WO2008039792A1

WO2008039792A1 - Stable pharmaceutical compositions of preserved formulation of ranitidine, process for making the same, and methods of their use

Info

Publication number: WO2008039792A1
Application number: PCT/US2007/079447
Authority: WO
Inventors: Naglesh R. Palepu
Original assignee: Scidose Llc
Priority date: 2006-09-25
Filing date: 2007-09-25
Publication date: 2008-04-03

Abstract

The present invention is generally related to ethanol free, liquid ranitidine formulations for oral administration. In particular, the present invention is related to stable, syrup formulations having ranitidine as an active ingredient for oral administration, processes for making the same, and methods of their use. The ranitidine of the present invention is stable in non-polar media or media having a relatively low polarity such that the dielectric constant is less than about 60, and is achieved by using certain saccharides, certain relatively high molecular weight starches, and/or certain celluloses instead of ethanol.

Description

STABLE PHARMACEUTICAL COMPOSITIONS OF PRESERVED FORMULATRION OF RANITIDINE, PROCESSES FORMAKING THE SAME,

AND ^IETHODS OF THEIR USE

FIELD OF THE INVENTION

The present invention is generally related to ethanol free, liquid ranitidine formulations for oral administratipn. In particular, the present invention is related to stable, preserved, syrup formulations having ranitidine as an active ingredient for multiple oral administration from a single container, processes for making the same, and methods of their use.

BACKGROUND OF THE INVENTION

Ranitidine [N-[2-[[[5-(dirtiethylamino)methyl-2-furanyl]methyl]thio]ethyl]-N'- methyl-2- nitro- 1 , 1 -ethenedi amine] and physiologically acceptable salts thereof (having, for example, the empirical formula Ci₃H₂₂N₄OsS-HC] and the structural Formula I shown below) are disclosed in British Patent Specification No. 1565966.

Formula I:

(CH₃)_? NCH₂ ^^^ NHCH_{3 •} HCI O

CHNO₂

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123601 00109/35749881 v i According to current prescribing information, the compound of Formula I is indicated for short-term treatment of active duodenal ulcer (most patients found to heal within 4 weeks; studies available have not assessed the safety of ranitidine in uncomplicated duodenal ulcer for periods of more than 8 weeks); maintenance therapy for duodenal ulcer patients at reduced dosage after healing of acute ulcers (no placebo- controlled comparative studies haye been carried out for periods of longer than 1 year); the treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome and systemic mastocytosis); short-term treatment of active, benign gastric ulcer (most patients found to heal within 6 weeks; the usefulness of further treatment has not been demonstrated; studies available hive not assessed the safety of ranitidine in uncomplicated, benign gastric ulcer for periods of more than 6 weeks); maintenance therapy for gastric ulcer patients at reduced dosage after healing for acute ulcers (placebo-controlled studies have been carried out for 1 year); treatment of GERD (symptomatic relief found to commonly occurs within 24 hours after starting therapy with 150 mg b.i.d.); treatment of endoscopically diagnosed erosive esophagitis (symptomatic relief of heartburn found to comrrionly occur within 24 hours of therapy initiation with 150 mg b.i.d.); and maintenance Of healing of erosive esophagitis (placebo-controlled trials have been carried out for 48 weeks). Many of the formulations containing the compound of Formula I disclosed in

British Patent Specification No. 1565966 are known to be unstable and, therefore, not appropriate for marketable formulations that are required to be stable. U.S. Patent No. 4,585,790, on the other hand, discloses improved aqueous formulations of ranitidine that

123601.00109/35749881 v. l are more stable. That patent discloses ranitidine formulations having a pH in the range 6.5 to 7.5 that are suitable formulations for injections for intravenous and intramuscular administration, continuous infusiohs, and oral preparations such as syrups. Similarly, U.S. Patent No. 5,068,249 discloses stabile, aqueous formulations of ranitidine containing ethanol as a stabilizer. That patent describes a pharmaceutical composition which is an aqueous formulation of ranitidine ^nd/or one or more physiologically acceptable salts thereof containing ethanol and thψ is suitable for administration to patients and will, in general, contain at least one conventional pharmaceutical excipient in addition to the ethanol and ranitidine and/or physiologically acceptable salts thereof. U.S. Patent No. 6,265,449 discloses an aqueous pharmaceutical composition for oral administration comprising ranitidine, or a pharmaceutically acceptable salt thereof, that contains alcohol and low colour, metal, turbidity (LCMT) sucrose, which was found to improved stability, bioavailability and taste-masking of ranitidine while allowing the volume of the alcohol required in the solution to be reduced. A commercially available version of a stable pharmaceutically acceptable salt form of the compound of Formula I is known as ZANTAC® syrup, which is described in prescribing information as being a clear peppermint- flavored liquid that contains 16.8 mg of ranitidine-HCl equivalent to l3 milligrams (mg) of ranitidine per 1 milliliter (ml) (75 mg/5 ml) in bottles of 16 fluid ounces (one pint). Because of its relative instability, ZANTAC® is usually stored between about 4° and about 25°C (39° and 77°F) in tight, light-resistant containers.

123601.00109/35749881v.l SUMMARY OF THE INVENTION

It has been surprisingly found that aqueous syrup formulations containing the compound of Formula I, or other physiologically acceptable salts of ranitidine, can be stabilized without the use of ethanol or other alcohols as taught in U.S. Patent Nos. 5,068,249 and 6,265,449, and at pH ranges that are higher and lower than the ranges set forth in those patents. In particular, it has been found that ranitidine is stable in non-polar media or media having a relatively low polarity such that the dielectric constant is less than about 60, the stability achieved by using certain relatively high molecular weight starches, and/or certain celluloses instead of ethanol; buffers are not needed.

Another advantage of the formulations of the present invention is that ethanol free aqueous formulations are generally preferred by, among others, parents who administer those formulations to their children.

Thus, the present invention involves a pharmaceutical composition which is an aqueous formulation containing a pharmaceutically effective amount of ranitidine and/or one or more physiologically acceptable salts thereof for treatment of conditions mediated through histamine H₂-receptors, the formulation having a pH preferably within the range of about 4.85 to about 7.99, and n^ost preferably within the range of about 5.5 to about 6.5, making it suitable for administration to humans and other mammals.

123601.00109/3574988Iv 1 DETAILED DESCRIPTION O^ THE INVENTION

The present invention involves a pharmaceutical composition of the compound of Formula I, or other physiologically acceptable salts of ranitidine, that is stable when dissolved in or combined with oτιe or more relatively high molecular weight starches, and/or celluloses as stabilizers. The formulation thus stabilized with high molecular weight starches and/or celluloses ^vill pass the USP preservative challenge test when a combination of preservatives system is incorporated in the formulation. In addition, physiologically acceptable carriers, excipients, diluents, colorants, flavorants, and other substances may also be added. The preferred preservative combination of the present invention include, but are not limited to, parabens and benzyl alcohol, parabens and cholorobutanol or parabens and propylene glycol.

The preferred starches of tihe present invention include, but are not limited to, ma pregelatinized starch and hydroxy! ethyl starch (HES).

The preferred cellulose of the present invention include, but is not limited to, hydroxyl propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), and hydroxyl ethyl cellulose (HEC).

The concentration of the stabilizers preferably varies from about 5% to about 80% volume per total final composition, preferably from about 40% to about 70% volume per total final composition, most preferably about 5%, especially in the case of cellulose.

The concentration of preservatives is preferably range from 0.01% to 1.0%. Preferably parabens range from 0.02% to 0.2%, benzyl alcohol ranges from 0.2% to 0.9% and chlorobutanol ranges from 0.05% to 0.5%. Most preferably, among the parabens,

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123601.00109/35749881 v.1 propylparaben, ranges from 0.02% toθ.04%, methylparaben ranges from 0.1% to 0.18%, benzyl alcohol ranges from 0.4% to 0.8% and chlorobutanol ranges from 0.1% to 0.3%

The concentration of the compound of Formula I is preferably about 16.8 mg/ml.

Excipients include those that are ssuitable for the manufacture of syrup include but are not limited to suspending agents, co losing agents, flavoring agents, and sweetening agents.

Excipients include those that are suitable for the manufacture of aqueous suspensions and include, but are φt limited to suspending agents, dispersing or wetting agents, coloring agents, flavoring agents, and sweetening agents.

Formulations of the present invention may be prepared by combining, in an appropriate sequence, an amount of the compound of Formula I, or other physiologically acceptable salts of ranitidine, preservatives, high molecular weight cellulose, and with one or more physiologically acceptable carriers, excipients, diluents, colorants, flavorants, or other substances, whereby the compound of Formula I is combined with the one more high molecular weight Starches, or one or more celluloses in order to achieve a generally stabilizing effect on the ranitidine. The resulting ranitidine concentration is about 15 mg/ml of free base (rani idine plus water), preferably 16.8 mg/ml of free base.

The formulations of the indention may be made according to the following process. First, potable water, e.g. 40 mL, is transferred into a beaker calibrated to a predetermined batch volume, of 30 ml. An amount of ranitidine is added to the water to make a solution having a desired boncentration, e.g. about 16.8 mg/ml. The pH of the

123601 00109/3574988 Iv I solution was adjusted to about 4.85 to about 7.99 with 0.1N NaOH, preferably about 5.5 to about 6.5. Next, a stabilizer, suόh as high molecular weight starches, and/or HPC or other cellulose, preservatives is/arέ admixed with the water/ranitidine/buffer solution in an amount necessary to stabilize the ranitidine. An amount of potable water is then added to fill to the predetermined batch volume.

In addition to the above components, one or more excipients may be added to the solution along with the stabilizing agent.

Without further description, it is believed that one of ordinary skill in the art can, using the preceding description and the following illustrative examples, make and utilize the compounds of the present invention and practice the methods. The following examples are given to illustrate the present invention. It should be understood that the invention is not to be limited to the specific conditions or details described in these examples.

Example 1

The formulations of the invention are made according to the following process.

First, 40 ml of potable water are transferred into a beaker calibrated to a batch volume of 50 ml. An amount of ranitidine is added to the water to make a solution having a concentration of about 16.8 mg/ml Into that solution, a sufficient amount of a buffer is dissolved to obtain desired pH. In some occasions. 0.1N NaOH was also used to adjust the pH in addition to buffer to get the target pH. Next, a stabilizing agent such as high molecular weight cellulose or starches is/are admixed with the water/ranitidine/preservative solution in an amount necessary to stabilize the ranitidine.

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123601 00109/35749881 v. l An amount of potable water is thei added to create a batch volume of 50 ml. Samples of the resulting composition are introduced into 5-ml flint stopper vials for accelerated

stability tests.

Example 2

In the next study, we studied the preservative effectiveness test two ranitidine formulations Rl 6 and Rl 7 was conducted . The formulation composition and stability data presented below :

Composition :

R-16

Drug : 16.8mg/ml

HPC : 50.0 mg/ml Sodium saccharin : 3.0mg/ml

Methylparaben : 1.8 mg/ml

Propylparaben 0.2mg/ml pH adjusted with 0.1N NaOH : 5.69

R- 17:

R- 17 formulated with higher levels of parabens. The sodium salt of parabens were used to for a better solubility of parabetns in the syrup formulation. Drug : 16.8mg/ml

HPC : 50.0 mg/ml

123601.00I09/35749881V.1 Sodium saccharin : 3.0mg/ml

Methylparaben-Sodium : 2.5 mg/ml

Propylparaben-Sodium 0.25mg/ml pH adjusted with 0. IN NaOH : 5.71

Both formulations were inoculated with 1 million each of three strains of bacteria, fungus and mold. The preservative effectiveness test was conducted according to the procedure described in the USP26/NF21. Thfe preservative data is summarized in the table below

Surprisingly, all three strains of inoculated bacteria survived in the syrup solution despite the presence of maximum permissible concentration of parabens. Generally at this concentration of methyl- and propyl- paraben concentration, all three strains of bacteria will be eradicated within a week. [The data suggest that the higmolecular weight cellulose might be impeding the eradication of the bacteria.

123601.00109/35749881v. l In the next set of experiments we have tired the following batches which contained different combinations of preservatives. The various tested formulations are tabulated below:

The preservative effectiveness studies were conducted on these four formulations.

The 28 days count on formulations R21 to R-24 was completed on all three strains of bacteria and 21 days count on C. Albicans and A.niger was completed. Since the PET

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123601.00109/35749881 v. i studies on formulation R-28 initiated at a later date we have completed up to 21 days

count. Formulation R-28 is modifi ed version of initial test formulation. A small amount

of propylene glycol was added wi :h reduced levels of parabens. The rationale to use

propylene glycol was to increase i he solubility of parabens in the formulations and to

ensure that parabens remain in so^' ution during the study. It was hypothesized that the

initial test formulation was probably did not pass USP PET due to the precipitation of parabens during the incubation thereby not adequate amount preservative is available for eradicating the microorganiams. flence propylene glycol was incorporated in the formulation with the hope that the^ parabens remain in the solubilized form during the study. The data are presented in the Table below:

Table : Preservative Challenge Study of Various formulations of Ranitidine Syrup CODE COdE CODE CODE CODE

R21 R22 R23 R24 R28 cfu/ml cfu/ml cfu/ml cfu/ml cfu/ml

E.coli

Odays 15x10e5 14x1 OeS 19x10e5 12x10e5 13x10e5

7 clays <5 cfu/ml <5 cfu/ml <5 cfu/ml <5 cfu/ml <5 cfu/ml

14 days <5 cfu/ml <5 cfu/ml <5 cfu/ml <5 cfu/ml <5 cfu/ml

21 days <5 cfu/ml <5cf(j/ml <5 cfu/ml <5 cfu/ml <5

28days <5 cfu/ml <5 cfu/ml <5 cfu/ml <5 cfu/ml in progress

S. aureus

Odays 17x10e5 18x1 0e5 15x10e5 13x10e5 15x10e5

7 days <5 cfu/ml <5 c u/ml <5 cfu/ml <5 cfu/ml <5 cfu/ml

14 days <5 cfu/ml <5 c u/ml <5 cfu/ml <5 cfu/ml <5 cfu/ml

21 days <5 cfu/ml <5cf j/ml <5 cfu/ml <5 cfu/ml <5

28 days <5 cfu/ml <5 c u/ml <5 cfu/ml <5 cfu/ml in progress

P. aeruginosa

0 days 3x10e5 8x1 C •e5 14x10e5 14x10e5 13x1 OeS

7 days <5 cfu/ml <5 c fu/ml <5 cfu/ml <5 cfu/ml <5 cfu/ml

14 days <5 cfu/ml <5 c fu/ml <5 cfu/ml <5 cfu/ml <5 cfu/ml

21 days <5 cfu/ml <5cfu/ml <5 cfu/ml <5 cfu/ml <5

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123601.00109/35749881 v. l 28 days <5 cfu/m! <5 cfψ/ml <5 cfu/ml <5 cfu/ml in progress

C. albicans

0 days 13x10e5 15x10e5 12x10e5 14x10e5 9x10e5

7 days <5 cfu/ml 4x10o4 53x10e1 61 x10e2 6x10e4

14 days <5 cfu/ml <5 cf j/ml <5 cfu/ml <5 cfu/ml 4x10e4

21 days <5 <5 <5 <5 7X10e3

28 days IP IP IP IP IP

A.niger

O days 8x10e4 10x10e4 3x10e5 2x10e5 2x10e5

7 days 11x10e2 2x10 =3 25 8.5x10e2 3x10e3 14 days 10x10e2 4x10 32 20 7.5x10e2 4x10e2 21 days 4x105e2 <5 1x10e1 11x10e1 20x10e1

28 days IP IP IP IP IP

As shown in the table all tested formulations eradicated all three strains of bacteria in 7 days. All formulations eradicated C. albicans at the end of 21 days while in R-28 slightly more than two-log reduction was observed. All formulations showed greater than 4 log

reductions of A.niger count. It should be noted that R-28 is an unique formulation in the sense it is identical to the formulation Rl 6 with the exception that 2% of propylene glycol was added to the formulations with reduced parabens level. As shown, the presence of a small amount of propylene glycol despite decreased levels of parabens enabled the modified version of lφad formulation to pass the USP PET test.

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123601.00109/35749881v.l

Claims

What is claimed is:

1. An ethanol-free aqueous pharmaceutical composition for oral administration

comprising ranitidine and/or one or more physiologically acceptable salts thereof

I wifh a stabilizing effective iimount of a cellulose and preservative effectiveness

using combination of preservatives, wherein the composition has a pH in the range of about 4.85 to about 7.9^.

1. The pharmaceutical composition of claim 1 , containing about 5% weight/volume cellulose based on the complete forrjiulation.

2. The pharmaceutical composition of claim 1 , wherein the cellulose is HPC.

3. The pharmaceutical composition in claim 1 , wherein the starch is hydroxyethyl starch

4. The pharmaceutical composition of claim 1 , having a pH in the range 5.5 to 7.5.

5. The pharmaceutical composition of claim 1 , wherein the pH is obtained without the use of buffer salts.

6. The pharmaceutical composψion of claim 1 , prepared using the compound of Formula I.

7. The pharmaceutical composition of claim 1 , wherein ranitidine concentration is 16.8 milligrams ranitidine per milliliter dose.

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123601.001Q9/35749881V. I

8. Th^ pharmaceutical composition of claim 1 , wherein the cellulose is present at 1 -5% weight/voliime based on the complete formulation

9. Th^ pharmaceutical composition of claim 1 , further comprising of a combination of preservatives

10. The pharmaceutical composition of claim 9 where the preservative combination is ϊ parabens and benzyl alcohol or paraψens and chlorobutanol.

11. The pharmaceutical composition of claim 9 where the preservative combination is parabens and propylene glycol or any other glycol or polyol.

12. The pharmaceutical composition of claim 1 , further comprising a sweetening agent, a buffer and a flavoring agent.

13. The pharmaceutical composition of claim 1 , wherein the cellulose stabilizer is hydroxypropyl cellulose .

14. ]Tfee pharmaceutical composition of claim 1 , further comprising a flavoring system selected from the group consisting of peppermint/orange, peppermint/raspberry, raspberry/orange, and combinations thereof.

15. The pharmaceutical compo; ϊition of claim 1 , wherein the ranitidine conentration is 16.8mg/n)l and the pH is 5.7, and further comprising HPC 50.0 mg/ml, Sodium Saccharin

3.0mg/mϊ, methyl paraben 1.8mg[ml, propyl parben 0.2mg/ml and propylene glycol

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123601.001 (JMD/35749881 v. l concentration is 2%(v/v).

16. Th| method of claim 15 , whejrein thφ ranitidine is of Formula I.

17. Thέ method of claim 15 , wherein thφ ranitidine concentration is 16.8 milligrams

[ 1 ranitidine ]j>er milliliter.

18. Thfc method of claim 15, wherein the cellulose is present at 1-5% weight/volume based on the corttplete formulation

19. The method of claim 15, furtfrier comprising the step of adding a sweetening agent and a flavoring agent.

20. Th& method of claim 15, whφrein the cellulose stabilizer is hydroxypropyl cellulose .

21. Th& method of claim 15, whφrein the pH is maintained by a buffer system comprising of acetate, citrate, phosphate, succinate, or any pharmaceutically acceptable acid or base with pKa ranging 4.5 to 6.5.

22. Thfc method of claim 15, wherein further comprising a step of adding saccharin or any pharmaceutically acceptable sweetehing agent

23. Thb method of claim 15, further comprising a step of adding a flavoring system selected from the group consisting of pepperlnint/oitange, peppermint/raspberry, raspberry/orange, andcombinations thereof.

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123601 001 (J9/35749881v, l

25. The method of claim 29, wherein the effective amount is about 1 mg/kgto about 5 mg/kg.

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123601.00109/35749881v.l