Pharmaceutical formulation

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medicine drugs, particularly pharmaceutical formulation including sodium levothyroxin, microcrystalline cellulose with average particle size under 125 mcm in amount of 60 to 85 wt % of the total formulation weight, and pre-gelatinised starch in amount of 5 to 30 wt % of the total formulation weight. Additionally, invention concerns method of obtaining claimed formulation and method of hormonal thyroid disorder treatment.

EFFECT: obtaining stable solid dosed formulation of sodium levothyroxin.

16 cl, 4 tbl, 3 ex

 

The present invention relates to stable pharmaceutical formulations form of levothyroxine sodium used to treat hormonal disorders of the thyroid gland in mammals, including humans. The invention relates also to a method for preparing such a formulation.

Levothyroxine sodium is widely used in the treatment and/or prophylaxis of hormone thyroid disorders. Levothyroxine sodium currently commercially available under the trademark Eltroxin™ in the form of tablets, 50 mcg and 100 mcg. These pills contain levothyroxine sodium, lactose, magnesium stearate, powder Arabian gum, sodium citrate and corn starch. Although levothyroxine sodium in pure form is relatively stable, containing levothyroxine sodium pharmaceutical formulation show a relatively short shelf life, especially in conditions of bright light, heat, air and moisture (see "Kinetics of Degradation of Levothyroxin Sodium in Aqueous Solution and in Solid State", Chong Min Won, Pharmaceutical Research, Vol. 9, No 1 (1992), 131-137). Therefore, the present invention is directed to the development of a stable solid dosage forms of levothyroxine sodium. It is also desirable that the solid dosage form quickly fell apart, thereby providing a quick release of the active ingredient, and was astete the Eski acceptable and palatable to the patient.

The authors of the present invention have found that the pharmaceutical preparative form comprising levothyroxine sodium, microcrystalline cellulose with an average particle size of less than 125 microns and pregelatinized starch, gives a solid dosage form with enhanced stability and characteristics of disintegration, which is aesthetically acceptable and palatable to the patient. Accordingly, the present invention provides pharmaceutical preparative form, comprising (a) an effective amount of levothyroxine sodium, (b) microcrystalline cellulose, which has an average particle size of less than 125 microns and is present in an amount of from 60 to 85 wt.% per the whole weight of the formulation, and (c) pregelatinized starch is present in an amount of 5 to 30 wt.% per the whole weight of the formulation. Pharmaceutical formulations of the present invention have improved stability, such that they are stable to such an extent that the efficiency is reduced by less than 5%, preferably less than 4%, more preferably less than 3%, when the pharmaceutical preparative form stored at 25aboutC and 60% RH (relative humidity) for 12 months. Pharmaceutical formulations of the present invention have superior characteristics disintegration, that is s, they have a disintegration time of less than 6 minutes, preferably less than 5 minutes, more preferably less than 4 minutes, when they are tested in the test for disintegration, as described below in the examples.

Chemical name sodium levothyroxine - (S)-2-amino-3-[4-(4-hydroxy-3,5-iodophenoxy)for 3,5-diiodophenyl]sodium propionate. Levothyroxine sodium is the monosodium salt levogyrate isomer of thyroxine. Levothyroxine sodium may exist in one or more polymorphic forms, for example in one or more crystalline forms, amorphous forms, phases, solid solutions and/or their mixtures. All such forms of levothyroxine sodium and/or mixtures thereof are encompassed by the present invention. Preferably levothyroxine sodium for use in the pharmaceutical formulation of the present invention is in hydrated form. More preferably levothyroxine sodium for use in the pharmaceutical formulation of the present invention is in the form of the pentahydrate.

Preferably, levothyroxine sodium is present in amount less than 1 wt.% per the whole weight of the formulation, more preferably from 0.01 to 0.30 wt.%, even more preferably 0.03 to 0.25 wt.%, most preferably 0,06-0,20 wt.%. The minimum number of levothyroxine sodium can the t to vary as long while the used amount, effective to cause the desired pharmacological effect.

Preferably microcrystalline cellulose has an average particle size of ≤100 μm, more preferably ≤75 μm, even more preferably ≤50 μm. Preferably microcrystalline cellulose selected from microcrystalline cellulose grade 101, 102 or 103, more preferably grade 101 or 102, most preferably grade 101. The term "class 101"as it is used in the description means a material with a nominal average particle size of 50 μm and a water content ≤5.0% in accordance with the European Pharmacopeia (2002). The term "class 102," as it is used in the description means a material with a nominal average particle size of 100 μm and a water content ≤5.0% in accordance with the European Pharmacopeia (2002). The term "class 103", as it is used in the description means a material with a nominal average particle size of 50 μm and a water content ≤3.0% in accordance with the European Pharmacopeia (2002). The term "class 200," as it is used in the description means a material with a nominal average particle size of 180 μm and a moisture content of ≤5.0% in accordance with the European Pharmacopeia (2002). Preferably microcrystalline cellulose receive from FMC Corporation, JRS Rettenmaler or Sähne (Germany), or Wei Ming (Taiwan), more preferably from Wei Ming (Taiwan).

Preferably mikroC istoricheskaya cellulose is present in an amount of from 60 to 85 wt.% per the whole weight of the formulation, more preferably from 65 to 80 wt.%, most preferably 70 to 80 wt.%.

The term "pregelatinized starch"as used in the description means partially pregelatinized starch, typically containing about 5% of free amylose, 15% free amylopectin and 80% unmodified starch. It is obtained, subjecting the moistened starch mechanical pressure in order to destroy part or all of the starch granules. The resulting material is thick, and the moisture content correct it so that it had a good flow and characteristics of the seal. Normal solubility in cold water partially pregelatinized starch, such as starch 1500 (use)is 10-20%. Pregelatinized starch is further defined in the European Pharmacopea (2002), which is included in the description by reference. Preferably pregelatinized starch is present in an amount of 5 to 30 wt.% per the whole weight of the formulation, more preferably from 10 to 30 wt.%, most preferably 15 to 25 wt.%.

Preferably the ratio of microcrystalline cellulose:pregelatinized starch is in the range from 2:1 to 15:1, more preferably from 2.5:1 to 8:1, most preferably from 3:1 to 5:1.

Preferably microcrystalline cellulose and Pragelato sereveny starch contain water. Preferably water is 3-6 wt.% per the whole weight of the formulation, more preferably about 4.5% (for example, 4,5-5,0%).

Preferably the pharmaceutical preparative form includes one or more glidants/lubricants. Suitable glidant/lubricants for use in the present invention include colloidal silicon dioxide, talc, magnesium stearate, zinc stearate, calcium stearate, stearate-sodium fumarate and sodium magnipapillata. Preferably glidant/lubricants are selected from one or more of colloidal silicon dioxide, talc and magnesium stearate.

Preferably glidant/lubricating substance is present in a quantity of 1-10% of the total weight of the formulation, more preferably 2 to 9% of the total weight of the formulation, more preferably 3-8% of the total weight of the formulation.

Preferably, talc is present in an amount of 1-5% of the total weight of the formulation, more preferably 2-4% of the total weight of the formulation, most preferably 2.5 to 3.5% of the total weight of the formulation.

Preferably colloidal anhydrous silicon dioxide is present in amounts of 1-5% of the total weight of the formulation, more preferably 1-3% of the total weight of the formulation, most preferably 1.5 to 2.5% of all mA the son preparative form.

Preferably the magnesium stearate is present in an amount of 0.1-5% of the total weight of the formulation, more preferably 0.5 to 4% of the total weight of the formulation, most preferably 0.8 to 1.5% of the total weight of the formulation.

Preferably the pH of the pharmaceutical formulation is in the range of pH from 6.8 to 8.2, preferably from 7.2 to 7.8 when suspendirovanie in the water in relation to water:pharmaceutical preparative form 10:1.

Preparative form according to the invention can, if desired, further include one or more pharmaceutically acceptable excipients. All such fillers must be "pharmaceutically acceptable" in the sense that they are compatible with other ingredients of the formulation and do not bring harm to the patient. Pharmaceutically acceptable excipients may include colorants, flavors, such as menthol, sweeteners such as mannitol, preservatives, stabilizers, antioxidants, and any other fillers known to specialists in this field.

It should be clear that the present invention covers all combinations of particular and preferred groups described above.

The present invention provides pharmaceutical preparative form for use in medical therapy, for example in the treatment of hormonal Rosstroy is in the thyroid gland of the animal, for example a mammal, such as man. Know that levothyroxine and other thyroid hormones used in hormone replacement therapy when the function of the thyroid gland attenuated or completely absent in various painful conditions, including hypothyroidism, myxedema, cretinism and obesity, preferably hypothyroidism.

For each of the above applications and indications required number of levothyroxine sodium will depend on a number of factors, including the severity of the condition that must be treated, and the nature of the recipient and, ultimately, should be the choice of the attending physician or veterinarian. Typically, the physician must determine the effective dose, which will be most appropriate for a particular patient. The specific dose level and frequency of dosage for any particular patient may vary and should depend on many factors, including the specific activity of the applied compound, the metabolic stability and length of action of that compound, the age, body weight, General health, sex, diet, mode and time of administration, rate of excretion, combination of drugs, the severity of the condition undergoing therapy patient. In General, however, each of these applications and indications, a suitable effective dose due is to be in the range of from 1.0 to 6.0 micrograms per kilogram of body weight of the recipient per day, preferably in the range from 1.5 to 5.0 micrograms per kilogram of body weight per day (unless otherwise specified, all weights are calculated with respect to the free base of the active ingredient).

The desired dose is preferably presented as one, two, three or four subdata entered through the designated intervals during the day. These subdata can be administered in unit dosage forms, for example, containing about 10-300 μg, preferably 10-200 μg, more preferably 25-150 µg active ingredient in a unit dosage form, most preferably 50 μg or 100 μg of the active ingredient in a unit dosage form.

For example, 50 mg tablet may include 0,0425-0,0575 mg of levothyroxine sodium, 50-60 mg microcrystalline cellulose, 12-17 mg pregelatinization starch, 2-3 mg of talc, 1-2 mg colloidal anhydrous silica and 0.5-1 mg of magnesium stearate. 100 mg tablet can include 0,085-0,115 mg of levothyroxine sodium, 100-120 mg microcrystalline cellulose, 24-34 mg pregelatinization starch, 4-6 mg of talc, 2-4 mg colloidal anhydrous silica and 1-2 mg of magnesium stearate.

Pharmaceutical preparative form is preferably administered orally, preferably in the form of tablets. However, in addition to tablets preparative form according to the present invention can takeaways in the form of capsules, dripping, gel capsules, pills and any other oral dosage forms known in the pharmaceutical field.

The term "treatment" and its derivatives, as it is used in the description, and includes treatment, and prevention. Prevention refers to protection against conditions such as hypothyroidism.

An additional aspect of the invention provides a method of preparing a pharmaceutical formulation according to the invention.

A tablet may be prepared or wet granulation, or direct compression. Preferably use the method of direct compression, i.e. the use of conventional high-speed rotary press.

Preferably, the pharmaceutical preparative form preparing, carrying out the initial preparation of triturate of levothyroxine sodium and the subsequent introduction of triturate the tablet. Triturate levothyroxine sodium contains levothyroxine sodium and suitable media, such as microcrystalline cellulose, where the levothyroxine sodium is present in triturate in greater concentration than in the final preparative form tablets. Preferably triturate includes 2-3 wt.% levothyroxine sodium from the total mass of triturate. Cooking using triturate improves the distribution of low concentrations of drug in the mixture and agnor the bullying; appropriate tablets, i.e. homogeneous introduction.

Preferably, the method comprises the stage of: (a) preparation of triturate levothyroxine sodium, (b) mixing triturate with other components of the pharmaceutical formulation, and (c) pressing.

Levothyroxine sodium may be obtained from the thyroid glands of animals or, alternatively, the hormone can be obtained synthetically. The methods of preparation of the active ingredient described in Hagers Handbuch der pharmazeutischen Praxis, - 5, vollst. Neubearb., Bd.8, Stoffe: E-O/F... Von Bruchhausen; (Hrgs.). Bearb... von M.Albinus - 1993, Springer-Verlag Berlin Heidelberg 1993, p.p. 733-734; S.Rolski, Chemialeczniczych, str. 654-655, PZWL, Warszawa, 1968, the contents of which are incorporated into this description by reference.

Preparative form may be introduced into a container which is then closed. The container can be sealed, for example, a snap-on plug-in congestion control opening of LDPE (low density polyethylene). The container may be a single dose or mnogochasovym. The container can be bubbles, cans, bags or sachets. Sasha, in particular sachet foil (blister foil-foil), especially suitable for single dose packaging. Bubbles, in particular air bubbles from high density polyethylene (PEAP) or polypropylene are particularly suitable for mnogochasovoj packaging.

The following examples serve to illustrate aspects of the present invention, but not to what should be regarded as in any way limiting the scope of invention.

Examples

EXAMPLE 1: PREPARATION of TABLETS LEVOTHYROXINE SODIUM

(a) preparative form

[kg]
Levothyroxine sodium pentahydrate0,074
Microcrystalline cellulose75,0
Pregelatinized starch20,0
Talc3,0
Colloidal silicon dioxide2,0
Magnesium stearate1,0

The cooking process

Tablets levothyroxine sodium were prepared by direct pressing method, comprising the following stages:

cooking triturate levothyroxine sodium part of microcrystalline cellulose by a simple mixing;

mix the rest of microcrystalline cellulose and pregelatinized starch with triturator levothyroxine sodium to obtain a homogeneous composition of the active substances;

adding talc, colloidal silicon dioxide and magnesium stearate, followed by mixing to prepare a powder mixture;

pressing tablets levothyroxine sodium crushing strength not less than 3 kPa and the ultimate strength of 3.5-10 kPa.

(b) preparative form

[kg]
Levothyroxine sodium pentahydrate0,074
Microcrystalline cellulose75,0
Pregelatinized starch20,0
Talc3,0
Colloidal silicon dioxide2,0
Magnesium stearate1,0

Manufacturing process

The manufacturing process for example 1(b) differed from example 1(a) the fact that the mixing balance of microcrystalline cellulose and colloidal silicon dioxide was carried out before mixing with trituration of levothyroxine sodium and pregelatinization starch.

EXAMPLE 2: STABILITY of TABLETS LEVOTHYROXINE SODIUM

A comparative study of the stability of the tablets levothyroxine sodium was based on testing the content of levothyroxine, and total impurities after storage of the tablets when (i) 40°C/75% RH; (ii) 30°C/60% RH; and (iii) 25°C/60% RH. Used appropriate methods GHUR. The stability was evaluated in terms of the content of levothyroxine, and total content of impurities:

The content of total impuritieswas determined using the method of analysis for tablets, levothyroxine sodium from the British Pharmacopoeia 2002 with a concentration in a sample of 50 μg/ml, the solvent in the sample: methanol è0,02M aqueous NaOH (1:1), the amount of injection of 100 μl and the flow rate of phase 1.5 ml/min

The content of levothyroxine sodiumwas determined using the method of analysis for tablets, levothyroxine sodium from the British Pharmacopoeia 2002 with a concentration in a sample of 50 μg/ml, the solvent in the sample: methanol and 0,02M aqueous NaOH (1:1), and the flow rate of phase 1.5 ml/min

The results of these stability tests are presented in tables (a) through (C).

Conclusions

(A) the stability of the tablets of levothyroxine sodium: comparison of tablets, levothyroxine sodium, prepared according to example 1(b), with tablets Eltroxin™

The data show that after 3-9 months of storage in tablets according to example 1(b) still has a higher content of levothyroxine sodium than in commercially available preparative form Eltroxin™and the total impurities in tablets according to example 1(b) is less than the commercially available preparative form Eltroxin™.

(B) the stability of the tablets of levothyroxine sodium: effect of particle size microcrystalline cellulose

The data show that when the preparative form of levothyroxine use microcrystalline cellulose with an average particle size of 50 μm or 100 μm compared to 180 microns, remains higher content of levothyroxine, and total content of total impurities in the smaller tablets.

(C) Stability of tablets lion is thyroxine sodium: effect of water content

The data show that a higher content of sodium levothyroxine after 3 months of storage is stored in tablets, where the initial water content is 4.1 or 4.7%, compared with 2.4 or 2.7%.

Table (A)Stability of tablets levothyroxine sodium:comparison of tablets, levothyroxine sodium, manufactured according to example 1(b), with tablets Eltroxin™

Tablets levothyroxine sodiumStrength tablets

[ug]
Storage conditionsThe content of levothyroxine sodium [%]*The total content of impurities [%]
Storage time [months]Storage time [months]
Initial value : 36912Initial value : 36912
Example 1(b)10040°C/75% RH

30°C/60% RH

25°C/60% RH
101,094,3

100,2

101,6
90,5

of 98.2

100,6
-96,11100,7-

94,3

97,7
1,23,5

1,7

1,2
4,8

2,8

1,8
-
3,3

2,6
-

3,8

2,6
Example 1(b)5040°C/75% RH

30°C/60% RH

25°C/60% RH
101,492,0

100,0

99,8
84,4

99,6

102,4
-

98,6

101,4
-

93,8

of 98.2
1,13,8

2,7

2,1
6,1

2,9

2,5
-

3,4

2,7
-

3,8

3,2
Eltroxin™10040°C/75% RH

30°C/60% RH

25°C/60% RH
98,089,5

93,4

95,7
of 83.4

88,2

of 92.7
-

89,5

to 92.1
-

-

-
1,27,5

4,9

4,5
8,9

7,0

4,8
-

6,6

of 5.4
-

-

-
* - % by definition.
Not determined.

Table (B)Stability of tablets levothyroxine sodium:the influence of particle size microcrystalline cellulose tablets, levothyroxine sodium, manufactured according to example 1(b)

The variety of micro-crystalline celluloseThe average particle size

[µm]
In the conditions of storage: 40° C/75% RH
The content of levothyroxine sodium [%]*The total content of impurities [%]
Time (weeks)Time (weeks)
28122812
1015099,7

99,6
98,1

95,6
98,3

95,4
0,0

0,6
2,6

2,3
2,8

1,6
10210095,8

96,0
90,2

90,5
88,6

86,8
4,8

2,3
6,1

5,0
6,6

5,5
200180to 91.687,580,92,17,7-
* - % from the initial value (initial value 100%).

Table (C)Stability of tablets levothyroxine sodium:the influence of water content on tablets, levothyroxine sodium, manufactured according to example 1(b)

Strength tablets [ug]Storage conditionsLosses during drying [%]The content of levothyroxine sodium [%]
Storage time [months]Storage time [months]
Initial value : 3Initial value : 3
10040°C/75% RH

30°C/60% RH

25°C/60% RH
4,15,1

5,1

4,4
100,6to 91.6

97,3

99,5
10040°C/75% RH

30°C/60% RH

25°C/60% RH
2,72,8

2,6

2,7
99,783,0

94,3

94,5
5040°C/75% RH

30°C/60% RH

25°C/60% RH
the 4.75,7

5,1

a 4.9
101,492,0

100,0

99,8
5040°C/75% RH

30°C/60% RH

25°C/60% RH
2,41,6

1,4

1,2
100,682,0

90,1

to 91.6

Example 3: Disintegration of tablets levothyroxine sodium

Disintegration of tablets, levothyroxine sodium, manufactured according to example 1(b), tested according to British Pharmacopoeia (BP) 2002 (General Monograph for Tablets, Uncoated Tablets, Desintegration Test).

The results are presented in table (D).

Table (D)Disintegration of tablets Le is tiroxina sodium

Strength tablets

[ug]
Storage conditionsThe disintegration time [min, sec]
Storage time [months]
The initial value36912
10040°C/75% RH

30°C/60% RH

25°C/60% RH
0 min 31 sec2 min 14 sec

0 min 37 sec

0 min 36 sec
2 min 00 sec

2 min 52 sec

1 min 00 sec
-

1 min SC

1 min SK
-

0 min 57 sec

0 min 53 sec
5040°C/75% RH

30°C/60% RH

25°C/60% RH
0 min 31 sec1 min 40 sec

0 min 33 sec

0 min 29 sec
1 min 56 sec

0 min 32 sec

0 min 46 sec
-

0 min 59 sec

0 min 45 sec
-

1 min 49 sec

0 min 53 sec
Not determined.

Conclusions

(D) Disintegration of tablets levothyroxine sodium

Data show that the disintegration of the tablets made according to example 1(b), is very fast (less than 4 minutes). According Pharmaco is it for tablets uncoated requires the disintegration time less than 15 minutes.

Throughout the application and claims, which indicated below, unless the context otherwise requires, the word "include" and variations such as "comprises" and "comprising"should be understood to imply the inclusion of the whole or stage, or group of integers but not the exclusion of the whole, or stage, or group of integers or steps.

1. Pharmaceutical preparative form, comprising (a) an effective amount of levothyroxine sodium, (b) microcrystalline cellulose, which has an average particle size of less than 125 microns and is present in an amount of from 60 to 85 wt.% per the whole weight of the formulation, and (c) pregelatinized starch is present in an amount of 5 to 30 wt.% per the whole weight of the preparative form.

2. Pharmaceutical preparative form according to claim 1, in which the microcrystalline cellulose has an average particle size of less than or equal to 100 microns.

3. Pharmaceutical preparative form according to claim 1 or 2, in which the ratio of microcrystalline cellulose: pregelatinized starch is in the range from 2:1 to 15:1.

4. Pharmaceutical preparative form according to any one of claim 1 or 2, in which the microcrystalline cellulose and pregelatinized starch include water, which is present in the amount of 3-6 wt.% per the whole weight of the preparative form.

5. Pharmaceutical preparati the Naya form according to any one of claim 1 or 2, where levothyroxine sodium is gidratirovannym.

6. Pharmaceutical preparative form according to claim 5, in which the levothyroxine sodium is in the form of the pentahydrate.

7. Pharmaceutical preparative form according to any one of claim 1 or 2, which further includes one or more glidants/lubricants.

8. Pharmaceutical preparative form according to claim 7, in which glidant/lubricating substance selected from colloidal anhydrous silica, talc and/or magnesium stearate.

9. Pharmaceutical preparative form according to any one of claim 1 or 2, which is stable to such an extent that the efficiency decreases to less than 5%, when the pharmaceutical preparative form stored at 25°C and relative humidity of 60% within 12 months.

10. Pharmaceutical preparative form according to any one of claim 1 or 2 in the form of a standard dosage forms.

11. Pharmaceutical preparative form of claim 10, where the standard dosage form is a tablet.

12. Pharmaceutical preparative form according to any one of claim 1 or 2 for use in medical therapy.

13. Pharmaceutical preparative form according to any one of claim 1 or 2 for use in the treatment of hormonal disorders of the thyroid gland in mammals such as man.

14. The use of a pharmaceutical formulation according to Liu the WMD of claim 1 to 11 in the preparation of drugs for the treatment of hormonal disorders of the thyroid gland in mammals, such as people.

15. A method of treating hormonal disorders of the thyroid gland, including the introduction of a pharmaceutical formulation according to any one of claim 1 to 11.

16. Method of preparation of a pharmaceutical formulation according to any one of claim 1 to 11, comprising (a) obtaining triturate levothyroxine sodium, (b) mixing triturate with other components of the pharmaceutical formulation; and (C) pressing.



 

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31 cl, 6 dwg, 5 tbl, 5 ex

FIELD: medicine; pharmacology.

SUBSTANCE: composition includes effective amount of carbamazepine as active ingredient, and carbomer 71G, microcrystalline cellulose, sodium carboxymethylstarch, aerosol, and stearate salt as auxiliary ingredients. The composition is manufactured by direct pressing method, preferably in form of tablets.

EFFECT: composition stability during storage period, release profile reproducibility of active substance, satisfactory pharmacokinetic characteristics, and high strength of the tablets.

5 cl, 1 tbl, 4 ex

FIELD: pharmaceutical industry.

SUBSTANCE: filmed tablet of improved stability including dried extract of red grape leaves, excipient and film coating taken in specified amount where dried aqueous extract of red grape leaves is produced with drying including silica addition stage during this process.

EFFECT: improved stability.

7 cl, 2 dwg, 6 tbl

Medicinal tablet // 2341249

FIELD: medicine.

SUBSTANCE: invention refers to medicinal agents, specifically to medicinal tablet made of solid body covered with elastic water-proof film containing data traffic identifying medical product, such as Validol, and has two holes used to fix the tablet on clothes.

EFFECT: this tablet design allows for quick finding and removal.

1 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention concerns medicine, particularly medical drugs with organic active components, medicines with sedative, vasodilating and antispasmodic effect, and methods of medicine obtainment, an can be applied in treatment of neuroses with high irritability, increased agitation, insomnia, neurocirculation dystonia, early stage of hypertension, non-acute cardiovascular spasm, digestive organ spasms related to neurovegetative disorders. Medicine of sedative and antispasmodic effect includes ethyl ether of α-bromisovaleric acid, Phenobarbital, peppermint oil, microcrystalline cellulose auxiliary substances for solid formulation obtainment in pellet form at the following component ratio, wt %: ethyl ether of α-bromisovaleric acid 1.37-8.2; Phenobarbital 1.25-7.5; peppermint oil 0.16-0.58; microcrystalline cellulose 2-15; the rest is auxiliary substances; pellets are covered with shell composed of β-cyclodextrin in amount of 10% of dry coating weight. First version of method of obtaining medicine with sedative and antispasmodic effect involves initial mixing of ethyl ether of α-bromisovaleric acid with peppermint oil, so that the mix comprises over 4.5% of total pellet, core pellet or capsule content weight, adding the mix to humid β-cyclodextrin taken in amount of up to 70% of total pellet core weight, stirring for 1-2 minutes, drying and pelletising of obtained mix, mixing granulate with Phenobarbital and microcrystalline cellulose powders and auxiliary filler, fluffer and slider substances, pellet compression and coating with shell containing β-cyclodextrin in amount of up to 10% of dry coating weight. Second version of method involves initial mixing Phenobarbital with auxiliary filler substance, separate preparation of mix of ethyl ether of α-bromisovaleric acid with peppermint oil, so that the ether oil mix comprises less than 4.5% of total pellet, core pellet or capsule content weight, adding microcrystalline cellulose powder, powders with extensive crystal surface area, auxiliary fluffer and slider substances, adding obtained mix to Phenobarbital and filler mix, pellet compression and coating with shell containing β-cyclodextrin in amount of up to 10% of dry coating weight.

EFFECT: medicine of sedative and antispasmodic effect in solid pellet form, with sedative and antispasmodic action matching that of drops with similar effect, ensuring stability of volatile components.

20 cl, 8 ex, 11 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: composition contains, essentially anhydrous ordered (adhesive) mixture of, at least, one pharmaceutically active agent in the form of microparticles linked to surface of carrier particles which are essentially greater than those of the active agent or agents, and, essentially are water insoluble or poor soluble, in a combination with the agent enabling bioadhesion and/mucoadhesion, linked to surface of specified carrier particles. The composition, mainly, is used for sublingual or intranasal introduction. Besides, the invention refers to method of composition preparation.

EFFECT: improved bioadhesive properties, fast release of active substance.

31 cl, 1 dwg, 1 tbl, 1 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention is used for treatment of bacteriemic infections, it is prepared as composition in the form of dry powder, adapted for delution by water with reception of the suspension important pH in a range from approximately 5.0 to approximately 5.5 at initial delution and which in addition contains the stabilizer pH which represents sodium-carboxymethyl cellulose. Besides, the invention concerns application sodium-carboxymethyl cellulose for reduction of degree of degradation clavunalate and for stabilisation pH the received suspension.

EFFECT: stability improvement in preparation.

7 cl, 1 dwg, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is capable to be attached to wet surfaces of tissues of the body, including the first water-soluble adhesive layer and the second water blasted not adhesive protective layer regulating time of stay of the water blasted device; and the first layer includes water-soluble film-forming polymer in a combination with mucoadhesive polymer, and the second water-soluble non-adhesive protective layer includes membrane consisting of one component from number hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrolidone, polyvinyl alcohol, polyethyleneglycol, polyethylene oxide or copolymers of ethylene oxide and propylene oxide, and covered with hydrophobic polymer and water-soluble polymer at a parity hydrophobic polymer(s) to water-soluble polymer (frames) 1:1-9:1 (on weight).

EFFECT: good stickiness of product, comfort, desirable duration of influence.

18 cl, 1 tbl, 18 ex

FIELD: medicine; pharmacology.

SUBSTANCE: sterile aripiprazole compound for injections with controllable elution in the form of sterile suspension provides aripiprazole release after an injection within at least one week, including: (a) aripiprazole which has the average size of particles approximately from 1 to 10 micron, (b) aripiprazole carrier, and (c) water for injections, and the specified structure for injections contains aripiprazole in amount from approximately 1% to 40% wt in relation to the total amount of the specified sterile compound for injections.

EFFECT: increase of adaptable ability of patients and decrease in frequency of relapses at schizophrenia treatment.

27 cl, 2 tbl, 3 dwg, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: composition includes effective amount of carbamazepine as active ingredient, and carbomer 71G, microcrystalline cellulose, sodium carboxymethylstarch, aerosol, and stearate salt as auxiliary ingredients. The composition is manufactured by direct pressing method, preferably in form of tablets.

EFFECT: composition stability during storage period, release profile reproducibility of active substance, satisfactory pharmacokinetic characteristics, and high strength of the tablets.

5 cl, 1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: agent for superficial mycoses treatment contains antimycotic Ketoconazole; emulsion carrier including emulsifiers, castor oil, water; end additives stabiliser and preserving agent. Agent is aerosol liniment additionally containing antioxidant Dibunolum or butylhydroxytoluene. As emulsifier agent contains emulsifiers of the first and second type that are distilled monoglycerides, emulsion wax, Tvin 80; as stabiliser it contains oxymethylpropylcellulose (OMPC), and preserving agent is mixture of Nipaginum and Nipazole.

EFFECT: provided lasting contact medicinal substance with affected region and its environmental protection; lowered risk of mycosis transfer from infected person to other people and higher sedimentation stability of agent.

3 tbl, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: pharmaceutical composition of controlled release, specifically composition of pulse release, includes nucleus containing physiologically active substance, unstable in acidic medium, leavening agent and alkaline additive. Nucleus has release control coating containing water-insoluble polymer, entero-soluble polymer and hydrophobic wax. Amount of hydrophobic wax in coating is 20-35 wt % of release control coating weight. Physiologically active substance, unstable in acidic medium represents compound based on benzimidazole or its pharmaceutically acceptable salt.

EFFECT: invention provides slight delay difference in composition dissolution and dissolution percent with the course of time providing high reliability of dissolution properties.

28 cl, 16 dwg, 23 tbl, 16 ex

FIELD: medicine; pharmacology.

SUBSTANCE: composition contains particles of water-swelling polymer, suspended in liquid diluting agent mixable with water. Polymer particles contain anionic polymer representing alginate, Rhodopol 23 or cellulose salt. Liquid diluting agent is water-free or includes water in amount insufficient to cause complete swelling of polymer particles. Composition does not include additional pharmaceutically active substance. When mixed with water composition described by invention solidifies and forms adherent layer within target body surface area.

EFFECT: provided barrier over the damaged surface; prevention or relief of inflammation or damage.

11 cl, 12 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: invention suggests pharmaceutical compositions intended for sublingual intake, as active ingredient of which agonist of central receptor of benzodiazepines is used, selected from the following list: diazepam, lorazepam, bromazepam, triazolam, alprazolam, flunitrazepam, nitrazepam, midazolam-maleate, in mixture with pharmaceutical excipient, which constitutes at least 70% of total weight of ready composition, and which contains lactose in amount from 40 to 45 wt %, corbite in amount from 15 to 27 wt % and cellulose in amount from 12 to 16 wt %. Excipient components lactose: cellulose: corbite are in ratio, approximately, 3:1,4-2,7:1.

EFFECT: ensuring fast action of benzodiazepines, similar to action of analogous preparations for injections and higher action than after peroral intake.

7 cl, 4 tbl, 8 ex

FIELD: medicine; oncology.

SUBSTANCE: method includes introduction of solution of chemical compound of amino acid L-phenylalanine with gold or silver nanoparticles intravenously prior to radiation. At that minimum concentration of nanoparticles is 108 cm-3, and maximum concentration is 1012 cm-3. Plasma resonance of nanoparticles has spectral maximum in the area of biotissues transparency at the wave length of 750-1200 nm. These nanoparticles are gold or silver nanoshells with core of silicon dioxide or nanorods. Radiation of melanoma is performed at least after 1 hour and not more than after 4 hours after solution introduction, laser beam with length of radiation wave that coincides with spectral maximum of nanoparticles plasma resonance absorption. At that radiation is done by sequence of laser impulses with duration of laser impulse in the range of 10 microseconds - 100 ns at minimum porosity of three and higher, at energy density of at least 20 J/cm2, but not more than 200 J/cm2.

EFFECT: local performance of melanoma destruction with minimum destruction of surrounding healthy cells.

10 dwg

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