH. The resistance of the active ingredient to degradation may also be improved.
By the term 'carbomer' is meant a polymer of acrylic acid cross-linked with a polyalkenyl polyether. Numerous grades of carbomer are available. Examples are the carbomers available from the Goodrich Chemical Co, USA, under the trade names Carbopol 934, Carbopol 940 and Carbopol 941. Those which are suitable for use in the present invention are of pharmaceutical purity; we particularly prefer the carbomer sold as Carbopol 934P and equivalents.
The solution preferably contains less than 1.5%, more preferably less than 1.0%, and more than 0.6%, eg about 0.8% w/w carbomer.
: ~ .

,:, ~ .: , : - , ,. ~ ,. - . :

2~56~7 The solution preferably contains more than 1.0%, eg 2% w/w, and more preferably more than 3%, eg 4% w/w, of sodium cromoglycate. The concentration of sodium cromoglycate in the solution is preferably less than ~-5% w/w.
A variety of inorganic bases may be used as neutralising agent in the solution. Examples are alkali metal hydroxides, eg potassium hydroxide or, more preferably, sodium hydroxide, and ammonium hydroxide. The concentration of inorganic base in the solution will depend on several factors including the precise concentration and grade of carbomer and the particular inorganic base used.
However, in general, a concentration in the range of about 0.1 to 1.5~ w/w is found to be satisfactory. Where sodium hydroxide is used, for example, a suitable concentration is of the order of 0.15 to 0.3% w/w.
We prefer the viscosity of the solution to be from 100 to 900, more preferably from about 300 to 800, and most preferably from about 400 to 700 mPa.s, as measured using -an RVT Brookfield viscometer at a shear rate of 9.6 s 1 and a temperature of 20C.
The solution may be hypertonic or hypotonic but is preferably made substantially isotonic by the incorporation of a suitable tonicity adjusting agent. Suitable tonicity 25 adjusting agents include sodium chloride and, more 2 0 ~ ~ 6 ~ ~

preferably, non-ionic agents such as polyols, in particular mannitol or, more preferably, glycerol. Non-ionic tonicity adjusting agents have the advantage that they do not interfere with the gel structure of the solution.
The solution may also contain an effective proportion of a pharmaceutically acceptable chelating or sequestering agent. Suitable sequestering or chelating agents include citric acid, tartaric acid, phosphoric acid and amino carboxylate compounds, preferably ethylenediamine tetraacetic acid or its salts, eg the disodium salt.
The concentration of the chelating or sequestering agent may vary considerably, but in any case should be such as to ensure that no precipitation of carbomer or of metal salts of the active ingredient occurs. A suitable concentration may be from 0.01 to 0.2, and preferably from 0.05 to 0.15% w/w.
The solution may also if desired contain an effective proportion, eg from 0.001 to 0.50% w/w of a pharmaceutically acceptable preservative. The preferred preservatives are the alkyl benzyl dimethyl ammonium chlorides and mixtures thereof, eg that known generically as 'benzalkonium chloride'.
The solution preferably has a pH of from about 5.5 to 6.5 and most preferably from about 5.8 to 6.2.
The solution may be prepared by dispersing the , ~:: , . : - .
. : ~ . . ~ .. .

2 ~

carbomer in a solution containing the sodium cromoglycate and preservative (if used) and then, if necessary, adjusting the pH and further diluting the solution with water.
The solution of the preservative and sodium cromoglycate may be made by dissolving the ingredients in water which is low in metal ions.
We have, however, in some cases experienced considerable difficulty in preparing such solutions in sterile form. These difficulties appear to be due to the thermal instability of certain of the components and/or to the viscosity of the solution which makes sterilisation of the solution by autoclaving a difficult and lengthy process causing some degradation of one or more of the constituents f the solution.
In order to overcome these difficulties, we have devised a process which greatly facilitates the preparation of sterile, viscous solutions containing a carbomer and a neutralising agent. This process for the preparation of an aqueous solution containing a carbomer and a neutralising agent comprises the steps of a) preparing and heat-sterilising a first solution containing the carbomer, b) preparing and sterilising a second solution 25 containing the neutralising agent, and --: ~ . , :. .
~ ~ , 4 , , -2 ~ 7 c) aseptically mixing the first and second solutions.
The above process is advantageous in that it permits the preparation of sterile viscous solutions containing a carbomer and a neutralising agent without any substantial degradation of any of the components of the solution.
The second solution may be sterilised by sterile filtration or, provided that the neutralising agent is stable to heat, eg when the neutralising agent is sodium hydroxide, by heat-sterilisation.

Active ingredient and, where the final solution is to contain them, a tonicity adjusting agent, a chelating or sequestering agent, and/or a preservative, may be incorporated into the second or, more preferably, the first solution prior to sterilisation and aseptic mixing.

lS Where the preservative used is benzalkonium chloride, some complex formation may occur when the benzalkonium chloride is added to the solution. It may therefore be necessary to use a higher concentration of preservative than is required in the final product.

The ratio of the volume of the first solution to the volume of the second solution is preferably in the range 20:1 to 1:1, more preferably about 10~
The pharmaceutical solution according to the invention is, when it contains a preservative, conveniently a 25 multi-dose formulation packaged in, for example, a dropper '~,',,~ ' . ~ ; , ............. ~. .: .. ~, 1. ................. .
'' , .. " . . , '', ., :.
- ~ , . . . ... .

- 2 0 ~ 7 bottle. For ophthalmic use, the bottle conveniently has a volume of from 5 to 20ml. In order to prevent loss of moisture during long-term storage, it may be desirable to enclose the bottle (or other container) in a water-impervious overwrap.
Conditions of the eye in the treatment of which the solution of the invention may be used include vernal catarrh (vernal kerato-conjunctivitis) and marginal corneal ulceration or infiltration. Other conditions which may be treated by the method of the invention include the ocular effects of hay fever, 'allergic eyes' where the allergen is known or unknown and spring/summer conjunctivitis. This latter term is used to mean allergic disorders of the eyes occurring in the spring and summer where an external -~
allergen plays a part in the disorder. Further conditions which may be mentioned are 'irritable eye' or 'non-specific conjunctivitis', Herpes Simplex Keratitis and Conjunctivitis, Herpes Zoster Keratitis and Conjunctivitis, adenovirus infections, phlyctenular conjunctivitis, corneal homograft rejection, Trachoma, anterior uveitis and drug sensitivity.
According to the invention we also provide a method of treatment of conditions of the eye in which allergy plays at least a contributory part, which method comprises 25 administering a therapeutically effective amount of a '.; ':` ' . " '.-: . ' ''.~ . . ' ~ .
s:
''' ' ' :'' -' ` ' - 2 0 ~

g solution as herein described to the eye of a patient suffering from such a condition.
The dosage to be administered will of course vary with the condition to be treated and with its severity.
However, in general, for use in the eye a dosage of about 1 or 2 drops (eg from about l.O to 4.Omg of active ingredient depending on the concentration of the solution) into the affected eye from 2 to 4 times ~ day is found to be satisfactory. More frequent dosage may, of course, be used if desired.
The invention is illustrated but in no way limited by ~ -the following examples.
Example 1 Inaredients 15 Sodium cromoglycate 4.0 % w/w Disodium edetate BP O.1 Benzalkonium chloride USNF O.O1 Glycerol 1.545 Carbopol 934P 0.8 20 Sodium hydroxide BP 0.276 Purified water BP to lOO
Method 1) Sodium cromoglycate (88g) and Disodium edetate BP
(2.2g) are dissolved in approximately lkg of purified 25 water.

. , : : . .
- ~ , , . ;. . . .
,.,~:, -.

- 2 0 ~ 7 2) 0.72g Benzalkonium chloride solution 50% USNF is dispersed in about 500g of Purified Water BP.

3) The solution from 2) is added to the solution from 1) with stirring.

4) 34.0g glycerol is dissolved in about 200g of Purified Water BP and added to the product from 3).

5) The solution from 4) is diluted to 2.Okg and stirred for 10 minutes.

6) The solution is stored overnight at 4C.

7) The solution is filtered via a glass fibre plus a 1.2 micron Millipore RA membrane discarding the first 50ml of filtrate.

8) 16.0g of carbopol 934P is added to approximately lkg of solution from 7) and dispersed.

9) The weight of the solution from 8) is adjusted to 1834.2g with solution from 7) and the solution is autoclaved.

10) 6.66g of sodium hydroxide BP is dissolved in 200g of purified water and sterile-filtered.

11) 165.8g of solution from 10) is mixed aseptically with the solution from 9).
Example 2 Ingredients Sodium cromoglycate 4.0 ~ w/w 25 Disodium edetate BP 0.1 .

2 ~ 7 Benzalkonium chloride USNF 0.01 --Glycerol 1.60 Carbopol 934P 0.8 Sodium hydroxide BP 0.2 5 Purified water BP to 100 Method Prepared by the method of Example 1.
Example 3 Inaredients Sodium cromoglycate 4.0 % w/w Disodium edetate BP 0.1 Benzalkonium chloride USNF 0.01 Mannitol 3.0 Carbopol 934P 0.8 15 Sodium hydroxide BP 0.276 ~:
Purified water BP to 100 Method Prepared by the method of Example 1.
Example 4 Inqredients Sodium cromoglycate 2.0 % w/w Disodium edetate BP 0.1 Benzalkonium chloride USNF 0.01 Glycerol 1.68 :
25 Carbopol 934P 0.63 ; ~';

. - - . . : -. ~ :, . , , . :

~, ,~- ~ . , ! . , 2 ~ 7 Sodium hydroxide BP 0.217 Purified water BP to 100 Method Prepared by the method of Example 1.

.

Claims

1. A pharmaceutical solution comprising 0.1 to 6.0% w/w sodium cromoglycate, 0.1 to 2.0% w/w carbomer, and sufficient quantity of an inorganic base to confer on the solution a pH of from 5.0 to 6.8, the solution containing no amino acids.

2. A solution according to Claim 1, containing from 0.6%
to 1.5% w/w carbomer.

3. A solution according to Claim 1 or Claim 2, containing from 3.0% to 5.0% sodium cromoglycate.

4. A solution according to Claim 2 and Claim 3.

5. A solution according to any one of the preceding claims in which the inorganic base is sodium hydroxide at a concentration of 0.15 to 0.30% w/w.

6. A solution according to any one of the preceding claims, which is made isotonic by the incorporation of a non-ionic tonicity adjusting agent.

7. A solution according to any one of the preceding claims which has a pH of from 5.5 to 6.5.

8. A process for the preparation of an aqueous solution containing a carbomer and a neutralising agent, which process comprises the steps of a) preparing and heat-sterilising a first solution containing the carbomer, b) preparing and sterilising a second solution containing the neutralising agent, and c) aseptically mixing the first and second solutions.

9. A process according to Claim 8, wherein the ratio of the volume of the first solution to the volume of the second solution is in the range 20:1 to 1:1.

10. A method of treatment of conditions of the eye in which allergy plays at least a contributory part, which method comprises administering a therapeutically effective amount of a solution according to any one of Claims 1 to 7 to the eye of a patient suffering from such a condition.