FIELD OF INVENTION

The present invention relates to a process for formulation of Omeprazole pellets of the formula .

The compound used in the treatment of peptic ulcer. The invention relates to stable pharmaceutical pellet preparation of having faster release rates of the active principle .

The pharmaceutical effects of omeprazole has been extensively researched and are widely known. On the other hand, the longer-term stability of pharmaceutical formulations and release rates containing omeprazole has so far proved troublesome. Because the stability of omeprazole is influenced by organic solvents, moisture and its sensitivity to acidic conditions, an oral omeprazole formulation must be protected with an enteric coating against the action of stomach acid so that it can develop its effect in the small intestine.

Conventionally, however, enteric coatings containing acid sensitive components when comes into contact with acids, omeprazole would be continuously decomposed and hence, over time, would change its appearance as well as lose its effect.

To reduce these disadvantages, attempts have been made e.g. to provide pharmaceutical omeprazole formulations with two coatings, the inner coating being intended to form a barrier against the outer enteric coating which decomposes the omeprazole, and against penetrating moisture.

It has been found, however, that the stability of such pharmaceutical formulations and high release rates still does not satisfy the desired criteria. Further coating the formulation twice greatly increases the cost of the manufacturing process

Description of the present Invention:

The object of the present invention is therefore to provide a stable pharmaceutical formulation with faster release rates with core containing omeprazole as the active ingredient by adopting a single coating, which avoids the above-mentioned disadvantages.

Surprisingly, it has now been found that the addition of cross linked polyvinyl pyrrolidone and calcium carbonate to the core and optionally to the enteric coating greatly improves the storage stability and release rates of the omeprazole formulation according to the invention compared with formulations of the state of the art.

The above object is achieved by the provision of a pharmaceutical pellet formulation with a core containing omeprazole in the form of its free base as the active ingredient, barrier coating and with an enteric coating, in which formulation the core and optionally the barrier coating contain sodium lauryl sulphate and of cross linked polyvinyl pyrrolidone as adjuvents.

Examples of suitable adjuvents for the pellet formulation according to the invention are binders such as …… sedimentation retarders such as….. and pH correctors such as …...

The active ingredient Omeprazole.


OUTLINE OF THE INVENTION

The present invention provides a dosage form of omeprazole which consists essentially of:

(a) a pellet comprising an inert core component, a therapeutically effective amount of omeprazole, a surface active agent such as ….., a filler, a pharmaceutically acceptable alkaline agent and a binder; and

(b) a double layer of coating on said pellet which comprises a layer of an film coating and enteric coating agent.

Accordingly, it is a primary object of this invention is to provide a pharmaceutical dosage formulation of omeprazole which is stable upon prolonged storage and faster release rates, is stable when administered to a patient and is capable of providing the desired therapeutic effect.

It is also an object of this invention to provide a pharmaceutical dosage form of omeprazole which is bioequivalent to dosage forms of omeprazole which have an film coating layer of an inert coating material.

It is also an object of this invention to provide a stable dosage form and release rates high of omeprazole which may be produced without the need to provide an film coating layer that separates the omeprazole containing core from the enteric coating layer.

These and other objects of the invention will become apparent from a review of the appended specification.

DETAILS OF THE INVENTION

To obviate the disadvantages of the prior art, the present invention provides a process for the formulation of Omeprazole pellets having the formula 1 a,
Core Materials

Omeprazole with formula 1 a, is preferably formulated into an oral composition which is pharmaceutically acceptable.

The core material for the individually enteric coating layered pellets can be composed and formulated according to different principles, omeprazole is mixed with pharmaceutical constituents to obtain preferred handling and processing properties and a suitable concentration of omeprazole in the final mixture. Pharmaceutical constituents such as fillers, lubricants, binders, disintegrating agents, surfactants and other pharmaceutically acceptable additives, can be used.

Preferably omeprazole, optionally after mixing with alkaline compounds, is mixed with suitable constituents including a binding agent and formulated into a core material. Said core materials has been produced by coating pan/Fluid bed coater, balling or compression utilizing different process equipments. The formulated core materials may have a size of pellets #18-22 mesh. The manufactured core materials can be layered further with additional ingredients, optionally comprising of active substance, and/or be used for further processing.

Alternatively, inert seeds layered with active substance (the active substance is optionally mixed with alkaline compounds) can be used as the core material for the further processing. The seeds, which are to be layered with the active substance, can be water insoluble seeds comprising different oxides, celluloses, organic polymers and other materials, alone or in mixtures or water soluble seeds comprising different inorganic salts, sugars, non-pareils and other materials, alone or in mixtures.

Before the seeds are layered, for instance by using pellets or spray coating/layering equipment, omeprazole is mixed with a binding agent and optionally further components.

Such further components can be binders, surfactants, fillers, disintegrating agents, alkaline additives or other pharmaceutically acceptable ingredients, alone or in mixtures.

The binders are for example celluloses such as hydroxypropyl methylcellulose, hydroxypropyl cellulose, microcrystalline cellulose and carboxymethyl-cellulose sodium, polyvinyl pyrrolidone, sugars, starches and other pharmaceutically acceptable substances with cohesive properties.

If hydroxypropyl methylcellulose E5 is used as the binding agent, Suitable surfactants are found in the groups of pharmaceutically acceptable non-ionic or ionic surfactants, such as for instance sodium lauryl sulphate.

Alternatively, the aforementioned core material can be prepared by using Coating pan or Fluid bed technique.

Film coating Layer(s)

The core material containing omeprazole must, according to separated from the film coating ,enteric coating polymer(s) containing free carboxyl groups, which may otherwise cause degradation/discoloration of omeprazole during the coating process or during storage.

According to the present invention, the Film coating layer comprises a specific quality of low viscosity HPMC E5, especially a HPMC with a viscosity of preferably 5.0 cps in 2% aqueous solution. This specific quality of HPMC E5 .

Alternatively, the quality of HPMC E5 is determined by a method which correlates with the above described methods, e.g. Near Infrared spectrophotometry.

Additives such as plasticizers, colorants, pigments, fillers, anti static, and anti-tacking agents, such as for instance magnesium stearate, titanium dioxide, talc and other additives may also be included in the film coating layer(s).

Enteric Coating Layer(s)

One or more enteric coating layers are applied onto the core material covered with Film coating layer(s) by using a suitable coating technique.
The enteric coating layer material may be dispersed or dissolved in water. As enteric coating layer polymers dispersions of methacrylic acid copolymers.
The enteric coating layers may contain pharmaceutically acceptable plasticizers to obtain desirable mechanical properties, such as flexibility and hardness of the enteric coating layers. Such plasticizers are for instance, but not restricted to, triacetin, citric acid esters,
phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates or other plasticizers. The amount of plasticizer is optimized for each enteric coating layer formula, in relation to selected enteric coating layer polymer(s), selected plasticizer(s) and the applied amount of said polymer(s). Additives such as dispersants, colorants, pigments, polymers e.g. poly(ethylacrylate, methylmethacrylate), anti-tacking and anti-foaming agents may also be included in the enteric coating layer(s). Other compounds will be added to increase film thickness and to decrease diffusion of acidic gastric juices into the acidic susceptible active substance.

To protect the acidic susceptible active substance, the enteric coating layer(s) preferably constitute(s) a thickness of at least approximately 10 µm. The maximum thickness of the applied enteric coating layer(s) is normally only limited by processing conditions.

The pellets or units covered with enteric coating layer(s) may further be covered with one or more over-coating layer(s). The over-coating layer(s) can be applied to the enteric coating layered pellets by coating or layering procedures in suitable equipments such as coating pan, or in a fluidized bed apparatus using water water for the layering process.

Final Dosage Form

The prepared pellets may be filled in hard gelatine capsules .

Experimental Section

Examples 1: Test of omeprazole pellets layered with two different types of low viscosity HPMC E5 used as a constituent of the film coating layer.

Omeprazole pellets prepared according to the description in (correspond to pellets from a. capsule) were tested with respect to rate of release of omeprazole. According to the marketing approval for the omeprazole. capsule formulation at least 95% of the omeprazole in a dose must be released within 30 minutes in a buffer solution.

The pellets were pre-exposed to 0.1N hydrochloric acid USP at 37° C. for 2 hours. Thereafter the drug release in buffer solution pH 6.8 at 30 minutes was determined by liquid chromatography. The buffer solution pH 6.8 was a mixture of 500ml of
0.1N hydrochloric acid and 400ml of 0.235 M disodium hydrogen phosphate solution, pH should be between 6.75 and 6.85. The 0.1N hydrochloric acid USP was prepared by
dissolving 8.5 ml conc. HC1 and add water to 1000 ml. The 0.235 M disodium hydrogen phosphate solution was prepared by dissolving 41.8 g Na2 HPO4. 2H2 O and add water to 1000 ml.

The composition of the tested omeprazole pellets was as follows.

I. Core material with the following composition was prepared.

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Core material
Omeprazole 18.5 kg
Mannitol 18.5 kg
Pulverised sugar 65.34kg
Disodium hydrogen phosphate 4.3Kg
Sodium Lauryl sulphate 2.3Kg
Cross linked poly vinyl pyrrolidone 2.0Kg
Starch 2.8Kg
Calcium carbonate 2.5Kg
Sugar Sphere #30-40 17.0Kg
Water approx 19 kg
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II. The prepared core material was coating layered with a Film coating layer consisting of HPMC E5, . The film coating layers with the following composition were applied in the stated amount.

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Film coating layer
Uncoated pellets from above
140 kg
Hydroxypropyl methylcellulose 5cps 12.5Kg
Cross linked poly vinyl pyrrolidone 0.5Kg
Sodium Lauryl sulphate 0.5Kg
Water 150 kg
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III. The prepared core material with a Film coating layer was further coating
layered with an enteric coating of the following composition.

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Enteric coating layer
Prepared pellets from above
153 kg
Methacrylic acid copolymer 120.0Kg
Talc 4.0Kg
Tween80 2.0Kg
Titanium Dioxide 1.0kg
Diethyl phthalate 3.5kg
Sodium hydroxide 0.32kg
Water 120 kg
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Omeprazole pellets prepared with film coating layer of
quality of HPMC 5 cps, were tested according to the description above. The pellets were prepared from the same batch of omeprazole, and with the same enteric coating material. The release of omeprazole within 30 minutes in a buffer solution was determined.

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Pellets
Release of omeprazole
containing
Ex. 1 Ex. 2 from enteric
HPMCE5 coated pellets [%]
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1. HPMC E5 (70-77)

2. HPMC E5,sodium lauryl sulphate and cross linked poly
vinyl pyrrolidone (96-99)
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The results from HPMC E5 determination for the two HPMC E5 solution preparation qualities are shown in FIGS. 1 and 2. As can be seen in the table above with the HPMC E5 the release of omeprazole was not acceptable for a pharmaceutical product, but with the HPMC E5 none of the discussed problems with the rate of release of omeprazole in an oral formulation occured.

Results from a number of experiments with different batches of HPMC E5 indicate that HPMC E5 with sodium lauryl sulphate and cross linked poly vinyl pyrrolidone is desirable in fulfilling the regulatory requirements on rate of release of omeprazole.

Solution preparation HPMC E5 conducted in the following way. The HPMC E5 solution preparation types was
determined in a mixed solution of phosphate buffer 0.235 M and 0.1N hydrochloric acid in the proportions 4:5. The mixed solution had a pH 6.75 and 6.85.

Example 3: Test of different types of solution preparation HPMCE5 used as binding agent in the preparation of core material for pellets.

I. Core material with the following composition was prepared by spray
layering in a fluidized bed. An aqueous suspension of omeprazole
and HPMC E5 was sprayed onto Drug pellets. Two batches of pellets were prepared using HPMC E5 1 and 2, respectively. The same batch of omeprazole was used for both experiments.

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EX.1.Core material
Omeprazole 18.5 kg
Mannitol 18.5 kg
Pulverised sugar 68.84kg
Disodium hydrogen phosphate 4.3Kg
Sodium Lauryl sulphate 2.3Kg
Starch 2.8Kg
Calcium carbonate 1.0Kg
Sugar Sphere #30-40 17.0Kg
Water approx 19 kg
Film coating layer
Uncoated pellets from above
140 kg
Hydroxypropyl methylcellulose 5cps 12.5Kg
Water 150 kg
Ex.2.Core material
2.Omeprazole 18.5 kg
Mannitol 18.5 kg
Pulverised sugar 65.34kg
Disodium hydrogen phosphate 4.3Kg
Sodium Lauryl sulphate 2.3Kg
Cross linked poly vinyl pyrrolidone 2.0Kg
Starch 2.8Kg
Calcium carbonate 2.5Kg
Sugar Sphere #30-40 17.0Kg
Water approx 19 kg
Film coating layer
Uncoated pellets from above
140 kg
Hydroxypropyl methylcellulose 5cps 12.5Kg
Cross li nked poly vinyl pyrrolidone 0.5Kg
Sodium Lauryl sulphate 0.5Kg
Water 150 kg
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The prepared pellets were tested with respect to rate of release of omeprazole in buffer solution pH 6.8 with identical composition as in Example 1, 37° C., paddle speed 100 rpm. The release of omeprazole was followed by spectrophotometer determination (302 nm) and the results are presented in FIG. 3. The graphs show that the release of omeprazole was delayed for the HPMC E5 2 compared with 1. Since the pellets were not coated with a film coating and an enteric coating layer they were not pre-exposed to 0.1N Hydrochloric acid.

Omeprazole pellets: Omeprazole 18.5kg,mannitol 18.5kg,pulverized sugar 65.34kg,di sodium hydrogen phosphate 4.3kg,sodium lauryl sulphate 2.3kg,cross linked poly vinyl pyrrolidone 2.0kg,Starch 2.8kg,calcium carbonate 2.5kg and sugar sphere #30-40 17.0kg.

Method: using Apparatus I, 100 rpm; 37.degree. C. Medium: pH 6.8 Buffer Solution, 1000 ml Dissolution Time (min) 0 5 10 20 30 45 60 0.00% 70.20% 90.60% 93.55% 98.48% 99.67% 100.2%

Minutes % Drug Release
0 0
5 70.2
10 90.6
20 93.55
30 98.48
45 99.67
60 100.2

Claims

1) A new process for making a pharmaceutical dosage formulation of oneprazole which is sable upon prolonged storage having faster release rates with the desired therapeutuic effect.

2) As claimed in claim 1 this process provides a pharmaceutical dosage from of omeprazole which is bioequivalent to dosage forms of omeprazole containing layer of an intert coating material.

3) As claimed in claim 1 it provides a stable dosage form with faster release rates of omeprazole by having a film coating layer that separates the omeprazole containing core from the enteric coating layer.