Solid pharmaceutical composition with content of levothyroxine and/or liothyroninum salts

FIELD: medicine.

SUBSTANCE: invention relates to a chemico-pharmaceutical industry, and concerns the solid pharmaceutical composition containing water-soluble salts of levothyroxine and-or liothyroninum as an active substance where water activity is set equal to less than 0.4 at measurement at a room temperature. The composition with 0.4 water activity or less possesses high stability at storage.

EFFECT: development of a composition which possesses high stability at storage.

18 cl, 4 ex

 

The technical field to which the invention relates.

The invention relates to solid pharmaceutical compositions containing as active substance, a water-soluble salt of levothyroxine and/or liotironina.

The level of technology

Thyroid hormones the above-mentioned type are produced for sale in a different form. For the production of traditional tablet of thyroid hormones requires a number of measures ensuring uniform distribution of the active substances on all tablets of one party and keeping it the same content for a certain period of time. Such problems in relation to the provision of the so-called “same content” (content uniformity) also include issues related to the stability of the active substance. For example, it is known that the sodium salt of levothyroxine or liotironina in case of their presence in the form of potassium salts are insoluble in water and more effective for the body. In addition, it was found that depending on humidity, temperature and light they are unstable, particularly during storage. In this regard, many attempts have been made to improve stability of tablets with thyroid hormones, and so far has been the attempt to improve the resistance to what esteem additives of the positive impact of excipients. In the US 5225204 for this purpose it is proposed to apply along with the corresponding sodium salts are water-soluble polyvinylpyrrolidon and adsorption of the mixture to cellulose media for production in subsequent tablets, powders or capsules.

In the US 5635209 described the application along with the sodium salt sodium levothyroxine well as sodium iodide, means for breaking the tablets and sizing.

In the US 5958979 proposed sodium thiosulfate as a stabilizing component.

From US 6399101 it follows that the use of siliconized microcrystalline cellulose provides certain advantages.

All these known attempts though and contributed to increased resistance, however, still sufficient resistance at the required storage time was not reached, when this was not provided and trudnoobogatimye uniformity at relatively low dosage of thyroid hormones.

Levothyroxine sodium is usually kind of stable at room temperature pentahydrate. This pentahydrate detects at room temperature for a certain water activity, comprising about 0.4 to 0.6. Under the water activity is an equilibrium moisture content and 50% relative humidity at a certain temperature correspond to a water activity of 0.5.

Disclosure of inventions

The purpose of ISO is retene is to provide, largely irrespective of additives, excipients and, in particular, without the use of specific additives, allegedly improving the resistance of auxiliary substances, enhanced stability of the pharmaceutical composition, its quick and easy preparation, improved uniformity of distribution of the active substance and its rapid dissolution (biological availability). To achieve this goal, the solid pharmaceutical composition according to the invention lead mainly in the state in which the water activity of this composition is set equal to the index of less than 0.4, mostly 0.1 to 0.3 at room temperature. Unexpectedly, it was found that in the case when the active substance is present, usually in the form of the pentahydrate, is removed, at least one mole of water, the resistance increases substantially, it is necessary only to ensure that later, when the choice may become necessary for the use of auxiliary chemicals were not applied hygroscopic excipients in order to prevent re-water saturation. This unexpected effect is due to the fact that one mole of water normally present in the pentahydrate is in contrast to the rest of 4 moles of water is not a classic hydrate, and cluster. This part of the water way is t excess water, able to easily move into the gas phase and also easy to get back in the form of cluster crystals of levothyroxine. Thus, this present in the form of cluster mol of water is relatively easily movable and loosely coupled with the crystal, and this is reflected in increased activity of water at room temperature. If the active substance itself is quite stable, despite the presence of this fifth, relatively easy rolling mole of water, volatile and easily movable, is not associated with the crystal water leads together with the usual, necessary for the manufacture of tablets excipients to the fact that this cluster mol of water causes the interaction, in particular the dissolution of auxiliary substances, and dissolved excipients in combination with free water in the form of a cluster in an invalid extent degrade the stability of levothyroxine sodium. Liotironin sodium also contains up to 4% water and has the same resistance with levothyroxine sodium. It has been unexpectedly found that in the case when this relatively movable water is removed due to the decrease of water activity at room temperature to less than 0.4 and, in particular, to a value of from 0.1 to 0.3, then reached a corresponding resistance during long-term storage without the use of the special stabilizing additives auxiliary substances. When uncontrolled drying and reduction of water activity below 0.1 levothyroxine sodium passes into the amorphous state, and this makes it even more unstable. This also deteriorates the solubility. The specified optimal water activity can be achieved either as a result of corresponding dry processing in the manufacture of tablets, applying dry source of substances with controlled water activity, and the active substance may also in appropriate dry form (water activity) and then directly tabletroute, either by drying, tableting the mixture to the desired water activity, either by target additional drying of the finished tablets. Manufacturing of tablets with such a low water activity in practice is not straightforward, as it requires you to carefully follow the uniform application of the active substance on the carrier with a large surface area. In the Supplement of the relevant quantities of substances for destruction tablets can provide accurate adaptation to low water activity in the range of 0.1. If such a pill, for example, with a water activity of 0.1-0.3 then firmly Packed, it can be ensured durability and safety. Along with the possibility of applying for the NGOs dense packing can also provide optimal water activity due to the fact, used mostly or exclusively non-hygroscopic excipients, known for its low water activity at room temperature, as, for example, mannitol, and others, in the manufacture of tablets and then tablets are packaged in a conventional transparent materials.

The problem with the lack of constant rapid solubility of the active substance in the known compositions and, therefore, with rapid and complete bioavailability, especially easily solved due to the fact that the active substance is evenly applied onto the water-soluble carrier. Such water-soluble carrier has subsequently after taking the pills, the effect that the active substance dissolves quickly and reliably, without the need to use damaging substances as insoluble in water, the active substance is applied onto a water-soluble carrier, a finely on it are distributed and with it quickly goes into solution. With optimal use mannitol as a water-soluble media.

It is advisable to prevent the problem of reduced activity due to the formation of water-insoluble salts to consider the content of calcium when using substances-carriers, excipients and solvents. The best option run is the tsya such when the carrier is treated with EDTA-sodium, the amount of which corresponds mainly to the content of CA++in the media, if necessary with the addition of citric acid to prevent the harmful effects of ions of CA++which is inevitably present, particularly in water-soluble media. The processing is carried out with an aqueous solution, and it is necessary to constantly monitor the removal of water to maintain a given water activity. In General, the required homogeneity, solubility and, in particular, the solubility with the formation of a clear solution, the ability to quickly manufacture and due to waterless technology enhanced resistance can be guaranteed due to the fact that composition was prepared in the form of tablets and its preparation are not used hygroscopic excipients and/or packaging is applicable with little or no permeability to water vapor.

The method is simple and fast preparation of the pharmaceutical compositions of the above type differs in the fact that the media of mannitol is filled or deposited methanol or alcohol solution of the active substance, after which the alcohol solvent is evaporated to obtain a water factor less than 0.4, in particular less than 0.3, and tabletirujut when necessary is Timoti with the addition of magnesium stearate as lubricant. In the use of alcoholic solvents, particularly methanol or ethanol solutions of sodium salts is achieved corresponding to a uniform distribution of the active substance on the carrier. Thus resolves the problems associated with a uniform distribution of active ingredients in the tablets (content uniformity). After evaporation of the solvent provided the corresponding uniform distribution of soluble salts in the media, and monitoring compliance with the required water factor can be obtained directly lasting product. Evaporation of the residual moisture with a drying process for evaporating solvent, such as methanol and/or ethanol, conducted for the water-soluble salts levothyroxine sodium or liotironin sodium provides immediate compliance required water factor, and using methanol or ethanol solutions can be observed during evaporation of some semblance effect of grip when drainage of excess water, resulting in rapid drying.

If during the tabletting process it is necessary to abandon other auxiliary substances, such as, for example, hygroscopic means the destruction of the tablets, as the carrier can be used directly tableting mannitol, the company shall and, pearlite. In any case, when choosing the necessary excipients for tableting, you must renounce the use of hygroscopic substances to avoid re-hydration. To do this optimally apply tabletiruemye excipients, in particular, oil, hydrophobic excipients such as magnesium stearate.

To avoid formation of water-insoluble salts of hormones, as mentioned above, the callee may be contained in the substance-carriers ions of CA++before applying or spraying of a solution of the active substance to the media mix EDTA-sodium, if necessary, with addition of citric acid, in a quantity sufficient to bind divalent ions of the carrier. After intermediate drying, including elevated temperature, put alcohol solution of the active substance. Immediately after that, add a further quantity of aqueous complexing solution, as described above, to link present additional ions, originating from the solvent or production equipment. The amount of EDTA-sodium, designed to bind ions of CA++in any case, should not be excessive, so as EDTA-PA/citric acid by themselves do not increase the resistance of the sodium salts of l is of vothyroxine and liotironina.

Alternatively, the carrier consisting of mannitol, after mixing, if necessary, with starch, guar or other auxiliary granulating agents can be filled with methanol or alcohol solution of the active substance and immediately thereafter subjected to wet granulation using water solution with the content if necessary EDTA-sodium and/or citric acid. The water is evaporated before reaching the corresponding water activity, optionally with further addition of destroying pill substances. After mixing sizing pills get low water activity. Used preferred packaging should be impervious to water vapor. Manufactured in this way and stored at 25°C tablets exceptional durability.

Below the invention is explained more by using examples of its implementation and comparative experiments.

Example 1.

The water-soluble salts of the active substances are dissolved in an organic anhydrous solvent such as, for example, methanol and ethanol. A small amount of hygroscopic substance carrier in the form of mannitol (Pearlitol 400 DC) moistened with a solution of the active substance coating liquid layer or coating. Then the solvent is removed by drying in a fluidized bed or vacuumed who eat in the drying process the water factor set equal to 0.3. When pelletizing completely abandoned the use of substances for the destruction of the tablets. As lubricant when pelletizing was used stearate.

In this example implementation used the following structure:

Pearlitol 400 DC2749 g
methanol60 g
levothyroxine sodium1632
magnesium stearate32 g

Thus prepared mixture were easy to direct pelletizing, and worked tablets with a flawless appearance, hardness, friability and other pharmaceutical properties. Decomposition of the tablets occurred within one minute, thus formed solution, which is transparent except for floating on the water surface of the stearate. It should be borne in mind that optimum bioavailability of active substances, as with the exception of small amounts of insoluble stearate solution does not contain any other insoluble substances.

At room temperature the re 25°With a water factor of tablets was 0.2. Water absorption was tested in the course of experience on storage at 25°C, 60% relative humidity and duration of 24 hours and compared with traditional tablets formulation (for example, media content for the destruction of tablets and other pharmaceutical auxiliary substances, which are also pre-dried before reaching the water factor of 0.2. In the embodiment of the invention was as follows: water absorption only of 0.11% and a water factor of 0.3, while the tablet formulation had a water absorption of 0.75% (almost 7 times more) and water factor of 0.5.

Example 2.

In example 2, before applying the solution of methanol and levothyroxine sodium, as described in example 1, the same amount pearlitol, 2749 g, moisturize first 60 g of methanol and then pretreated with a solution consisting of 40 g of water, 0.12 g of anhydrous citric acid and 4.0 g of EDTA-disodium. The resulting mixture is dried to achieve a water factor of 0.2-0.25 and then tabletirujut, at the same time was a good tabletirovanie, the disintegration of the tablets was within about 1 minute. The results of example 1 was confirmed in this case. The active substance as in example 1 was uniformly applied on the carrier, there was no risk of delamination (content uniformity). Additional protection against divalent ions generated by the application of complexing solution is, protected active substance from the corresponding loss of activity.

Example 3.

In example 3, the drying was carried out in two stages, with the first drying occurred after treatment pearlitol described above EDTA and methanol, after which the active substance is applied using the above methanol solution and at the same time additional partial amount of EDTA-disodium, after which drying is repeated.

Example 4.

This example suggests that in the manufacture of conventional methods of water granulation using traditional tabletiruemyh excipients, such as carriers (mannitol), granulating means (guar), means for breaking the tablets (natrocarbonatite starch), oiling agents (magnesium stearate, talc), and conventional complexing funds (EDTA-sodium, citric acid), you can get a tablet with an unusual resistance of the active substance, provided that the water activity will correspond to the specified values (0,3) and is hermetically sealed packaging.

In this example implementation used the following structure:

mannitol11,78944 kg
guar0,44 kg
methanol0.3 kg
levothyroxine sodium0,00816 kg
water2.5 kg
EDTA-sodium0.08 kg
citric acid0,0024 kg
natrocarbonatite starch1.2 kg
talc0.32 kg
magnesium stearate0.16 kg

Mixed with guar carrier filled with a solution of the active substance, then stirred into an aqueous solution of EDTA-sodium and citric acid and damp granulation, and then dried to a water activity of less than 0.3. Tablets are manufactured with a water activity of 0.45, Packed in PVC at 25°C and 60% relative humidity and stored over 12 months, the content of the active substance was more than 88,6% of the stated rate (100% output), therefore, the tablets were to apply not suitable. Similar tablets, which are dried to achieve a water activity of 0.3, Packed in PVC and impermeable to water vapor bags, stored in similar conditions within 12 m of the months, have, taking into account normal fluctuations composition, the initial content (99,6%), that is, these pills have extraordinary durability.

The resistance of the preparations described in examples 1-3, increased as follows, and this increase was installed at various concentrations of the active substance: 100 mcg levothyroxine sodium, a relative humidity of 40-50% (water factor of 0.4-0.5). Within three months, the content of levothyroxine sodium had dropped to 87 wt.%, moreover, in order to faster results storage was carried out at 40°C and 75% relative humidity. Accordingly, the preparations containing 100 mcg levothyroxine sodium with a water factor of 0.3 three months had still the activity of 92.9%. For preparations containing 160 μg of levothyroxine sodium under the same storage conditions and measurements obtained with a water factor of 0.4-0.5 three months residual activity 90.7 percent, while when the water factor of 0.3 activity has accounted for 95.2 wt.% from the original number. In respect of the combined preparations containing levothyroxine sodium and liotironin sodium, observed comparable performance improvements, and drug content of pure liotironina sodium in the amount of 25 μg in a month with a water factor of 0.4-0.5 of its contents fell to 87.2%, at the same time when the water factor of 0.25 after one month according to stuudy analysis showed active content of 97.7 wt.% the used amount.

In General, it was found that the direct tableting in dry conditions is particularly quick and simple method of making homogeneous and persistent long time stand composition.

1. Solid pharmaceutical composition comprising as active substance a water-soluble salt of levothyroxine and/or liotironina, wherein the water activity of the pharmaceutical composition is less than 0.4 when measured at room temperature.

2. The pharmaceutical composition according to claim 1, characterized in that the water activity of the pharmaceutical composition is set to 0.1 to 0.3 when measured at room temperature.

3. The pharmaceutical composition according to claim 1, characterized in that the active substance contained in the methanol/ethanol solution, evenly applied to the carrier, mixed if necessary with starch, guar or granulating auxiliaries.

4. The pharmaceutical composition according to claim 2, characterized in that the active substance contained in the methanol/ethanol solution, evenly applied to the carrier, mixed if necessary with starch, guar or granulating auxiliaries.

5. The pharmaceutical composition according to claim 1, characterized in that the active substance is applied in water-soluble media.

6. farmacevticheskaja composition according to claim 2, characterized in that the active substance is applied in water-soluble media.

7. The pharmaceutical composition according to claim 5, characterized in that as the water-soluble carrier is mannitol.

8. The pharmaceutical composition according to claim 6, characterized in that as the water-soluble carrier is mannitol.

9. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that the carrier is processed EDTA-Na and optionally citric acid, the amount of which basically corresponds to the content of CA++in the carrier.

10. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that the composition has the form of tablets and made using non-hygroscopic excipients and/or Packed in the material, which is slightly or completely impermeable to water vapor.

11. A method of obtaining a pharmaceutical composition according to any one of claims 1 to 10, characterized in that the carrier of mannitol is applied or sprayed alcohol solution of the active substance, after which the alcohol solvent is evaporated to obtain a water factor less than 0.4, in particular less than 0.3, and then tabletirujut.

12. The method according to claim 11, characterized in that before evaporation of the solvent causing the water or aqueous solution with a content of EDTA-Na and/or citric acid.

13. Pic is b according to item 11, characterized in that as the carrier is applied directly tableting mannitol, in particular pearlitol.

14. The method according to claim 11, characterized in that as tabletiruemyh AIDS are used, in particular, oil, hydrophobic excipients, such as, for example, magnesium stearate.

15. The method according to claim 11, characterized in that before applying or spraying of a solution of the active substance on the carrier, supplementing it with EDTA-Na and optionally citric acid in a quantity sufficient to bind divalent ions from media and other sources, such as a solvent.

16. The method according to item 15, wherein before the adulteration of EDTA-Na and optionally citric acid carrier moistened with methanol.

17. The method according to any of § § 11 to 16, characterized in that the composition does not contain hygroscopic excipients.

18. The method according to any of § § 11 to 16, characterized in that the composition contains hygroscopic excipients, but Packed in impermeable to water vapor material.



 

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Solid medication // 2357757

FIELD: pharmacology.

SUBSTANCE: invention relates to pharmacon immediately dealing with preparation of a solid medication for treatment of diabetes and its sequela. The medication contains metformin or a salt thereof, pioglitazone or a salt thereof, homogenously dispersed, as well as target admixtures. The ratio of the average particle size of metformin or the salt thereof to the average particle size of pioglitazone or the salt thereof varies from 2.23:1 to 8.06:1.

EFFECT: provision for high homogeneity and dissolution degree of the active ingredient.

5 cl, 3 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical industry and concerns method for making antiulcer and antacid tablets containing an active material made of hairgrass rhizome and buckthorn bark, as well as base bismuth nitrate, base magnesium carbonate, sodium hydrocarbonate and microcrystalline cellulose, all being mixed with humid granulation and pelletisation. Herewith the active material is polyextracted buckthorn bark and hairgrass rhizome resulted from multistage counter-current extraction of hairgrass rhizome and buckthorn bark in specific environment followed by graduation of the extract.

EFFECT: method allows for tablets made of standardised extractive complexes of natural raw materials with low microbial semination, high biological activity of components, improved biological availability and stability.

2 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to pharmacology and medicine and concerns a pharmaceutical composition for treatment or prevention of vascular pathological condition, diabetes, obesity or low-sterol plasma concentration in mammals containing sterol absorption inhibitor of formula (II), lactose monohydrate, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium salt, sodium lauryl sulphate and magnesium stearate.

EFFECT: invention provides improved solubility of the composition.

21 cl, 4 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and medicine, namely to solid formulation betahistine dihydrochloride containing lactose, microcrystalline cellulose, copolymer vinylpyrrolidone and vinyl acetate, as well as stearic acid and/or its salts as additives in ratio as specified in the patent claim, and to production procedure of the present formulation.

EFFECT: solid formulation under the invention is characterised with good disintergration and high strength.

6 cl, 1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, particularly to pharmacy. There is disclosed new preparation. Controlled-release Proxodolol is prepared effectively and conveniently with applying one or more mixed swelling or gelling components, an active component and pharmaceutically acceptable filler. It is preferential to apply a tableted preparation containing Proxodolol dosed 120 mg, hypromellose and pharmaceutically acceptable fillers, e.g. microcrystalline cellulose, calcium stearate and aerosil. New pharmaceutical forms with a suitable Proxodolol release profile allow reducing number of daily dosages while concentration of active component is constant within a therapeutic dose.

EFFECT: stable kinetic indicators of active material delivery.

8 cl, 5 ex, 5 tbl

FIELD: medicine.

SUBSTANCE: claimed invention relates to chemical-pharmaceutical industry and concerns auxiliary binding substances for manufacturing drop-shaped tablets and to preparation of drop-shaped tablets. Auxiliary binding substances according to claimed invention are selected from group which consists of monosaccharide, oligosaccharide, polysaccharide, sugar ester, sugar of alcohol structure, alpha-hydroxy acid, higher fatty acid derivative, higher aliphatic alcohol, polyol, urea and poly(ethyleneoxide) derivative.

EFFECT: claimed invention reduces toxicity caused by polyethylene glycol, improves drop-shaped tablet quality and accelerates development of drop-shaped tablets.

20 cl, 68 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: method of obtaining soluble molecular complexes, containing one or several acting substances, poorly soluble in water medium, included into one or several host molecules representing cyclodextrin, which is distinguished by the fact that it includes following stages: (a) bringing one or several acting substances in contact with one or several host-molecules; (b) carrying out stage of molecular diffusion by bringing liquid liquefied under pressure in contact in static conditions with mixture obtained at stage (a), in presence of one or several agents favouring diffusion; (c) isolation of thus obtained molecular complex. Carrying out stage of molecular diffusion also favours dissolution in water medium with increase of solubility approximately by 100 fold.

EFFECT: method, including stage of molecular diffusion in static conditions applying liquid liquefied under pressure, excluding stage of further washing with liquid with supercritical parameters, considerably increases part of including depending on amount of favouring diffusion agent, added to medium.

6 cl, 7 ex

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