HU210115B - Process for prepg. metoclopramid-hydroclorid solutions for peroral use - Google Patents

Description

The present invention relates to the preparation of aqueous solutions of metoclopramide for oral administration.

Metclopramide, 4-amino-5-chloro-N - [(2-diethylamino) -ethyl] -2-methoxybenzamide, is a well-known and well-established drug used mainly for the symptomatic treatment of nausea and vomiting as an antiemetic or for gastric is used to regulate bowel motor activity. Solutions containing metoclopramide hydrochloride are e.g. in the form of drops, available under the trade name Paspertin ^R Drops.

Aqueous pharmaceutical compositions sold in multiple-dose containers generally contain preservatives; the purpose of the addition of a preservative is to exclude contamination with microorganisms during storage and use. Oral fluids are most commonly known as antibacterial preservatives. containing p-hydroxybenzoic acid esters (i.e., methyl, ethyl or propyl esters of 4-hydroxybenzoic acid); these are the acronyms "PHB esters" used in practice. Sorbic acid (2,4-hexadienoic acid) is often added as a fungistatic preservative. Commercially available multiple-dose orally administrable aqueous metoclopramide formulations (e.g., Paspertin ^R droplets) generally contain a mixture of p-hydroxybenzoic acid esters and sorbic acid as a preservative. A major disadvantage of the use of preservatives in the pharmaceutical industry is that such substances can lead to allergic reactions or sensitization in susceptible patients. In view of the increasing number of allergic diseases, the use of preservatives in the manufacture of pharmaceutical compositions is being restricted as far as possible. In order to ensure the safety and tolerability of the drugs, it is desirable to have drugs with as few components as possible. For these reasons, the authorities which authorize the registration of medicinal products are increasingly relying on the manufacture of medicinal products with as few components as possible.

Farm. Pol. 32/11, 927-932 (1976), CA 86, 177223b (1977) performed a study on the thermal stability of metoclopramide at 60 ° C, 70 ° C and 80 ° C, in the pH range of 2.0 to 7.6. However, there are no data available on the durability of aqueous solutions of metoclopramide against microbial infections.

WO 86/02553. International Patent Application No. 5,123,195 discloses nasal administration of metoclopramide. This literature does not include any reference to the stability of aqueous metoclopramide solutions against microbial contamination.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a simple formulation of metoclopramide in water, which can be administered orally and has an antiemetic effect.

We have found that metoclopramide alone, in aqueous solution, has not only known medicinal properties, but also has a preservative effect against microbial contaminants.

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of aqueous metoclopramide hydrochloride solutions which are stable orally to microbial contaminants and which contain at least 0.4% by weight of metoclopramide hydrochloride, by addition of metoclopramide hydrochloride, conventional flavoring agents and, if desired, dissolved.

The preservative-free methoclopramide hydrochloride solutions of the present invention contain a preservative-effective amount of methoclopramide hydrochloride. Metoclopramide hydrochloride is present in a concentration of at least 0.4% by weight, generally about. 0.4 to 4 wt.%, Preferably ca. 0.4 to 2% by weight, particularly preferably ca. 0.8% to 1.5% by weight, preferably about. 1% by weight.

The aqueous metoclopramide salt solutions prepared according to the present invention contain flavor enhancers and may also contain other conventional pharmaceutical excipients. Sweetening agents used in the manufacture of pharmaceuticals, beverages and foodstuffs, particularly pharmaceutically acceptable sweeteners and sugar substitutes, or mixtures thereof, may be considered as flavor enhancers. These additives may be used in the usual amounts in aqueous pharmaceutical solutions. so e.g. the following sweeteners may be used: saccharin (o-benzoic acid sulfimide); the sodium, potassium or calcium salt of saccharin; calcium or sodium cyclamate (calcium or sodium salt of cyclohexylaminosulfonic acid); acesulfam-K [a

6-methyl-1,2,3-oxathiazin-4 (3H) -one-2,2-dioxide potassium salt] or aspartame (L-aspartyl-L-phenylalanine methyl ester). As a sugar substitute, e.g. sugar alcohols such as mannitol, xylitol or sorbitol may be used. Naturally, the appropriate flavor can also be obtained by combining the above materials and / or natural flavoring substances identical or naturally occurring with naturally occurring substances. The compositions may, if desired, also contain additional pharmaceutical excipients (e.g., thickeners, such as polyvinylpyrrolidone). In a preferred embodiment of the invention, sweeteners are added to the composition as flavor enhancers, most preferably saccharin sodium and / or sodium cyclamate.

The solutions of the present invention may be filled into multiple-dose containers, which may include dispensing devices for repeated drug removal (e.g., central drip, screw pipettors, dispensing nebulizers, dosing cups, or dosing cups). The above containers contain the solution of the present invention in the form of a finished drug, preferably in the form of drops.

The aqueous metoclopramide solutions prepared according to the present invention differ from the known and practical metoclopramide solutions in that they do not contain a preservative. The self-preserving properties of the solutions of the present invention are clearly demonstrated by conventional preservation tests. To this end, the solutions of the present invention are exposed to microorganisms that are likely to develop as infectious germs in subsequent use of the composition. The inoculated,

In the solutions of the present invention, the germ numbers are determined at intervals. There is a very strong reduction in the number of germs. In addition, a usability test is carried out in which the solutions of the present invention exhibit self-preserving properties under normal conditions of storage and use. During the test, the solution of the present invention is stored in a multiple-dose container for extended periods of time, dropwise samples of the solution are periodically taken and the number of germs in the remaining solution is determined. Infection by microorganisms cannot be detected.

The following examples further illustrate the invention without limiting the invention to the examples.

Example 1

Preparation of drip solutions containing metoclopramide hydrochloride.

The composition of the solution is as follows:

Component Quantity

Metoclopramide monohydrochloride 10.0 g

Sodium cyclamate 2.0 g

Germ-free water gives 1000.0 ml

Preparation

Metoclopramide hydrochloride (10.0 g) was dissolved in germ-free distilled water with stirring. 2.0 g of sodium cyclamate are added with stirring. After complete dissolution of the sweetener, make up the solution to 1000 ml with demineralized water. The solution is sterile filtered through a membrane filter (0.2 µm), filled into 50 ml germ-free drops and sealed vigorously.

In a manner analogous to that described in Example 1, the following formulations of methoclopramide hydrochloride were prepared.

example Number 2 3 4 5 6 7 8 (X) (G) Metoclopra- mid-mono- hydrochloride 10.0 4.0 8.0 20.0 4.0 10.0 40.0 10.0 Saccharin- sodium 1.0 2.0 1.0 1.0 0.1 1.0 Nátriumcik- llama 0.9 sorbitol 2.0

For each example, make up to 1000 ml with distilled water, free from germ.

Example I

Determination of a suitable preservative effect (according to German Pharmacopoeia, 9th edition (1986), Annex VIII NI). The method is described below:

To test the appropriate preservative effect, the solution of the present invention is depicted in Figure 1.1. Inoculate with the suspension containing the microorganisms listed in Table II. The microorganisms used are examples of possible infectious germs. Pure cultures deposited with the American Type Culture Collection (ATCC) and commercially available under the given ATCC numbers are used in the assay.

1.1. spreadsheet

bacteria Yeasts and fungi S. aureus ATCC6538 A. niger ATCC9642 E. coli ATCC 11229 C. albicans ATCC10231 P. aeruginosa ATCC 15442 B. Subtilis ATCC6051

The solutions of the present invention are inoculated with an amount of the microorganism suspension to produce a solution of 10 ^{5 to} 10 ⁶ microorganisms per ml of germ.

= test solution: pure aqueous solution of metoclopramide hydrochloride without excipient.

** = Agar Medium (pH 7.3): Handin Peptone (Pancreas Hydrolyzate) g; soybean peptone (papin hydrolyzate) 5 g; sodium chloride 5 g; agar 15 g; distilled water 1000 ml.

*** = agar medium (pH 5.6): huspepton 10 g; glucose monohydrate 40 g: agar 15 g; distilled water 1000 ml. Immediately before use, 0.1 g of benzylpenicillin sodium and 0.1 g of tetracycline are added in a sterile solution per liter of medium.

The volume used for the inoculation should not exceed 1% of the volume of the solution according to the invention. The inoculated solution was grown at 25 ± 1 ° C. Samples are taken at intervals to determine the number of colony forming units (CU / ml). Samples of 1 ml are diluted aseptically with 9 ml of sodium chloride / peptone buffer * and applied to agar plates. Sodium chloride / peptone buffer (pH7) ^x has the following composition: potassium dihydrogen phosphate 3.56 g; sodium monohydrogen phosphate dihydrate 7.23 g; sodium chloride 4.3 g; casein peptone 1.0 g; distilled water 1000 ml. Petri dishes containing B-agar medium * ** ^*** were used to determine bacterial counts and the diluted sample was uniformly distributed over the surface of the medium. The culture was carried out at 30-35 ° C for 5 days. The colonies that develop are counted. The number of mushrooms is 3

For this purpose, Petri dishes containing C-agar medium *** were used and the diluted sample was spread evenly on the surface of the medium. The culture was continued at 20-25 ° C for 5 days. The colonies formed are counted. After counting the number of colonies developed, the number of microorganisms per ml was determined.

Example I / a

No. 3 of the present invention. Determine the preservative effect of the solution by the specified test germs in section 1.2. The results are summarized in Table III.

1.2. spreadsheet

Test germ inoculum (CFU / ml) Csíraszám- decrease Metoclopramide solution seed number after the time given below 24 hours 7 days 14 days 21 days 28 days bacteria 650,000 98,000 40,000 7200 640 0 Yeast / fungi 230,000 55,000 4600 4500 300 100

Example 1 / b is also determined. The results obtained are as follows

Additional flavoring additives and excipients 1.3. Table.

non-containing test solution * suitable preservative limit1.3. spreadsheet

Test germ inoculum (CFU / ml) Csíraszám- decrease Metoclopramide solution seed number after the time given below 24 hours 25 7 days 14 days 21 days 28 days bacteria 1.9 Mio. 800 20 20 40 0 Yeast / fungi 380,000 300 60 90 50 0

Example I / c organisms from the Americal Type Culture Collection

No. 3 The solution of the present invention is deposited at a suitable constitution and is depicted in Section 1.4. Table Serving Effect in Section 1.4. ATCC numbers in the microorganisms listed in Table II are also commercially determined using benisms. The microservices are available.

1.4. spreadsheet

bacteria Yeasts and fungi E. coli ATCC8739 C. albicans ATCC10231 P. aeruginosa ATCC9027 A. niger ATCC9642 S. aureus ATCC6538

For bacteria, the number of colony forming units (CFU / ml) is given separately for the microorganisms. The test results are shown in Table 1.5. Table.

1.5. spreadsheet

Test germ inoculum (CFU / ml) Metoclopramide solution seed number after the time given below 24 hours 7 days 14 days 21 days 28 days E. coli 150000 1600 0 0 0 0 P. aeruginosa 320,000 0 0 0 0 0 S. aureus 150,000 540 0 0 0 0 Yeast / fungi 1000 550 410 130 30

II. example

The I.c. The preservative effect of solution 5 containing 2.0% methoclopramide hydrochloride is determined in a manner analogous to that described for solution 3 containing 0.4% by weight methoclopramide hydrochloride. The results obtained are described in H.l. are summarized in Table.

HU 210 115 Β

11.1. spreadsheet

Test germ inoculum (CFU / ml) Metoclopramide solution seed number after the time given below 24 hours 7 days 14 days 21 days 28 days E. coli 222,000 0 0 0 0 0 P. aeruginosa 160,000 0 0 0 0 0 S. aureus 350,000 800 20 20 40 0 Yeast / fungi 310,000 300 60 90 50 0

III. example

Usage test

The metoclopramide hydrochloride solution of Example 3 was placed in a 100 mL dropping bottle with a central drip. Remove 5 to 5 drops three times a day for six weeks from the dropping bottle and reseal after sampling. Before and after the start of the six-week period, samples of the solution remaining in the drips are taken for the presence of the following germs:

- Staphylococcus aureus

- Echerichia coli

- Pseudomona aeruginosa

- Salmonella

- Enterobacteriaceae

No germs were detected in the solution.

Claims (5)

PATIENT INDIVIDUAL POINTS 1. A method of stable, peroral administration of microbial impurities at least 0.4% by weight of methoclopramide hydrochloride, i.e., 4-amino-5-chloro-N - [(2-diethylamino) ethyl] -2-methoxybenzamide hydrochloride for the preparation of aqueous metoclopramide hydrochloride solutions, characterized in that metoclopramide hydrochloride, conventional flavor enhancers, and, if desired, additional non-preservative pharmaceutical excipients are dissolved in water. Process according to claim 1, characterized in that 0.4 to 2% by weight of methoclopramide hydrochloride is dissolved based on the weight of the solution. 3. A process according to claim 2, wherein 0.8 to 1.5% by weight of methoclopramide hydrochloride is dissolved based on the weight of the solution. 4. The method of claim 1, wherein the flavoring additive is a sweetener. 5. A method according to claim 4, wherein the flavoring additive is a sweetener.