Layers for mechanical protection of solid dosage forms

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a layer for mechanical protection of dosage forms, containing two or more plasticizing agents, wherein the first plasticizing agent represents first polyethylene glycol of average molecular weight between 3000 and 6000, and the second plasticising agent represents second polyethylene glycol of average molecular weight between 5000 to 7000. The above layer for mechanical protection is found on an enteric coated granule. The declared invention also refers to the pharmaceutically acceptable enteric solid dosage forms comprising the layer for mechanical protection, and to methods for preparing and using the above layer.

EFFECT: declared invention prevents the mechanical damage of the solid dosage forms, especially compression, as well as provides their resistance to gastric acid.

21 cl, 1 dwg, 6 tbl, 10 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to a layer to protect the granules from mechanical impact, to a method for obtaining and solid dosage forms comprising this layer.

The LEVEL of TECHNOLOGY

In the technique used dosage forms with different layers that have different functions. During manufacturing, solid dosage forms are subjected to pressing, during which some of the layers are partially damaged and, therefore, required additional protective layer or the modification of existing layers. It is crucial, when these layers have functional properties that they lose after physical damage, especially when the said layer is an enteric layer, which protects the active ingredient from the gastric juice. If the intestinal layer is damaged, the active substance may collapse under the action environment of the stomach, with high acidity.

International patent application WO 96/01624 relates to multi-element tableted dosage form comprising an inhibitor of H+K+-ATPase, resistant to acids, in which the active substance is present in the form of individual granules with an enteric coating, pressed into a tablet. Layer (s) enteric coating, which can survive in separate granules of active substance, plasticized, which allows you to extrude these granules into a tablet without a significant effect on resistance to acids individual granules with enteric coating.

In WO 99/59544 and Chem.Pharm.Bull., 2003, 51(10), 1121-1127 described tablet, able to disintegrate in oral administration and comprising fine granules with an enteric coating. These granules have a layer made of a water-soluble sugar alcohol, preferably mannitol, covering plasticized enteric layer, which may consist of several layers of plasticized enteric coatings.

In the application US 2005266078 described protective sheath containing at least one deformable organic component (e.g., polyethylene glycol (PEG) 6000-20000), which protects the pellets with a long release, where these granules produced by the method of applying an organic coating.

Application WO 99/26608 linked with the problem of pressing. To solve this problem in the application of the proposed compressible spherical particles which comprise a core coated with a flexible and deformable polymer film. The core contains at least one thermoplastic filler having a consistency of from pasty to a semi-solid at 20°C, which allows plastic deformation and gives an opportunity to put out some of the tensions that may occur on the stage of pressing. The shell covering the core, is deformable flexible film-based polymeric material (e.g., PEG) with a glass transition temperature below 30°C, which provides protection, masking the taste or modified release of the current started (started).

In U.S. patent US 4684516 described tablets, which are mostly (80-100% tablets) contain granules with a long release, covered in retarding agent, like wax.

In the application WO 2005120468 described granules with a long release, including a layer of plasticized ethyl cellulose and an external coating that protects it from damage during the production and dosing, made of film-forming substance, pigment and plasticizer. The layer may be made of Opadry, i.e. hydroxypropylmethylcellulose, PEG 400 and PEG 6000. Opadry widely applied as an external coating to the granules to protect them from humidity, light and giving a good appearance.

In the application US 2002176894 not described enterosolubilae pharmaceutical composition, which includes the core and the drug layer of the emulsion and, optionally, a protective layer, which contains PEG 20000 and printed on the emulsion layer. The proposal says nothing about pressing.

ILLUSTRATIVE MATERIAL

Figure 1 is a graph showing the results of example to change the resistance to gastric juice (%) in different granules, as a function of PEGEQ.

BRIEF description of the INVENTION

Thus, the pressing solid enteric dosage forms can affect the solubility of the components and directly related to the splitting and destruction of protective layers (for example, intestinal layers) and, subsequently, with resistance to gastric juice in an acidic environment. Therefore, in the technique there is an urgent need to develop a protective layer for solid dosage forms to prevent spoilage from mechanical impacts, particularly pressing.

In accordance with one aspect of the present invention is directed to a layer to protect the dosage form against mechanical impacts, including two or more plasticizing means.

This layer provides mechanical protection, provides advantages in comparison with known in the art compositions. For example, a layer to protect against mechanical impacts according to the present invention can be included in the composition of the drug using spray drying, using concentrated (for example, 27% solids) aqueous solution, which allows to obtain a high content of intestinal granules into a solid dosage form (to 93 % of the mass. or more per tablet) and, therefore, a high content of active ingredient in a solid dosage form (for example the EP, 30-93,2 mg intestinal lansoprazole per tablet weight 800 mg), and this layer can be used without additional modifications other layers present in a brittle solid dosage form, giving excellent mechanical protection specified solid gazirovannoi form.

In addition, a new layer for protection against mechanical influences allows to obtain tablets with high hardness, at least up to 8.5 KP, which does not depend on the particle size; extruding the granules of at least 0.8 mm, receiving the above-mentioned characteristics.

According to the second aspect of the present invention is directed to a method of obtaining the specified layer to protect against mechanical impacts, which includes the dispersion of all the ingredients in water and then coating the dosage form specified variance.

According to a third aspect of the present invention is directed to a solid dosage form including a layer to protect against mechanical impacts according to the present invention.

According to a fourth aspect of the present invention is directed to a tablet comprising a layer to protect against mechanical impacts according to the present invention.

DETAILED description of the INVENTION

As indicated above, the layer for protection against mechanical impacts dosage forms of the present invention includes the VA or more plasticizing means.

In the framework of the present invention layer to protect against mechanical impacts" is a layer that can withstand mechanical stress (for example, during tabletting), while protecting the inner contents of the specified layer.

In the framework of the present invention the plasticizer is a substance which is usually used to improve the mechanical properties of a thin layer formed from a polymeric material. He is a product that is not returned to the original shape after deformation. When added to polymeric substance plasticizers allow you to obtain a material with improved stability and flexibility. For the purposes of the present invention, the plasticizers are preferably solid at room temperature and soluble in water.

Thus, it is preferable that at least one plasticizing means selected from the group consisting of waxes, alcohols type lanolin, gelatin, polyethylene glycol, polypropyleneglycol, triacetin, tributyltin, triethylcitrate, dibutylsebacate, triglycerides of fatty acids with medium chain length, resin acids, fatty acids with long chains (for example, stearic acid, palmitic acid) or mixtures thereof.

Other preferred plasticizing means are prophetic is STV, which, in addition, possess lubricating properties, such as glyceryl the monostearate, stearic acid, glyceryl palmitate-stearate, glyceryl dibehenate etc.

According to a preferred variant implementation layer for protection against mechanical impacts according to the present invention includes, as the plasticizing means of glyceril the monostearate.

Layer to protect against mechanical impacts according to the present invention may include other materials commonly used in engineering, for example, at least one additive selected from the group consisting of dezintegriruetsja funds, with swelling and/or capillary absorption, lubrication, dyes, means for masking the taste/smell, flavoring agents, stabilizers, binders, fillers, foaming agents, sweeteners, pore-forming agents, acids (e.g. citric or tartaric acid), sodium chloride, bicarbonate (e.g. sodium or potassium), sugars and alcohols.

As examples of the masking means may be provided water-insoluble polymers, such as ethylcellulose, polymers, insoluble in saliva, but soluble in gastric juice, such as a copolymer of methyl methacrylate, butyl methacrylate and diethylaminoethylmethacrylate etc.

The term "dezintegriruetsja with adsto" refers to a substance which when added to a solid preparation facilitates its mechanical destruction or disintegration after administration, makes possible the release of the active ingredient with maximum efficiency to ensure its rapid dissolution. As examples dezintegriruetsja means may be provided starches, such as corn starch and potato starch, starch, partially transformed into the alpha form, sodium carboxymethyl starch, carmellose, carmellose calcium, croscarmellose sodium, polyvinyl alcohol, crosspovidone, nizkozameshhennoj hydroxypropylcellulose, crystalline cellulose, hydroxypropylmethyl, etc. in Addition, as dezintegriruetsja means you can apply hydroxypropylcellulose.

As an example, flavoring and aroma additives may be given a lemon, lemon-lime, orange, menthol, peppermint, vanilla or powders listed substances obtained their absorption dextrin or cyclodextrin, etc.

As an example, the lubricating means may be provided stearate, magnesium fumarate stearin, stearic acid, colloidal silicon dioxide (Aerosil 200®), etc.

As an example, dyes can be given food dyes such as food yellow No. 5, food red No. 3, food blue No. 2, food lacquer paint is ü, red iron oxide, etc.

As examples of the stabilizer or solubilizer depending on the applied physiologically active component can be brought antioxidants, such as ascorbic acid and tocopherol, surfactants such as Polysorbate 80, etc.

As examples of binders can be given hypromellose, carboxyvinyl polymers, carmellose sodium alpha form of starch, polyvinylpyrrolidone, gum Arabic, gelatin, pullulan etc.

As examples of fillers can be given sucrose, glucose, lactose, mannitol, xylitol, dextrose, microcrystalline cellulose, maltose, sorbitol, calcium phosphate, calcium sulfate, etc.

As an example, a blowing agent may be given sodium bicarbonate.

As examples of sweeteners can be given saccharin sodium, dialogicity, aspartame, stevia, thaumatin etc.

According to a preferred variant implementation layer for protection against mechanical impacts according to the present invention includes a first plasticizing agent, which represents the first polyethylene glycol, more preferably, the second plasticizing agent, which is the second polyethylene glycol, different from the first polyethylene glycol. There are different designs for the e types of glycols, having different physical properties. For example, a number of manufacturers, you can buy various glycols with different molecular weights or densities.

According to a preferred variant implementation, the average molecular weight of the specified first polyethylene glycol is less than 6000, preferably more than 3000 and less than 6000, more preferably from 3000 to 5000.

According to another preferred variant implementation of the first polyethylene glycol has an average molecular weight of from 3000 to 5000, more preferably equal to 4000, and the second polyethylene glycol has an average molecular weight equal to 6000.

According to a preferred variant implementation layer for protection against mechanical impacts according to the present invention includes a third plasticizing agent, which is the third polyethylene glycol, different from the first peg and the second peg.

The best results were obtained when using a mixture of PEG with different viscosity and molecular weight. For example, as shown in the following examples, the mixture of PEG 8000, 6000 and 4000 provides excellent mechanical stability and elasticity during pressing, and therefore has the best indicators of resistance to the action of gastric juice.

the thus, the according to a preferred variant implementation layer for protection against mechanical impacts according to the present invention includes a first polietilenglikol with an average molecular weight of from 3000 to 5000, more preferably 4000, the second polietilenglikol with an average molecular weight from 5000 to 7000, more preferably 6000, and a third polyethylene glycol with an average molecular weight of 7000 to 9000, more preferably 8000.

According to a separate variant implementation, the average molecular weight of the first polyethylene glycol is equal to or exceeds 6000, preferably from 6000 to 7000.

According to a separate variant implementation layer for protection against mechanical impacts according to the present invention includes a first polyethylene glycol with an average molecular weight of from 6000 to 7000, more preferably equal to 6000 and a second polyethylene glycol with an average molecular weight of 7000 to 9000, more preferably equal to 8000.

Layer to protect against mechanical impacts according to the present invention can be applied without modifying the structure of the other layers present in the solid dosage form.

According to a preferred variant implementation layer for protection against mechanical impacts includes at least 80% of the mass. plasticizing means, preferably at least 90% of the mass. plasticizing means more pre is respectfully not less than 95% of the mass. plasticizing means.

In a preferred embodiment of the present invention all plasticizing means mixed in a separate layer. However, the protective effect can be achieved even if the layer for protection against mechanical impacts according to the present invention includes two or more sublayers, each sublayer comprises one or more plasticizing means. According to a separate variant implementation layer for protection against mechanical impacts according to the present invention includes two or more sublayers, each sublayer includes one plasticizing agent.

According to another preferred variant implementation layer for protection against mechanical impacts according to the present invention is able to withstand the mechanical stress of the protection of the internal contents of the specified layer during pressing (for example, tableting).

As indicated above, another aspect of the present invention is a solid dosage form comprising a layer to protect against mechanical impacts according to the present invention, preferably pharmaceutically acceptable solid dosage form.

The term "solid dosage form" refers to the drug in solid form such as tablet, granule, cap the ula, minitablets, fine granules, coatings, etc. which preferably include physiologically active ingredient, which should be released in a suitable environment, such as saliva, gastric juice, water, soap, milk, etc.

The term "pharmaceutically acceptable solid dosage form" refers to the drug in the solid state, for example, tablet, granule, capsule, minitablets, fine granules, coatings, etc. that include a pharmaceutically active ingredient.

The term "pharmaceutically acceptable" refers to a solid dosage form that is physiologically tolerated and, as a rule, does not cause allergic or similar adverse reactions, such as stomach upset, dizziness and the like, when administered to man. Preferably in the present description, the term "pharmaceutically acceptable" means approved by a regulatory Agency of the Federal government, or state government or listed in the U.S. Pharmacopoeia or other generally recognized Pharmacopoeia for use of animals and more specifically to the people.

The term "resistant to gastric juice" is the quantity of the active ingredient, isolated after treatment for 2 hours in 0.1 N HCl at 37°C in accordance with the requirements USP23 for drugs with intestinal pok is the eve ENT (values for individual units of the product does not exceed 10% of the dissolved amount).

These solid dosage forms comprising a layer to protect against mechanical impacts according to the present invention have excellent resistance to gastric juice after pressing. For example, managed to get a tablet with the contents of the intestinal granules to 93%, preserving the values of resistance to gastric juice less than 10%.

Solid dosage forms according to the present invention preferably contain at least one physiologically active ingredient selected from pharmaceutically active ingredient, a flavoring ingredient and nutritional ingredient. In a separate embodiment, the solid dosage form of the present invention is pharmaceutically acceptable and includes pharmaceutically active ingredient. In another separate embodiment, the solid dosage form is a nutritional product that contains nourishing ingredient.

As the pharmaceutically active ingredient can be used, for example, one or more ingredients selected from the group consisting of means for normalizing the activity of the gastrointestinal tract, anti-inflammatory drugs, analgesics, anti-migraine, antihistamines, cardiovascular agents, diuretics, anti-hypertension, which of rest against hypolipidemia, antiulcer drugs, antiemetics, anti-asthma agents, antidepressants, vitamins, antithrombotic funds, chemotherapeutic agents, hormones, deworming drugs, antidiabetic agents, antiviral agents, and mixtures thereof.

Typical examples of the above-mentioned means for normalizing the activity of the gastrointestinal tract include bromopride, metoclopramide, cisapride and domperidone; examples of anti-inflammatory drugs include aceclofenac, diclofenac, flurbiprofen, sulindac and celecoxib; examples of analgesics include acetaminophen, ibuprofen and aspirin; anti-migraine include sumatriptan and ergotamine; examples of antihistamines include loratadine, Fexofenadine and cetirizine; examples of cardiovascular drugs include nitroglycerin and the isosorbide dinitrate treatment; examples of diuretics include furosemide and spironolactone; examples of anti-hypertension include propranolol, amlodipine, felodipine, captopril, ramipril, losartan, valsartan, eprosartan, irbesartan, tasosartan, telmisartan; examples funds against hypolipidemia include simvastatin, atorvastatin and pravastatin; examples of the antiulcer medicines include cimetidine, ranitidine, famotidine, lansoprazole, omeprazole, rabeprazole and pantoprazole; examples protivorvotny the x means include meclizine hydrochloride, ondansetron, granisetron, ramosetron and tropisetron; examples of anti-asthma funds include aminophylline, theophylline, terbutaline, fenoterol, formoterol and ketotifen; examples of antidepressants include fluoxetine and sertraline; examples of the antithrombotic funds include sulfinpirazon, dipyridamole and ticlopidine; examples of chemotherapeutic agents include cefaclor, bacampicillin, sulfamethoxazole and rifampicin; examples of hormones include dexamethasone and methyltestosterone; examples of deworming drugs include piperazine, ivermectin and mebendazole; and examples of antidiabetic agents include acarbose, gliclazide and glipizide.

In some cases, the implementation of the present invention, the pharmaceutically active ingredient is an anti-ulcer agent or inhibitor of H+/K+-ATPase, preferably benzimidazole derivative or one of its enantiomers, or its salt, more preferably, lansoprazole, omeprazole, rabeprazole or pantoprazole, even more preferably, lansoprazole.

In another separate embodiment, the pharmaceutical ingredient is a nonsteroidal anti-inflammatory drug or its salt, more preferably represents an aspirin.

Nutritional ingredient that is included in the solid dosage is Orme, can be selected from the group consisting of vitamins, such as vitamin a, vitamin D, vitamin E (d-alpha-tocopheroxyl acid), vitamin B1(Dibenzoyl thiamine, fursultiamine hydrochloride), vitamin b2(Riboflavin of tetrabutyrate), vitamin WB (pyridoxine hydrochloride), vitamin C (ascorbic acid, L-sodium ascorbate) and vitamin B12(hydroxocobalamin acetate); mineral salts, such as calcium, magnesium and iron; proteins; amino acids; oligosaccharides, unsaturated fatty acids, herbs and mixtures thereof.

An additional advantage of the present invention is that there is no need to modify the structure of the granules to cause the layer to protect against mechanical impacts according to the present invention (or replace the upper layer by layer to protect against mechanical impacts according to the present invention). For example, the same fragile intersolubility pellet (dissolved in the intestine)used in the composition of the capsules may also be used in the tablet, simply due to its coating layer to protect against mechanical impacts according to the present invention and pressing together with the basis for pressing (mixture), with preservation of its properties and release profile. In addition, the layer for protection against mechanical impacts according to the present invention can provide the e masking of taste and chemical protection without the use of other additives.

According to a preferred variant implementation of the solid dosage form contains a core comprising an inert beads coated with the specified layer to protect against mechanical impacts.

According to another preferred variant implementation of the solid dosage form includes a layer with modified release, preferably, intersolubility layer.

According to a preferred variant implementation of the specified dosage form is a pellet or ball.

Another aspect of the present invention relates to a tablet containing a different number of granules or beads comprising layer to protect against mechanical impacts according to the present invention. Preferably, the tablet comprises more than 80% of the mass. pellets or balls, more preferably more than 90% of the mass. granules or balls.

According to another aspect of the present invention is directed to the application layer to protect against mechanical impacts according to the present invention for the production of solid dosage forms.

Layer to protect against mechanical impacts according to the present invention can be obtained by the following methods known in the art. According to another aspect of the invention is directed to a method of obtaining a layer to protect against mechanical impacts on the present image is ateneu, which includes the dispersion of all the ingredients in water and then coating the dosage form specified variance.

The hardness of all tablets obtained in the present invention, was measured using a device Schleuniger Tablet Tester 8M.

EXAMPLES

Example 1: granules lansoprazole with enteric coating layer without

for protection against mechanical influences

Got granules lansoprazole with enteric coating without layer to protect against mechanical impacts, having the composition shown in table 1.

Table 1
Amount (mg)Component name
Core111,61Inert balls
139,29Lansoprazole
FC124,33The hypromellose
40,54Magnesium carbonate
18,24Crosspovidone
5,27Talc
FC2 66,84The hypromellose
8,10Titanium dioxide
8,51Talc
4,05Crosscarmelose sodium
FC3106,9530% dispersion of a copolymer of methacrylic acid-ethacrylate (1:1)
15,95Triethylcitrate
15,18Talc

Each of the film coating (FC) has received consistently spraying various water dispersion on the previous coating apparatus with fluidized bed with subsequent drying. I.e. first took inert balls cellulose. Then prepared the variance of the components of the first film coating (FC1) and was applied by spraying onto inert beads. Then sprayed dispersion FC2 to FC1, and then sprayed dispersion FC3 to FC2.

Example 2: a method of obtaining a layer to protect against mechanical impacts according to the present invention

First introduced TEWN 80 and glycerylmonostearate in purified water at 60-75°C under stirring. The mixture was cooled to 25-30°C and was added PEG 4000, PEG 6000, PEG 8000, saccharin sodium and to obychnyj taste. At the final stage as a red dye was added iron oxide (III). Thus obtained dispersion is ready for application.

Example 3: General method of coating layer to protect against mechanical impacts according to the present invention

Layer to protect against mechanical impacts according to the present invention (obtained according to the General method of example 2) was sprayed in the unit fluidized bed above the granules lansoprazole with enteric coating of example 1 and then dried under the following conditions: temperature of supplied air: 50-55°C, the flow of air supplied: 7000-8000 m3/h, the temperature of the outlet air 40-42°C, microclimate: 1 bar, the pressure of the air in the spray: 3,0 bar, flow rate: 0.8-0.9 l/h

Example 4: granules comprising layer to protect against mechanical impacts according to the present invention

Following the General method of example 1 was applied a layer to protect against mechanical impacts according to the present invention, having the composition shown in table 2.

Table 2
Amount (mg)Component name
40,66Glycerol monostearate
105,71P the G 4000
75,22PEG 6000
193,94PEG 8000
0,31iron oxide (III)
6,10saccharin sodium
10,17strawberry flavor
3,05Polysorbate 80

Example 5 (comparative): a Protective coating on the basis of PEG 6000

The granules of example 1 were coated with PEG 6000, following the method described in US 2005266078, but applying the method of water cover in Assembly with the fluidized bed. Thus obtained pellets was compared with the coated granules of the present invention obtained in example 4. When spraying in a fluidized bed granules of the present invention obtained in example 4 showed less tendency to agglomerate than the granules obtained in this example.

A General method of measuring the resistance to gastric juice

Quality protective layers, including a new layer for protection against mechanical impacts according to the present invention, were evaluated in examples 6-10 before and after tabletting process by determining the amount of lansoprazole released after treatment in 0.1m HCl for 2 h, according t is ebouaney USP23 for drugs with enteric coating (value of resistance to gastric juice).

To obtain the tablets described in examples 6-10, granules (26,93% mass.) mixed with the base for pressing in the ratios shown in table 3, and then extruded into pellets.

Table 3
Component namewt. -%
Xylitol 10064,28
Klucel EF5,01
Aspartame2,13
Strawberry flavor0,38
The concealer0,15
Red dye0,01
Stearyl fumarate sodium1,13
Only % with respect to 26,93% granules100,0

Example 6 (comparative): Allocation of lansoprazole

Granules of examples 4 and 5 (26,93% mass.) mixed with the base for pressing in the ratios shown in table 3, and extruded into pellets with a final hardness of 4-6 KP; measured the resistance of both types of tablets to gastric juice.

Tablets, Poluchenie granules of example 4 (a protective coating of PEG 4000 + PEG 6000 + PEG 8000), demonstrated by the increased value of resistance to gastric juice only 50-60% compared with granules of example 4 is not subjected to pressing, whereas the tablets obtained from the pellets of example 5 (protective coating only PEG 6000), showed an increase of resistance to gastric juice at 100-140% compared to non-compacted tablets of example 5. Thus, the layer to protect against mechanical impacts according to the present invention clearly improves resistance to gastric juice. Low values of resistance to gastric juice indicate a smaller quantity of active ingredient selected in the acidic environment, and, therefore, more effective protective action of the intestinal layer.

Example 7: Effect of PEG of low molecular mass

This example shows the effect of PEG with a molecular mass of less than 6000 on plasticity layer to protect against mechanical impacts according to the present invention.

Following the procedure of example 3 was coated granules lansoprazole example 1 layer to protect against mechanical impacts according to the present invention, having the composition shown in table 4, receiving granules 7a-7d. Received four layers for protection against mechanical impacts shown in table 4, following the methods described in example 2. The composition of these layers differed only relative to what iCustom various glycols. In all cases the total amount of plasticizer (PEG + glyceril the monostearate) remained largely constant.

Table 4
The composition of the protective layerExample 7a
wt. -%
Example 7b
wt. -%
Example 7c
wt. -%
Example 7d
wt. -%
Glycerylmonostearate9,39,39,39,3
PEG 400063,044,6--
PEG 600023,1the 17.386,136,7
PEG 8000-24,3-49,5
Iron oxide (III)0,10,10,10,1
Saccharin sodium 1,41,41,41,4
Strawberry flavor2,32,32,32,3
Polysorbate 800,70,70,70,7
PEGEQ4537553560007157
Only100,0100,0100,0100,0

The amount of PEGEQwas calculated as the "average" molecular weight of PEG in the composition. For example, a mixture of 1:1 PEG 6000 and PEG 8000 would be a PEGEQequal to 7000. Thus, a mixture of polyethylene glycols with PEGEQequal to 7000, not identical PEG 7000.

Granules 7a-7d (26,93% of the mass. in every case) extruded using the basics for pressing in the ratios shown in table 3, to obtain a final hardness of tablets 4-6 KP and measured the resistance to gastric juice. The results are shown in figure 1.

As can be seen from figure 1, the inclusion of PEG with molecular m is ssoi less than 6000 (for example, PEG 4000) provides greater flexibility and the ability to deformation during pressing and, therefore, more protection for enteric coating, which leads to a better resistance to gastric juice. The value of resistance increases with increasing molecular weight polyethylene glycols, which indicates the deterioration of the resistance to gastric juice.

Thus, the introduction of the mixture of plasticizers are polyethylene glycols with a molecular mass of less than 6000, apparently, provides more flexibility and the ability to deformation, compared to PEG with higher molecular masses.

Example 8: the Dosage of active ingredients

Layer to protect against mechanical impacts according to the present invention makes it possible to increase the number of granules in the tablet and, therefore, increase the dosage of the active ingredient, saving a lot of pills unchanged. Table 5 presents the 800 mg tablets containing granules of example 1, coated with a layer of example 4 are mixed with the base for pressing in the ratios shown in table 3, but for a different number of granules and subjected to pressing to obtain tablets (hardness range 4-6 KP).

Table 5
The grain is s (% mass) The value of resistance
to gastric juice
Lansoprazole (mg)
17the 5.730
48,78,248,9
72,18,980,4
93693,3

Basically, an increase in the percentage of intestinal granules with respect to the base for pressing the pill increases the magnitude of resistance to gastric juice after tabletting, because the granules are destroyed during pressing, as the basis for pressing does not provide sufficiently effective depreciation. It was unexpectedly found that a layer to protect against mechanical impacts according to the present invention makes possible the inclusion of large quantities of intestinal granules into a tablet with minor changes resistance to gastric juice.

Example 9: the hardness of the tablets.

Layer to protect against mechanical impacts according to the present invention makes it possible to use tablets with high hardness (up to 8.5 KP), therefore, can be applied more force when pressing the save the AI values unchanged resistance to gastric juice.

Table 6 shows the values of resistance to gastric juice 800 mg tablets, containing 27% of the granules of example 1, coated with a protective layer of example 4 and subjected to pressing with a basis for pressing in the ratios shown in table 3 to different values of the final hardness.

Table 6
Hardness (KP)Resistance to gastric juice
36,1
56,2
8,56,3

Example 10: the size of the granules

The stability of the granules with a protective layer of the present invention to gastric juice does not depend on size. Granules lansoprazole with enteric coating of example 1 was coated with a protective layer of example 4. Selected granules are two sizes of 0.4 and 0.8 mm and extruded into pellets (26,93% of the mass. granules) with a basis for pressing in the ratios shown in table 3, to the hardness of 4-6 KP. The magnitude of resistance to gastric juice for both sizes of granules was approximately 5%.

1. Layer to protect the dosage form against mechanical impacts, including two or more plasticizing means, where n is pout plasticizing agent is a first polyethylene glycol with an average molecular weight of more than 3000 and less than 6000 and a third of the plasticizing agent is a second polyethylene glycol, different from the first polyethylene glycol with an average molecular weight from 5000 to 7000, and where the specified layer to protect against mechanical damage is present on the granule with intersolubility the floor.

2. Layer to protect against mechanical impacts according to claim 1, where at least one plasticizing means selected from the group consisting of waxes, alcohols type lanolin, polyethylene glycol, polypropyleneglycol, triacetin, tributyltin, dibutylsebacate, triglycerides of fatty acids with medium chain length, resin acids, fatty acids with long chain or mixtures thereof.

3. Layer to protect against mechanical impacts according to claim 1, comprising a first polyethylene glycol with an average molecular weight of 4,000 and a second polyethylene glycol with an average molecular weight of 6000.

4. Layer to protect against mechanical impacts according to claim 3, further comprising a third plasticizing agent, which is the third polyethylene glycol, different from the first peg and the second peg.

5. Layer to protect against mechanical impacts according to claim 4, comprising a first polyethylene glycol with an average molecular weight of 4000, a second polyethylene glycol with an average molecular weight of 6000 and a third polyethylene glycol with an average molecular weight of 8000.

6. Layer for protection against fur the practical impacts according to claim 1, comprising at least 80 wt.% plasticizing means; preferably, at least 90 wt.% plasticizing means; and most preferably at least 95 wt.% plasticizing means.

7. Layer to protect against mechanical impacts according to claim 1, where all the plasticizing means mixed in one layer.

8. Layer to protect against mechanical impacts according to claim 1, comprising two or more sublayers, each sublayer comprises one or more plasticizing means.

9. Layer to protect against mechanical impacts of claim 8, comprising two or more sublayers, each sublayer includes one plasticizing agent.

10. Layer to protect against mechanical impacts according to claim 1, further comprising a plasticizer selected from the group consisting of glyceryl of monostearate, stearic acid, glyceryl palmitate-stearate and glyceryl of dibehenate.

11. Layer to protect against mechanical impacts according to claim 1, additionally comprising at least one additive selected from the group consisting of dezintegriruetsja funds, with swelling and/or capillary absorption, lubrication, dyes, means for masking the taste/smell, flavoring agents, stabilizers, binders, fillers, foaming agents, sweeteners, a pore-forming means, Ki the lot, sodium chloride, bicarbonate, sugars and alcohols.

12. Layer to protect against mechanical impacts according to claim 1, characterized in that the protective layer is able to withstand mechanical stress, protecting the inner contents of the specified layer in the pelletizing.

13. Pharmaceutically acceptable enteric-soluble solid dosage form comprising an active ingredient and a layer for protection against mechanical impacts according to any one of claims 1 to 12.

14. Solid dosage form according to item 13, including a core covered with the specified layer to protect against mechanical impacts.

15. Solid dosage form according to item 13, including a layer that provides a modified release.

16. Solid dosage form according to item 15, where the specified layer, providing a modified release is intersolubility layer.

17. Solid dosage form according to item 13, where this dosage form is a pellet or ball.

18. Enteric-soluble tablet containing not more than 93 wt.% pellets or balls, as defined in 17.

19. Tablet p comprising from 80 to 93 wt.% granules or balls.

20. Application layer to protect against mechanical impacts, including two or more plasticizing means according to any one of claims 1 to 12 for the production of solid dozirovanno the x form.

21. A method of obtaining a layer to protect against mechanical impacts according to any one of claims 1 to 12, which includes the dispersion of all the ingredients in water and then coated dosage forms specified variance.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pharmaceutical composition of such an active agent, as sucralfate for treating disorders, e.g. gastric ulcers, duodenal ulcers, acute gastritis, symptomatic chronic gastritis, gastropathy caused by the intake of anti-inflammatory agents, gastroesophageal reflux disease characterised by the fact that is contains one or more phospholipids.

EFFECT: invention refers to using phospholipids in a combination with the above active agents when administered orally for the purpose of improving the taste of the preparation, and to using phospholipids in a combination with the above active agents when administered orally for the purpose of treating disorders, including gastrointestinal irritation, for the synergetic enhancement of the anti-ulcer effect.

19 cl, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, and represents a nice to taste solid composition for treating or preventing gastric distresses or such diseases, as acid indigestion, epigastric burning, or gastritis, containing at least one de-acidifier and neutral salivation stimulator, with the neutral salivation stimulator specified in hydrotalcite, calcium carbonate, magnesium hydroxide, magnesium oxide, magnesium carbonate, sodium bicarbonate or mixtures thereof, and the neutral salivation stimulator is specified in Pellitorine.

EFFECT: invention provides nice taste, no taste of chalk in the mouth or teeth.

8 cl, 6 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery, and may be used for prevention of acute postoperative pancreatitis. For this purpose, the underlying background therapy is combined with intravenous bolus administration of dalargin 0.002 g and the antioxidant thioctic acid depending on a risk level of the complication measured in terms of the area of intervention in abdominal operations. A high risk level requires thioctic acid to be administered in a dose of 600 mg intravenously drop-by-drop 1 hour before the operation and on the following day, and thioctic acid in a dose of 300 mg on the third day intravenously drop-by-drop. In a moderate risk level thioctic acid is administered intravenously drop-by-drop in a dose of 600 mg 1 hour before the operation and in a dose of 300 mg on the following day. And in a low risk level, thioctic acid is administered intravenously drop-by-drop in a dose of 300 mg 1 hour before the operation.

EFFECT: method enables the more effective prevention of acute postoperative pancreatitis ensured by the combined use of drugs with antisecretory and antioxidant activity.

2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: controlled release solid preparation contains a combination of (1) an antacid, (2) an immediate release portion containing a proton pump inhibitor, preferentially lansoprazole, and a basic substance, and (3) a delayed release portion comprising a proton pump inhibitor and a pH-independent material.

EFFECT: solid preparation according to the invention shows an increase in gastric pH up to 4 or higher 0,5 h after oral administration into a mammal and a retention time at pH 4 or higher for at least 14 hours a day.

16 cl, 8 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to gastroenterology, laser therapy. The method involves administering the drugs: a proton pump inhibitor and a prokinetic accompanied by laser therapy. The proton pump inhibitor is presented by Controloc 20 mg 2 times a day. Gaviscon is administered in a dose of 2 tablets 3 times a day daily. Trimedat 200 mg is administered 3 times a day. The laser therapy is differentiated. That involves taking into account a severity of gastroesophageal reflux disease, a degree of manifestation of endothelial dysfunction and a severity of upper gastrointestinal motor dysfunction. The manifestation of endothelial dysfunction is shown by the contents of nitrogen oxide, pro-inflammatory, namely IL-1β, IL-6, TNF-α and anti-inflammatory, namely IL-4 cytokines. The degree of upper gastrointestinal motor dysfunction is shown by a stomach/duodenum ratio Pi/P(i+1). A mild degree of gastroesophageal reflux disease implying the levels of nitrogen oxide 35.2±2.7 mcmole/l and more, IL-1β 1.5±0.3 pg/ml or more, IL-6 1.8±0.8 pg/ml or more, TNF-α 2.78±0.35 pg/ml or more, IL-4 4.4±0.42 pg/ml or less, the ratio Pi/P(i+1) of 11.2±5.6% or less requires 6-7 daily procedures of the intravenous laser blood irradiation. The exposure length is 15 minutes at wave length 0.405 mcm, end face output density 1-1.5 mWt, pulse frequency 80 Hz, in a continuous mode. The moderate or severe gastroesophageal reflux disease with the levels of nitrogen oxide less than 35.2.2±2.7 mcmole/l, IL-1β 1.83±0.3 pg/ml or less, IL-6 1.98±0.8 pg/ml or less, TNF-α 10.04±2.84 pg/ml or less, IL-4 3.15±0.43 pg/ml or more, the ratio Pi/P(i+1) of 12.3±4.8% or more requires 9-10 daily procedures of the intravenous laser blood irradiation. The exposure length is 15 minutes at wave length 0.405 mcm, end face output density 1-1.5 mWt, pulse frequency 80 Hz, in a continuous mode.

EFFECT: method reduces the drug-induced load, reduces the length of treatment.

3 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to preparing a drug possessing antiulcerogenic, antistress and hemostatic activities. The declared method involves mixing the dry extracts of great nettle leaves, knotgrass herb and nosebleed herbs with fine powders of ginger rhizomes and cinnamon bark in ratio, weight fraction 35: 30 : 10 : 20 : 5. The above dry extracts prepared by multiple extraction of the herbal raw materials in ethanol and water, filtration of the prepared extracts, evaporation thereof, concentration and drying in a vacuum oven, wherein the first and second extractions of the herbal material is carried out in 80% ethanol, the third and fourth extractions - in 40% ethanol, and the fifth and sixth extractions - in boiled water.

EFFECT: invention provides preparing the effective and safe drug for preventing the digestive diseases.

7 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new alkylthiopyrimidines of formula III or pharmaceutically acceptable salts thereof: In the compound III X represents a direct bond; R2 means hydrogen, halogen, (C1-C6)alkyl, (C3-C7)cycloalkyl, -NR8aR8b or the group -SR3; each R3 independently represents (C1-C6)alkyl, optionally mono-, di- or trisubstituted by halogen; or (C3-C7)cycloalkyl; R4a and R4b represent hydrogen; R6 represents aryl; or heteroaryl; wherein aryl and heteroaryl are optionally substituted in a substituted position by one or more substitutes specified in a group consisting of (a) halogen; (b) cyano; (c) nitro; (a) hydroxy; (e) guanidino; (f) heteroaryl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy (k) -NR8aR8b; (1) -C(O)R9; (m)-C(O)NR8aR8b, (n) - OC(O)NR8aR8b; (o) -C(O)OR9; (p) -NR7C(O)0R9; (q) -NR7C(O)R9; (r) sulphamoyl; (s) (C1-C6) alkylsulphonyl; (t) (C1-C6)alkylaminosulphonyl; (i) di(C1-C6)alkylaminosulphonyl; (v) (C1-C6)alkyl, optionally mono-, di- or trisubstituted by halogen; (w) (C1-C6) alkoxy, optionally mono-, di- or trisubstituted by halogen; and (x)(C1-C6)alkylthio, optionally mono-, di- or trisubstituted by halogen R7 represents hydrogen. The other radical values are specified in the patent claim.

EFFECT: compounds possess CRTH2 (G-protein related chemoattractant receptor expressed on Th2 cells) antagonist activity and are applicable for treating and preventing the diseases related to CRTH2, including treating allergic diseases, eosinophil and basophile related diseases.

14 cl, 6 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are presented prolonged release pharmaceutical oral dosage form for preventing or treating an upper gastrointestinal disorder (dyspepsia, epigastric burning, erosive esophagitis, gastrooesophageal reflux disease, peptic ulcer, esophagitis, Barrett's esophagus and esophageal adenocarcinoma), containing a therapeutically effective amount of at least one bile acid sequestrant specified in colesevelam and colesevelam hydrochloride, and a carrier composition providing gastric retention containing one or more hydrogels, wherein the dosage form expands upon contact with gastric juice, respective methods of treating or preventing the upper gastrointestinal disorder and protecting the multilayer squamous epithelium against an attack of any hazardous substances by administering the composition, and a kit for the same application comprising the composition, a label or a package insert with instructions for use. The composition may contains a proton pump inhibitor, and one or more agents specified in antacids, histamine H2-receptor antagonists, γ-aminobutyric acid-b (GABA-B) agonists, and protease inhibitors.

EFFECT: invention aims at retaining the active agent in the stomach for relieving and improving prolonged delivery thereof.

16 cl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and aims at treating acute alcoholic enteritis. Gastric lavage, ample drinking, intravenous infusions of normal saline or 5% glucose are prescribed. At admission to hospital, the patient is additionally examined for blood triglycerides. If the value is more than 2.5 mmole/l, the antibiotics are withdrawn, while the preparations of lipoic acid 900 mg before meals are prescribed within the 7-day course.

EFFECT: method enables reducing side effects of the therapy of acute alcoholic enteritis.

3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to gastroenterology and physiotherapy, and may be used for treating acute gastric and duodenal ulcer. For this purpose, placental hydrolysate at 2 ml of the preparation per 200 ml of water at temperature 37°C is orally introduced on an empty stomach. That is followed by magnetophoresis. For this purpose, the patient is laid on a back, and an epigastric region and a projection of duodenum are exposed to MAG-30 magnetotherapeutic apparatus. The magnetic induction makes 30±15 mT at frequency 50 Hz of variable magnetic field. The length of the exposure is 10 minutes. The procedure length is prolonged to 15 minutes after 2 procedures to the end of the therapeutic course. The therapeutic course consists of 15 daily courses.

EFFECT: method provides faster ulcer healing and stable remission of the disease ensured by stimulation of the regenerative processes, manifested anti-inflammatory effect, functional normalisation of the coupled organs, and arrest of the asteno-vegetative syndrome.

4 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to biotechnology, more specifically, to using a chimeric somatostatin-containing protein for improving the reproductive properties of male farm animals and cocks, and may be used in veterinary science. The injection preparation is used in the form of a chimeric protein suspension with water-insoluble enzyme-inactive chloramphenicol acetyltransferase with no 10 C-terminal amino acids, amino acid spacer (Sp)n, wherein n=1, 2, 4, 8 and somatostatin-14 with AGCFWKTFTSC amino acid sequence in the refined vegetable oil with bee wax added at 250-1000 mg of the above chimeric protein per 100 ml of the refined vegetable oil containing 0.9-1.1 wt % of bee wax. The injection preparation is used in cocks and farm animals after achieving the physiological maturity at 50-200 mcg of the protein per 1 kg of a live body weight.

EFFECT: invention enables increasing sperm production: increasing the ejaculate volume and reducing the biologically damaged sperm in farm animals and cocks by using the preparation for injections with a low-reactogenicity adjuvant.

2 cl, 13 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, namely to compositions of ingredients, which have therapeutic purpose by external application on person's body. Ointment for treatment in case of frostbites includes wax, amaranth and glycerol with the following component ratio, wt %: wax 13-15; glycerol 15-20; amaranth oil - the remaining part.

EFFECT: ointment increases efficiency of healing action with absence of side complications, fast elimination of edema, absence of intoxication.

1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to a stable composition in the form of oral emulsion containing at least 50% of water, 0.2 to 3 wt % of oil containing at least 12 wt % of docosahexaenoic acid and eicosapentaenoic acid, an antioxidant, an aromatiser and at least 0.01 wt % of edible phospholipid emulsifier.

EFFECT: oral stable emulsion visible skin if used on a regular basis.

8 cl, 1 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to field of medications, in particular to tablet, manufactured by method of building-up coating, in composition of which included are core, containing medication, and core-surrounding coat from non-soluble or badly water-soluble material, core being located inside said coat in such way that coat on axis (X-Y) has greater thickness and lower density than on axis (A-B), orthogonal to axis (X-Y), coat porosity on axis (X-Y) being sufficient for ensuring penetration of water medium, so that when immersed into water medium after period from 2 to 6 hours destruction of coat and release of medication takes place. Invention also relates to method of said tablet manufacturing, pharmaceutical package containing it and treatment method. Said tablet form ensures fast release and delivery of active component after period of delay, which can be set with great accuracy.

EFFECT: system will ensure directed delivery of active component to place of absorption or action.

19 cl, 2 dwg, 3 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition of fast release includes granules obtained by granulation from melt. Granules contain DPP-IV inhibitor and meltable hydrophobic component with ratio from 1:1 to 1:10 (per dry weight). At least 90% of granule surface are covered with meltable hydrophobic component. Granules release approximately 50% of DPP-IV inhibitor during 30 minutes after peroral introduction of medication. DPP-IV inhibitor is N-(substituted glicyl)-2-cyanopyrrolodin or its pharmaceutically acceptable salt. Preferably DPP-IV is (S)-1-[(3-hydroxy-1-adamantyl)amino]acetyl-2-cyanopyrrolidin.

EFFECT: composition for fast release according to invention possesses improved stability in presence of moisture in comparison with known compositions for controlled or prolonged release.

20 cl, 9 tbl, 10 ex

FIELD: food products.

SUBSTANCE: edible composition that contains at least one facility for conditioning with covering layer, which consists of agent that imparts hydrophobic properties and inorganic particles and at least one material that has been selected from the group that consists of pharmaceutically active agent, powdered food components and their combinations. At that agent that imparts hydrophobic properties directly covers mentioned inorganic particles and is available in mentioned facility for conditioning in amount of approximately from 1 weight % to 10 weight %, in conversion to total mass of facility for conditioning. Facility for conditioning with covering layer is used in pharmaceutical products, such as acetaminophen.

EFFECT: prepared composition expresses better fluidity properties.

25 cl, 11 tbl, 29 ex

FIELD: chemical-and-pharmaceutical industry, in particular solid pharmaceutical formulation coated with enterosoluble coating.

SUBSTANCE: claimed coating has four layers wherein the first and the third layers comprise of hydroxypropyl cellulose, and the second and the fourth ones comprise of acetatephthalate cellulose, bee wax and twin 0-20 in specific component ratio in coating.

EFFECT: enhanced assortment of drug active ingredients coatable with claimed coating, including thermolabile immunobiological medicines.

4 cl, 7 ex

FIELD: chemical-pharmaceutical industry.

SUBSTANCE: it has been suggested to apply a solid composition for manufacturing a pharmaceutical tablet or a suppository, its melting point being 25°C or higher and it contains an uninterrupted lipid component that contains either one or more than one galactolipids, one or more glyceride ether of fatty acids, possibly one or several out of the following: water and mono-triatomic alcohol at the quantity being up to 15 weight% against the weight of composition, and one or more agent chosen among pharmacologically active agent. The method for manufacturing the composition mentioned includes mixing galactolipids and glyceride ethers of fatty acids followed by dissolving pharmacologically active agents in a liquid phase, cooling up to a solid state and forming a tablet or a filled capsule. Pharmaceutical tablet or suppository are depicted that include uninterrupted lipid phase possibly containing an inert nucleus and, also, food tablets or suppositories of similar composition that include food agents instead of pharmacologically active agent and, possibly, having got one or more submembranes consisting of food excipients. The innovation provides economy and increased comfort in usage.

EFFECT: higher efficiency.

42 cl, 13 ex, 10 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine and describes a solid pharmaceutical composition applicable for oral administration and containing: S1P receptor modulator which represents 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol in the free form or in the form of a pharmaceutically acceptable salt or a phosphate thereof and monocrystalline cellulose in the absence of a sugar alcohol.

EFFECT: invention provides higher storage stability of the composition.

9 cl, 40 ex, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for the correction of cerebrovascular disease accompanying cardiovascular diseases which contains the active ingredients presented by atorvastating or pharmaceutically acceptable salt thereof and nicergolin in the therapeutically effective amounts.

EFFECT: pharmaceutical composition is characterised by high stability and bioavailability.

8 cl, 8 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, and concerns a pharmaceutical composition for prevention and treatment of thrombosis, containing (A) N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazol[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethandiamine, its pharmaceutically acceptable salt or hydrate, (B) sugar alcohol which is mannitol, xylitol or erythritol, and (C) a water-swellable additive.

EFFECT: composition has higher water solubility.

18 cl, 8 dwg, 4 tbl, 4 ex

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