SI9400338A - Vancomycin hydrochloride suspensions for peroral use and for filling into soft ,gelatine capsules. - Google Patents

Abstract

Described are two novel stable and organoleptically acceptable pharmaceutical forms of vancomycin hydrochloride with a smaller moisture-sensitivity of the active ingredient. The peroral suspension contains 250 or 500 mg of vancomycin hydrochloride per 5 mL of suspension, a pharmaceutically acceptable oil vehicle without taste and with neutral odor, an artificial sweetener and flavors, a protective colloid, and optionally also a drying agent, an antioxidant and a preservative. It is filled into plastic bottles and glass bottles as well as into single dosage forms such as bags and such like. Soft gelatin capsules contain a stable homogeneous nonaqueous suspension of 125 or 250 mg of vancomycin hydrochloride and a pharmaceutically acceptable oil vehicle and optionally a drying agent, an antioxidant and a surfactant.

Description

VANCOMYCIN HYDROCHLORIDE - SUSPENSIONS FOR ORAL USE AND FOR FILLING IN SOFT GELATIN Capsules

Technique (MPK: A 61 K 37/02; A 61 K 9/10)

The present invention contemplates novel stable and organoleptically acceptable pharmaceutical forms of the vanally mycotic hydrochloride orally active antibiotic and methods for their preparation.

Vancomycin is an amphoteric glycopeptide antibiotic produced by strains of the species Mycropolyspora orientalis, called Streptomyces orientalis and Nocardia orientalis in earlier systematic classifications.

Vancomycin, substantially protected in U.S. Patent No. 3,067,099, is a well-known antibiotic for the treatment of staphylococcus infections, especially those infections caused by the methicillin-resistant staphylococcus strain. Vancomycin is isolated from the fermentation broth in which it was formed. For treatment, vancomycin is useful in the form of hydrochloride.

Vancomycin hydrochloride has so far been available for oral and parenteral use as a dry solid (in sterile bottles) obtained by lyophilization of an aqueous solution of vancomycin hydrochloride, which is prepared from the vancomycin and HCl free base in aqueous solution. In order to reduce the time, it is desirable to keep the lyophilization in as few batches as possible and preferably directly in the container for further use, e.g. in sterile bottles.

Vancomycin hydrochloride is one of the ingredients that is unstable in the presence of moisture. Therefore, the present invention contemplates new pharmaceutical forms to overcome this problem.

View the problem

Vancomycin oral dosage forms are intended for topical action in the intestine, so dissolution should be good and vancomycin absorption into the blood is undesirable.

Vancomycin is one of the many highly sensitive active substances in the world. These substances also have unpleasant organoleptic properties, especially taste, as well as smell and appearance. Pharmaceutical preparations for diabetics should not contain sugars. Most patients, especially the elderly and children, require easy-to-administer preparations.

Combining all of the above requirements has led to the development of new pharmaceutical forms of vancomycin hydrochloride that are stable, organoleptically acceptable, sugar-free and easy to administer.

Our invention, therefore, is based on the task of preparing vancomycin hydrochloride in novel, stable and organoleptically acceptable pharmaceutical forms for oral use, in the form of oil suspensions with a pleasant taste and with a neutral odor and without sugars. Such forms are well suited for bottling or bottling, allowing the dosage to be adjusted to individual patients (especially in pediatrics) and for various single dose forms such as bags, soft gelatin capsules and the like.

The state of the art

Vancomycin hydrochloride is commercially available in the form of hard gelatin capsules, injections and powders.

A key patent for protecting hard core soft gelatin capsules is EP-B-49.909 or the equivalent of US 4,450,877, which generally describes hard gelatin capsules in which the active ingredient is homogeneously dispersed in a carrier melt, e.g. in a PEG that gel or solidify, thereby losing its liquid character. The process is not specifically adapted for any type of active substance.

Vancomycin hydrochloride as an active substance in oral oil suspensions or in soft gelatin capsules has not yet been patented. EP-A-295.941 describes only liquid suspensions for oral use in which pharmaceutically acceptable carriers are different animal, mineral or vegetable oils, and various peptides, antibiotics (including penicillin and amoxicillin) and other active ingredients. These liquid suspensions are also filled into capsules.

Also disclosed in U.S. Pat. No. 5,114,929 (and equivalent EP-A-389,177) are pharmaceutical formulations comprising homogeneous non-aqueous suspensions of orally active ingredients, a pharmaceutically acceptable oil carrier and emulsifier, and fine-grained sugar. Among the active substances are also antibiotics, e.g. penicillin. Various vegetable oils were used for the oil carrier, including mainly fractionated coconut oil under the trade name Miglyol 812. An emulsifier and up to 40 wt. % of sugar. Suspensions of this composition are not suitable for general use, especially for diabetics, and due to the risk of caries, careful oral hygiene is necessary after each use of such suspensions.

Various suspensions are also described by other patents, such as e.g. EP-A-10.904 (amoxicillin / potassium clavulanate, coconut oil, molecular sieves).

Description of the new solution with implementation examples

Pharmaceutical factories want to make preparations that are stable under normal feeding conditions and can be used directly by the patient. For vancomycin hydrochloride, the manufacture of a stable oral suspension is a significant improvement in the prior art, since such a preparation is stable at room temperature for a long time, and dilution in pharmacies is not necessary.

The first object of the invention is a stable, organoleptically acceptable pharmaceutical formulation containing a homogeneous non-aqueous suspension of the moisture-sensitive active ingredient, vancomycin hydrochloride, in an oil carrier, in addition additives, optionally a drying agent and a protective colloid, and a suitable combination of flavors and artificial sweeteners.

The choice of oil carrier is important to achieve stable and neutral homogeneous oil suspensions. We have found that the commercially available ESMA-MCT 643 oil from Verner Schluter, Germany, is tasteless and odorless, so there is no need to cover the oil taste with sugars or emulsifiers. This oil is a triglyceride of fractionated coconut oil with Cg-CjQ-fatty acids, which is obtained from a natural source, and this can be crucial for better taste. The taste of homogeneous non-aqueous suspensions prepared with such an oil carrier is only to be controlled by a suitable combination of artificial sweetener and / or different flavors, e.g. milk or fruit.

Another object of the invention is a soft gelatin capsule containing a stable homogeneous non-aqueous suspension of moisture-sensitive vancomycin hydrochloride, an edible oil carrier, and up to 2 wt. % molecular sieves or other desiccants and pharmaceutically acceptable stabilizers such as antioxidants, preservatives, protective colloids, etc. The oil carrier is usually of vegetable (flax, fractionated coconut, sunflower, sesame, palm, soy, olive, corn or peanut oil), but also of animal (North Sea fish oil) origin.

The taste of the oil suspensions in soft gelatin capsules is not problematic, as with oral suspensions, so no special choice of oil carrier or flavoring additives is required.

Both objects of the invention represent improved pharmaceutical forms when compared with those of the prior art.

The pharmaceutical formulations of the invention need not be reconstituted before use or stored in the cold in order to maintain the active substance in a stable manner.

Oily suspensions for oral use are filled into bottles, bottles and similar containers and dispensed with a spoon or filled into various single dose forms such as soft gelatin capsules, bags, etc.

The amount of orally active vancomycin hydrochloride in the pharmaceutical forms of the invention is 0.1-60 wt. %. The amount of ESMA-MCT 643 oil carrier is 40-99 wt. %.

Of the additives, homogeneous non-aqueous suspensions may contain up to 10% by weight. % protective colloids, such as inorganic salts of higher fatty acids (aluminum stearate), 12-hydroxystearin (Thixcin R), silica (Aerosil 200, Aerosil R 972), microcrystalline waxes (Lunacera M), solubilizers, wetting agents, surface absorption enhancers active substances with an HLB value exceeding.

Up to 2 wt. % molecular sieves or e.g. silica (which may also be a protective colloid). Up to 1 wt. % artificial sweeteners (aspartame, cyclamate, saccharin or their alkali salts) and flavorings (artificial milk; natural flavors of oranges, tangerines, lime, grapefruit, peppermint, strawberries, bananas, blueberries and other fruits or combinations thereof).

The daily doses of vancomycin hydrochloride in oil suspensions are the same as for conventional dosing with known commercially available preparations.

Doses of vancomycin hydrochloride in soft gelatin capsules are up to 0.5 g per capsule.

The pharmaceutical forms of the invention are prepared by suspending, in a pharmaceutically acceptable oil carrier, the necessary additives, such as protective colloids, at a suitable temperature, e.g. from 40 to 120 ° C, depending on the type of protective colloid used. Vancomycin hydrochloride, artificial sweetener, flavors, desiccant and preservative are added to the mixture thus prepared and cooled to give a homogeneous product with the desired consistency.

δ

The suspension can be filled into conventional bottles and bottles and into various single dose forms such as e.g. bags and soft gelatin capsules.

The invention is explained, but not limited in any way, by the following examples:

Example 1

We have prepared the following oral suspension formulation:

Ingredients mg / 5.0 ml vancomycin hydrochloride 500.0

Aerosil 200 100.0

milk aroma, artificial saccharin 10,0 2.0 ESMA-MCT 643 ad 5.0 ml

In the oil carrier, suspend Aerosil 200 and heat to 70 ° C. The colloidal solution was cooled to 25 ° C, the saccharin was dissolved, the aroma was added and the vancomycin hydrochloride was suspended while stirring.

Example 2

We have prepared the following oral suspension formulation:

Ingridients mg / 5.0 ml vancomycin hydrochloride 250,0 molecular sieves 0.5 nm, powder methylhydroxybenzoate butylhydroxyanisole saccharin 20,0 1.0 0.1 0.4 aluminum stearate orange flavor, natural milk flavor, artificial ESMA-MCT 643 15.0 1.6 1.0 ad 5.0 ml

Ί

In a duplicator, heat 3/4 of the oil carrier to a temperature of 100 ° C and suspend the aluminum stearate homogeneously while stirring. The suspension was heated to 120 ° C and stirred until dissolved. The clear colloidal solution was cooled to 100 ° C and methyl hydroxybenzoate dissolved therein. The resulting substrate was cooled to 60 ° C and butylhydroxyanisole was added. The clear solution was then cooled to 30 [deg.] C. and molecular sieves, a specially prepared saccharin solution in the portion of the oil carrier, and aromas were added. Mix well and add a specially prepared homogeneous suspension of vancomycin hydrochloride in the remaining oil carrier. The suspension thus prepared is cooled to room temperature.

Example 3

We have prepared the following suspension formulation for soft gelatin capsules:

Ingredients mg per capsule vancomycin hydrochloride ESMA-MCT 643 250,0 730,0

Vancomycin hydrochloride is suspended in an oil carrier while stirring at room temperature. The resulting suspension was filled into soft gelatin capsules.

Example 4

We have prepared the following suspension formulation for soft gelatin capsules:

Ingridients mg per capsule vancomycin hydrochloride molecular sieves 0.5 nm, powder butylhydroxyanisole ESMA-MCT 643 125,0 12,0 0.1 362,9

s

Vancomycin hydrochloride is suspended in an oil carrier while stirring at room temperature. The resulting suspension was filled into soft gelatin capsules.

Example 5

We have prepared the following gelatin capsules: form of suspension for filling into soft Ingridients mg per capsule vancomycin hydrochloride adeps solidus ESMA-MCT 643 250,0 220,0 516,0

Vancomycin hydrochloride is suspended in the oil carrier melt while stirring. The resulting homogeneous suspension was filled into soft gelatin capsules.

Example 6

We have prepared the following gelatin capsules: form of suspension for filling into soft Ingridients mg per capsule vancomycin hydrochloride Vitepsol S 58 * ESMA-MCT 643 125,0 110,0 258,0

* Vitepsol S 58 consists of adeps solidus, polyethylene glycol-1000 monocetyl ether and glyceryl castor oil.

Vancomycin hydrochloride is suspended in the oil carrier melt while stirring. The resulting homogeneous suspension was filled into soft gelatin capsules.

Example 7

We have prepared the following suspension formulation for soft gelatin capsules:

Ingridients mg per capsule vancomycin hydrochloride 250,0 Vitepsol S 58 * 220,0 ESMA-MCT 643 516,0

* Vitepsol S 58 consists of adeps solidus, polyethylene glycol-1000 monocetyl ether and glyceryl castor oil.

Vancomycin hydrochloride is suspended in the oil carrier melt while stirring. The resulting homogeneous suspension was filled into soft gelatin capsules.

Example 8

Stability

The three-month accelerated stability of soft gelatin capsules according to Example 6 and the hard gelatin capsules of the usual composition (vancomycin hydrochloride, silica, magnesium stearate, lactose) were comparatively tested. The following parameters were monitored: color, appearance, odor, decomposition, weight, moisture, active substance content, related substances and degradation products, dissolution rate. Differences between soft and hard gelatin capsules were observed for the following parameters: vancomycin content (Table 1), content of related substances and degradation products (Table 2), and dissolution rate (Table 3):

Table 1: Vancomycin content [mg / capsule] as determined by HPLC

time vancomycin 125 mg vancomycin they claim 125 mg gelatin, caps. soft gelatin, caps. (month) 30 ° C / 60% RH * 40 ° C / 75% r.v. * 30 ° C / 60% RH * 40 ° C / 75% r.v. * 0 120.4 oz. 96.3% 125.5 oz. 100,4% 1 118.2 oz. 94.6% 112.6 oz. 90.1% 122.5 oz. 98.0% 113.8 oz. 91.0% 3 117.0 oz. 93.6% 108.7 oz. 87.0% 115.2 oz. 92.2% 98.2 oz. 78.6%

* relative humidity

Vancomycin content declined more slowly in both soft and hard gelatin capsules under both feeding conditions.

Table 2: Related substances and degradation products (vancomycin B and maximum individual impurity) [%] determined by HPLC

time vancomycin 125 mg soft gelatin, caps. vancomycin 125 mg hard gelatin, caps. (month) 30 ° C / 60% RH * 40 ° C / 75% r.v. * 30 ° C / 60% RH * 40 ° C / 75% r.v. * 0 van.B.B: 90.0% m.p.n .: 1.9% van.B.B: 91.1% m.p.n .: 1.7% 1 van.B.B: 87.8% pp: 2.2% van.B.B: 85.3% m.p.n .: 2.9% van.B.B: 88.2% pp: 2.1% van.B.B: 81.4% m.p.n .: 3.4% 3 van.B.B: 84.7% van.B.B: 75.6% van.B.B: 80.4% van.B.B: 68.5% m.p.n .: 2.9% m.p.n .: 5.7% m.p.n .: 2.9% m.p.n .: 5.8%

* relative humidity

In all samples, the decrease in vancomycin B content is greater with hard gelatin capsules, which means that soft gelatin capsules are more stable.

in

Table 3: Average dissolution rate determined microbiologically (according to USP XXIII)

time vancomycin 125 mg vancomycin 125 mg soft gelatin, caps. they claim gelatin, caps. (month) 30 ° C / 60% RH * 40 ° C / 75% r.v. * 30 ° C / 60% RH * 40 ° C / 75% r.v. * 0 100,9 % 99.5 % 1 98.4% 91.7% 97.6% 98.1% 3 95.4% 85.2% 92.8% 81.8%

* relative humidity

The soft gelatin capsules dissolve faster than the hard capsules, thus ensuring a better therapeutic efficacy of the preparation.

From the results of the analysis, we can conclude that the vancomycin soft gelatin capsules are more stable than the hard ones in three characteristic parameters, they are similar in the other parameters, but not worse in any one. Thus, soft gelatin capsules are a significant improvement in the state of the art compared to hard gelatin capsules.

Example 9

Pilot study of non-absorption of vancomycin from soft gelatin capsules

Because vancomycin oral dosage forms are intended for topical action in the intestine, absorption of vancomycin into the blood is undesirable.

In an open-label and crossover randomized volunteer trial, non-absorption of vancomycin after administration of soft gelatin capsules was verified by determining vancomycin in plasma of subjects after ingesting single doses of the test or reference formulation. The single dose was 500 mg vancomycin (2 250 mg capsule capsules from Example 7 and 4 commercially available 125 mg vancomycin capsules). There were 5 healthy volunteers, smokers, and non-smokers of both sexes between 18 and 55 years of age who did not take any other medication 14 days before the experiment began. Twelve hours before and during the experiment were not allowed to consume alcohol and real tea and coffee. The subjects consumed the tested drugs after fasting all night with 240 ml of water. Two hours after ingestion, subjects were given 2 dl of fruit juice and 4 hours after ingestion a standardized lunch. We did not register the couples. Plasma vancomycin concentrations were determined by reverse phase HPLC and extraction with dichloromethane. The surface of the vancomycin signal in the chromatogram of the plasma extract was measured. Vancomycin concentrations (Example 7 sample and commercially available sample) in the plasma of five volunteers are listed in Table 4:

Table 4: Plasma concentrations of vancomycin [pg / ml]

time os. 1 person 2 OS. 3 os. 4 os. 5 (hi vz. ref. vz. ref. vz. ref. vz. ref. vz. ref. 0 0 0 0.50 0.58 0 0 0 1.10 0 0 1 0 0 0.39 0.52 0 0 0 0.92 0 0 2 0 0 0 0 0 0 0 0.82 0 0 3 0 0 0.39 0.45 0 0 0 0.89 0 0 4 0 0 0.43 0.51 0 0 0 0 0.75 0 6 0 0 0.50 0.65 0 0 0.45 1,27 0 0

vz. - sample according to Example 7, ref. - commercially available sample.

From the results of the time-dependence analyzes of vancomycin plasma concentrations, it can be seen that the extent of vancomycin absorption from the soft gelatin capsule is negligible and therefore no systemic undesirable side effects can occur. Vancomycin concentrations in all plasma samples are at or below the quantization limit; there is no difference between the test sample and the commercially available preparation.

Claims (11)

Patent claims A stable, organoleptically acceptable pharmaceutical form, characterized in that it contains a homogeneous non-aqueous suspension of orally vancomycin hydrochloride, a pharmaceutically acceptable oil-free, neutral-odorless carrier, optionally a desiccant and a protective colloid, and a suitable combination of flavors and artificial sweeteners. Pharmaceutical form according to claim 1, characterized in that the oil carrier is ESMA-MCT 643, which is a triglyceride of fractionated coconut oil with Cg-C0- ^{m 3} acidic acids, a mixture of 50-65% of caprylic triglycerides, 35 -45% caprine triglycerides, up to 3% capron triglycerides and up to 3% lauric acid triglycerides. 3. A stable, organoleptically acceptable pharmaceutical form, characterized in that it contains a homogeneous non-aqueous suspension of 0.1-60% orally active vancomycin hydrochloride, a pharmaceutically acceptable oil carrier ESMA-MCT 643, which is a mixture of 50-65% caprylic triglycerides, 35- 45% caprine triglycerides, up to 3% capron triglycerides and up to 3% lauric acid triglycerides; up to 2 wt. % molecular sieves, up to 2 wt. % flavoring and artificial sweetener, and optionally up to 10% by weight % protective colloid. Pharmaceutical form according to claim 3, characterized in that the artificial sweeteners are selected from the group consisting of aspartame, saccharin, cyclamate and their alkali salts. Pharmaceutical form according to claim 3, characterized in that the flavors are selected from the group consisting of artificial milk aroma and natural flavors of orange, tangerine, grapefruit, lime, peppermint, banana, strawberry, blueberry and other fruits, or combinations thereof. 6. Soft gelatin capsule, characterized in that it contains a stable homogeneous non-aqueous suspension of orally active vancomycin hydrochloride, a pharmaceutically acceptable oily carrier of vegetable or animal origin, and optionally a desiccant and a protective colloid. - / R Soft gelatin capsule according to claim 6, characterized in that the oil carrier is selected from the group consisting of soybean, sunflower, olive, corn, sesame, palm, flax, peanut and fractionated coconut oil. 8. A soft gelatin capsule according to claim 6, characterized in that it contains a homogeneous non-aqueous oil suspension of 0.1-60% orally active vancomycin hydrochloride, a pharmaceutically acceptable oily carrier ESMAMCT 643, which is a mixture of 50-65% caprylic triglycerides, 35-45 % caprine triglycerides, up to 3% capron triglycerides and up to 3% lauric acid triglycerides. 9. Soft gelatin capsule, characterized in that it contains a stable homogeneous non-aqueous suspension of orally vancomycin hydrochloride and a pharmaceutically acceptable oily carrier of vegetable or animal origin with the addition of surfactants. Soft gelatin capsule according to claim 9, characterized in that it contains an oil carrier of 0.01-50% surfactants. Soft gelatin capsule according to claims 9 and 10, characterized in that the surfactants are polyethylene glycol-1000 monocetyl ether of the formula CHg 15aiii7 * O ~ CH2 "(θ ^ 2 19-23 OHgOH and glyceryl castor oil.