SK166096A3 - New oral pharmaceutical formulation containing magnesium salt of omeprazole - Google Patents

Abstract

A new oral pharmaceutical formulation containing a novel physical form of a magnesium salt of omeprazole coated with one or more enteric coating layers, a method for the manufacture of such a formulation, the use of such a formulation in medicine and a blister package containing the new formulation.

Description

Technical field

The present invention relates to a novel pharmaceutical composition comprising a new physical form of the magnesium salt of omeprazole, a process for the manufacture of such a composition and the use of such a composition in medicine.

BACKGROUND OF THE INVENTION

A compound known by the generic name omeprazole, 5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl} -1H-benzimidazole is described, inter alia, in EP-A 0005129.

Omeprazole is useful for inhibiting gastric acid secretion in mammals and humans. In a more general sense, said substance may be used to prevent and treat gastric acid related diseases in mammals and humans, including, for example, esophageal reflux, gastritis, duodenitis, gastric ulcer and duodenal ulcer. In addition, omeprazole may be used to treat other gastrointestinal disorders where gastric acid inhibitory effect is desirable, for example in patients with NSAID therapy, patients with non-ulcer dyspepsia, patients with symptomatic gastro-esophageal disease, and patients with gastrinomas. Omeprazole can also be used in patients in intensive care situations, in patients with acute upper gastrointestinal bleeding, pre- and postoperatively to prevent acidic gastric aspiration and to prevent and treat stress ulceration. Furthermore, omeprazole may be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections and related diseases.

Omeprazole is susceptible to degradation / transformation in acid and neutral environments. The half-life of omeprazole in aqueous solutions at pH values less than three is less than ten minutes. Omeprazole can be stabilized in mixtures with alkaline compounds. The stability of omeprazole is also affected by moisture, heat, organic solvents and, to some extent, light.

From what has been said about the stability properties of omeprazole, it is apparent that the oral dosage form of omeprazole must be protected from contact with acidic gastric juice and the active ingredient must be converted in intact form to such part of the gastrointestinal tract where pH is close to neutral and rapid absorption of omeprazole.

The pharmaceutical dosage form of omeprazole can be well protected from contact with acidic gastric juice by an enteric coating. US-A 4786505 discloses an enteric coated omeprazole formulation. Said omeprazole formulation comprises an alkaline core comprising omeprazole, a subcoat and an enteric coating.

Hard gelatine capsules containing the enteric-coated pellet formulation of omeprazole currently available on the market from the applicant are not suitable for packaging in extrusion blisters. Accordingly, there is a need for the development of new enteric coated omeprazole formulations with good chemical stability as well as improved mechanical stability that make it possible to produce functional packages that satisfy the patient.

Certain salts of omeprazole, including the alkali metal salts of omeprazole, are described in EP-A 0124495. The specification and specification emphasizes the requirements and importance with regard to the stability of omeprazole for incorporation into pharmaceutical compositions.

However, there is a need for the development of novel enteric formulations of omeprazole with increased stability and environmental aspects when the use of water-based processes in the manufacture of pharmaceutical products is also strictly desired.

In the isolation and purification of the full-scale production of the magnesium omeprazole salts described in EP-A 0124495, the main problem is that the magnesium omeprazole salt particles are very brittle, making pharmaceutical manufacturing processes that make this product less attractive for mass production. Treatment of magnesium omeprazole without a separate crystallization step provides a product which is less suitable than the pharmaceutical substance.

In order to use the magnesium salt of omeprazole, herein referred to as magnesium-omeprazole, in the large-scale manufacture of pharmaceutical preparations, primarily for oral administration, such as tablets, it is necessary that said magnesium-omeprazole exhibits a combination of properties that allow such large-scale production.

The combination of the physical properties of the novel magnesium omeprazole product described in WO 95/01977 with respect to the degree of crystallinity, particle diameter, density, hygroscopicity, low water content and low content of other solvents is excellent and allows the production of magnesium omeprazole in a form which is advantageous for production. new pharmaceutical preparations.

The novel form of magnesium omeprazole can be formulated into various dosage forms for oral and rectal administration. Examples of such formulations are tablets, granules, pellets, capsules, suppositories and suspensions.

j

SUMMARY OF THE INVENTION

It is one object of the present invention to provide a pharmaceutical formulation of magnesium omeprazole.

It is a further object of the present invention to provide a process for the manufacture of pharmaceutical preparations of omeprazole to a large extent, in particular an enteric coated dosage form of omeprazole which is resistant to dissolution in an acidic medium and which dissolves rapidly in neutral to alkaline medium.

Yet another object of the invention is to provide an environmentally acceptable, completely water-based process for the manufacture of pharmaceutical preparations of omeprazole.

Another object of the present invention is to provide a dosage form comprising omeprazole which is suitable for extrusion blister packaging and which is also more acceptable to the patient.

The new dosage form is characterized as follows. The core material in the form of pellets, granules, beads or tablets comprises a novel form of the magnesium salt of omeprazole, and on said core material there is one or more enteric coating layers.

The method of forming the enteric coated dosage form is preferably water based. Also, the step of performing the enteric coating can be carried out using a water-based process that is desirable both for the working environment in the pharmaceutical factory and for global environmental reasons.

Magnesium-omeprazole with a degree of crystallinity greater than 70% has been found to be advantageous for the production of pharmaceutical omeprazole formulations of the present invention.

Detailed description of the invention *

The novel pharmaceutical composition is defined in claims 1 to 9, the method of manufacturing the pharmaceutical composition of the present invention is defined in claims 10 to 11, the use of the composition in medicine is defined in claims 12 to 18, and the extruder blister package is set forth in claim 19.

Magnesium omeprazole

Magnesium-omeprazole preferred for the manufacture of the claimed composition is described in WO 95/01977, which is incorporated herein by reference in its entirety. Said magnesium omeprazole has a degree of crystallinity of less than 70%, preferably greater than 75% as determined by X-ray powder diffraction.

Pharmaceutical formulations containing magnesium omeprazole are produced as described below.

Core material

The novel magnesium salt of omeprazole, herein referred to as magnesium-omeprazole, is mixed with the pharmaceutical ingredients to obtain preferred handling and processing properties and a suitable concentration of the active ingredient in the final mixture. Pharmaceutical ingredients such as fillers, binders, lubricants, disintegrants, surfactants and other pharmaceutically acceptable excipients may be used. The core may also contain alkaline pharmaceutically acceptable excipient (s). The optionally added alkali component (s) is not essential to the invention. However, it can further improve the chemical stability of the formulations. Such pharmaceutically acceptable substances may be selected from a variety of ingredients, but are not limited to ingredients such as sodium, potassium, calcium, magnesium and aluminum salts, phosphoric acid, carbonic acid, citric acid, or other weak inorganic or organic acids; aluminum hydroxide / sodium bicarbonate coprecipitate; components normally used in antacid preparations such as aluminum, calcium and magnesium hydroxides; magnesium oxide or * composite components such as Al ₂ O ₃ .6MgO.CO ₂ .12H ₂ O, (Mg ₆ Al ₂ (0h) ₁₆ CO ₃ .4H ₂ O),

MgO.A1 ₂ O ₃ .2SiO ₂ · ηΗ ₂ 0 or similar compounds; organic pH-buffering components such as trihydroxymethylaminomethane; basic amino acids and their salts or other similar, pharmaceutically acceptable pH-buffering components.

The powder mixture is then formulated into pellets, granules, beads or tablets by pharmaceutical procedures. Pellets, granules, beads or tablets are used as the core material for further processing.

Enteric coating layer

The enteric coating layer is applied in one or more layers to the formulated core material by coating processes in suitable devices such as pan coating, coating granulator or fluid bed apparatus using solutions of polymers in water or using latex suspensions of said polymers or optionally using polymeric coatings. solutions in suitable organic solvents. As enteric coating polymers, one or more of the following may be used, for example, solutions or dispersions of acrylates (methacrylic acid / methacrylic acid methyl ester copolymer), cellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, enteric cellulose acetate, polyvinyl acetate phthalate, coating polymer (s). Preferably, water-based polymer dispersions such as those known under the trade names Aquateric® (FMC Corporation), Eugradit® (Rohm Pharma), Aqoat ™ (Sin-Etsu Chemical), Opadry ™ (Colorcon) or the like are used to obtain enteric coatings. compound. The enteric coating layer may optionally contain a pharmaceutically acceptable plasticizer such as cetanol, triacetin, citric acid esters such as those known under the trade name Citroflex® (Pfizer), phthalic acid esters, dibutylsuccinate, polyethylene glycol (PEG) or similar plasticizers. The amount of plasticizer is usually optimized for each enteric coating polymer (s) and is usually in the range of 1 to 50% of the enteric coating polymer (s). Additives such as talc, dyes and pigments can also be incorporated into the enteric coating layer or sprayed onto the enteric coated material as a topcoat.

The thickness of the enteric coating can vary over a wide range without affecting the release rate of omeprazole. To protect the acid-sensitive oraeprazole compound and to obtain acceptable acid resistance, the enteric coating comprises at least 1.0 wt. weight of the core, preferably at least 3.0% and more preferably greater than 8.0%. The maximum amount of enteric coating applied is normally limited only by the manufacturing conditions. The possibility of increasing the thickness of the enteric coating without adversely affecting the release rate of omeprazole is particularly desirable in large-scale production processes. The enteric coating layer (s) can be applied to the pretreated formulation without exact control of the thickness of the applied coating layer (s).

The composition of the invention also includes a core material that contains magnesium omeprazole. The core material is coated with enteric coating (s) which make the dosage form insoluble in acidic medium but disintegrating / dissolving in a neutral to alkaline medium such as, for example, the liquid present in the proximal small intestine, the site where dissolution is expected.

Final dosage form

The final dosage form is either an enteric-coated tablet or capsule or, in the case of enteric-coated pellets, beads or granules, the pellets, beads or granules are enclosed in hard gelatin capsules or sachets. The final dosage form may further be coated with another layer comprising pigment (s) and / or colorant (s). For long-term storage stability, it is essential that the water content of the final dosage form containing magnesium omeprazole ‘(enteric coated tablets, capsules, granules, beads or pellets) is kept low.

process

The method of manufacturing the dosage form of the present invention is another aspect of the invention. After formation of the core material, said material is coated with an enteric coating layer (s). The coating (s) are formed as described above. Another aspect of the invention is that the pharmaceutical process can be entirely water based.

The composition of the invention is particularly advantageous for reducing gastric acid secretion. It is administered one to several times a day. The typical daily dose of the active ingredient varies and will depend on various factors such as individual patient requirements, route of administration and disease. In general, the daily dose will be in the range of 1 to 400 mg of omeprazole.

The invention is illustrated in detail by the following examples. Examples 1 and 2 describe enteric coated tablet compositions containing magnesium omeprazole. The examples also show the result of the gastric acid resistance test in vitro. Example 3 describes an enteric coated pellet formulation. This example also shows the result of the gastric acid resistance test in vitro.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

A tablet formulation comprising magnesium omeprazole produced as described in WO 95/01977.

Amount of omeprazole 10 ingredient (mg / tablet) tablet core magnesium omeprazole 11.2 mannitol 68.7 microcrystalline cellulose 25.0 sodium starch glycolate 6.0 hydroxypropylmethylcellulose 6.0 talcum 5.0 stearyl fumarate sodium 2.5 purified water 50.0 enteric methacrylic acid copolymer polyethylene glycol coating

9.1

1.0 titanium dioxide colored iron oxide, red-brown purified water polish paraffin powder

0.82

0.04

45.0

0.05

The tablets of the composition described above were manufactured at a laboratory rate of about 20,000 tablets.

Description of production

Magnesium omeprazole, mannitol, hydroxypropylmethylcellulose, microcrystalline cellulose and sodium starch glycolate are dry mixed, moistened with water and wet mixed. The wet mass is dried and ground and finally mixed with the anti-adherent and lubricant ingredients. The milled granulate is pressed into tablets with a diameter of 7 mm. The tablets are enteric coated with a film of methacrylic acid copolymer. The water used in the manufacture of the tablets is discarded during subsequent processing.

Evaluation of acid resistance

Six individual tablets are exposed to an enzyme-free artificial gastric liquid, pH 1.2. After six hours, the tablets were removed, washed and analyzed for omeprazole content by HPLC. The amount of omeprazole is considered acid resistance.

Tablet acid resistance strength (mg) (%)

101 (98 to 103)

Example 2

A tablet formulation comprising magnesium omeprazole produced as described in WO 95/01977.

Amount of omeprazole component (mg / tablet) tablet core magnesium-omeprazole 45.0 mannitol 34.9 microcrystalline cellulose 25.0 sodium starch glycolate 6, o hydroxypropylmethylcellulose 6.0 talcum 5.0 stearyl fumarate sodium 2.5 purified water 50.0 enteric coating layer methacrylic acid copolymer 9.1 polyethylene glycol 1.0 titanium dioxide 0.51 colored iron oxide, red-brown 0.43 purified water 45.0

I paraffin wax 0.05

Description of production

Magnesium omeprazole, mannitol, hydroxypropylmethylcellulose, microcrystalline cellulose and sodium starch glycolate are dry mixed, moistened with water and wet mixed. The wet mass is dried and ground and finally mixed with the anti-adherent and lubricant ingredients. The milled granulate is pressed into tablets with a diameter of 7 mm. The tablets are enteric coated with a film of methacrylic acid copolymer. The water used in the manufacture of the tablets is discarded during subsequent processing.

Evaluation of acid resistance

Six individual tablets are exposed to an enzyme-free artificial gastric liquid, pH 1.2. After six hours, the tablets were removed, washed and analyzed for omeprazole content by HPLC. The amount of omeprazole is considered acid resistance.

Tablet acid resistance strength (mg) (%) (92 to 101)

Example 3

An enteric coated pellet formulation comprising magnesium omeprazole produced as described in WO 95/01977.

Pellet core magnesium-omeprazole non-pareil pellets hydroxypropylmethylcellulose purified water

Enteric coating layer uncoated pellets methacrylic acid copolymer triethyl citrate mono- and diglycerides (NF)

Polysorbate 80 purified water

1,5 kg

1,5 kg

0.23 kg

4,0 kg

500 g 300 g 15 g

1.5 g 1290 g

Description of production

Suspension layering was performed in a fluid bed apparatus. Magnesium omeprazole was sprayed onto inert non-pareil cores from an aqueous suspension containing dissolved binder. The prepared pellets were enteric coated in a fluid bed apparatus.

Evaluation of acid resistance

Pellets were added to gastric acid USP (no enzymes), 37 C (scoop) 100 rpm. After 2 hours, the actual amount of omeprazole remaining intact in the formulation was determined.

acid resistance (n = 6) Pellets% omeprazole 20 mg (93 to 95)

Claims (19)

PATENT CLAIMS An oral enteric coated preparation comprising a core material of the active ingredient coated with one or more enteric coating layers, characterized in that the core material comprises as the active ingredient a magnesium salt of omeprazole having a degree of crystallinity greater than 70% by X-ray powder diffraction and the core material enteric coating layer (s), wherein the thickness of the enteric coating has no significant effect on the release of omeprazole into aqueous solutions at pH values predominantly present in the small intestine. The composition of claim 1, wherein the composition is a tablet formulation. The composition of claim 1, wherein the composition is a pellet composition. The composition of claim 1, wherein the enteric coating comprises an enteric coating material which optionally comprises one or more pharmaceutically acceptable plasticizers, dispersants, dyes, and pigments. The composition of claim 4, wherein the enteric coating comprises polymeric solutions or dispersions of acrylates, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetate trimellitate and / or water-based cellulose phthalate acetate. The composition of claim 1, wherein the enteric coating comprises from 1.0 wt. weight of nuclear material. The composition of claim 6, wherein the enteric coating comprises at least 3.0 wt. weight of nuclear material. The composition of claim 6, wherein the enteric coating comprises at least 8.0 wt. weight of nuclear material. The composition of claim 1, wherein one of the coating layers is a topcoat applied to an enteric coated formulation, wherein the topcoat optionally comprises one or more pharmaceutically acceptable plasticizers, dispersants, dyes, and pigments. The process of claim 1, wherein the magnesium omeprazole-containing core material is coated with one or more enteric layers having a thickness that does not substantially affect the rate of omeprazole release into aqueous solutions at pH values predominantly present in the small intestine. The method of claim 10, wherein the enteric coated composition is further coated with a topcoat. An oral enteric coated composition according to any one of claims 1 to 9 for use in therapy. An oral enteric coated composition according to any one of claims 1 to 9 for use in inhibiting gastric acid secretion in mammals and humans. ( The oral enteric coated preparation of any one of claims 1 to 9 for use in the treatment of diseases associated with gastric acid secretion in mammals and humans. Use of an oral enteric coated composition according to any one of claims 1 to 9 for the manufacture of a medicament for inhibiting gastric acid secretion in mammals and humans. Use of an oral enteric coated composition according to any one of claims 1 to 9 for the manufacture of a medicament for the treatment of gastric acid related diseases in mammals and humans. A method of inhibiting gastric acid secretion in mammals and humans by administering to a host in need thereof a therapeutically effective dose of the enteric coated composition of any one of claims 1 to 9. A method of treating gastric acid related diseases in mammals and humans by administering to a host in need thereof a therapeutically effective dose of the enteric coated composition of any one of claims 1 to 9. An extrudable blister pack comprising a formulation according to any one of claims 1 to 9.