Stable pharmaceutical composition of water-soluble salt of vinorelbine

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine, namely a stable pharmaceutical composition of a water-soluble salt of vinorelbine. The composition contains approximately 56 wt % of a diluent, approximately 2.5 wt % of a binding agent, approximately 5 wt % of a disintegrant, approximately 0.25 wt % of a flow agent and approximately 0.5 wt % of a lubrication agent. The water-soluble salt of vinorelbine is preferentially vinorelbine ditartrate.

EFFECT: pharmaceutical composition is preferentially presented in the form of a gelatine capsule or a tablet.

5 cl, 6 ex, 12 tbl

 

The present invention relates to a solid and stable dosage forms water-soluble derivatives of alkaloids in periwinkle (Vinca) and, in particular, the derivative of vinorelbine, namely ditartrate vinorelbine, intended for oral administration.

Anticancer chemotherapy was originally developed by way of the use of intravenous method of administration in the body. Arguments in favor of this route of administration are:

low toxicity to the gastrointestinal tract,

- overall bioavailability, and

- potentially lower variability of individual exposure between patients and patient than the oral route.

However, the intravenous route of administration is associated with significant drawbacks that limit its application: pain venous access, possible complications of the major venous paths (infection, thrombosis)the risk of extravasation.

In recent years, on the basis of undoubted benefit to the patient, in anticancer therapy increasingly receive oral form. In addition, pharmacoeconomic considerations increasingly important when choosing treatment strategies, also focused on the development of oral therapies.

Conducted a lot of research in the area of potential IP is the use of molecules, intended for the treatment of malignant tumors and oral input, whether it is already used active ingredients (e.g. etoposide, cyclophosphamide and idarubitsin), new synthetic derivatives of torpedinidae (for example: UFT, capecitabine, S-1), platinum derivatives (for example: JM-216), or Vinca alkaloids (eg: vinorelbine).

Vinorelbine or 3',4'-didehydro-4'-deoxy-8'-normenklarheit is a derivative of Vinca alkaloid exhibiting cytotoxic effect by inhibiting the polymerization of tubulin.

Vinorelbine and, in particular, its salt, ditartrate vinorelbine, along with other shows activity in the treatment of non-small cell lung cancer and breast cancer.

Unfortunately, this salt is unstable in the solid state.

Injectable form went on sale for the first time in 1989 in France. Currently it is sold all over the world in the form of a solution, subject to dilution for perfusion, with a concentration of 10 mg/ml, expressed in terms of vinorelbine, and distributed in standard bottles of 1 and 5 ml

Later was opened oral dosage form of vinorelbine in the form of a solution, sold under the name of Navelbine Oral (Navelbine Oral) (WO 03/101383). This product is a soft gelatin capsule, stereoscopically vinorelbine in dissolved form and a mixture of excipients, includes polyethylene glycol, glycerol, ethanol and water. The average molecular weight of polyethylene glycol is from about 200 to 600: this is a liquid polyethylene glycols, such as Macrogol 400. Unitary dose, expressed in terms of vinorelbine, range from 5 mg to 100 mg, and more preferably equal to 20 mg, 30 mg, 40 mg and 80 mg

Created also oral formulations containing ditartrate vinorelbine in dispersed form in a mixture on the basis of molten polyethylene glycol, they are the object of the patent published under the number FR 2880274). Unitary dose, expressed in terms of vinorelbine, range from 5 mg to 100 mg, and more preferably equal to 20 mg, 30 mg, 40 mg and 80 mg

However, as it turned out, it is difficult to improve soft capsules filled with liquid. In the case of liquid compositions, on the one hand, we should pay attention to the material of the capsule and to prevent the destruction of the latter, while the encapsulation. You should also prevent adverse chemical interaction between the excipients and the active ingredient. And, finally, the biological activity of the active ingredient should not be seriously affected.

Thus, it is very difficult to ensure a sufficient stability of the ingredient of this type, with cytotoxic activity in solid dosage f is rmah for oral administration. Ditartrate vinorelbine in dried form, in fact, should be stored in an airtight container in an inert atmosphere and at a temperature below minus 15C.

When selecting excipients must be a compromise between stability and availability of the active ingredient. Excipients must protect the latter, at the same time not being an obstacle to its dissolution and its quick accessibility for the body.

In addition, another problem that needs to be addressed, is harmful to health and the environment associated with working with powdered cytotoxic compounds on an industrial scale.

The aim of the present invention is, thus, creating a solid dosage form that has a shelf life of at least 24 months in storage conditions that do not require freezing, at the same time with bioavailability equivalent bioavailability soft capsules available on the market.

Oral forms based ditartrate vinorelbine according to the present invention are solid forms, fabricated using standard auxiliary substances for pressing or gelatin capsules (solvents, binders, disintegrating agents, agents, providing fluidity, lubricating agents). Unexpected is about was, what these forms have sufficient stability in the case of storage at 5C in a closed container for 24 months.

Thus, using the present invention can improve the convenience for the patient, because gelatin capsule and tablet form for oral administration allow treatment at home. Thus, they favor implementation of treatment by the patient.

In addition, when working with solid oral forms in the form of gelatin capsules or tablets can be reduced manufacturing costs compared to technologies that require the active ingredient inside the dosage form contained in the solution or dispersion (for example, are soft capsules).

The oral form according to the invention are solid forms made from mixtures of water-soluble salts vinorelbine, preferably ditartrate vinorelbine, and auxiliary substances. They contain at least one diluent and one lubricating agent, and can be obtained through various industrial processes. These methods are standard methods of preparation of solid dosage forms, well-known specialist in this field.

The method of preparation of the compositions according to the invention may consist of a dry mixture of different components which then distribute them in gelatin capsules or pressing them with the final stage of drawing on the tablet film coating.

Thus, in the case of preparation of compositions by direct dry blending the active ingredient in the first stage is mixed with a diluent, optionally with the baking powder and agent, providing fluidity, in a standard mixer used in the pharmaceutical industry, for example, such as a drum mixer. This premix is stirred at room temperature for approximately 10 minutes to obtain a homogeneous mixture. Then in a mixer add lubricating agent, and then proceed to lubrication by continuous stirring for about 5 to 10 minutes. Thus obtained mixture may be used to fill gelatin capsules on the corresponding equipment used in the pharmaceutical industry. Alternatively, the mixture can also be pressed on the press with reception of tablets. In the latter case, the resulting tablets preferably may be submitted to the step of applying a film shell.

In addition, at the stage of smearing the mixture can also be subjected to wet or dry granulation, and then in the same way as described earlier, to be distributed in gelatin capsules or tablets, followed by the possible application of the film shell.

Thus, in the case of preparation by wet granules is of the active ingredient in the first stage directly mixed with the diluent and binder using a standard mixer, used in the pharmaceutical industry. Whereas cytotoxic nature of the active ingredient, it is desirable that this mixing was carried out using a mixer-granulator / dryer in order to avoid working with multiple pieces of equipment.

The actual granulation can be achieved by adding a solvent granulation. The solvent granulation may be water, alcohol or water-alcohol. In the case of using an alcohol solvent, preferred as the alcohol solvent is ethanol, and in the case of water-alcohol system solvent that is a mixture of ethanol/water mass ratio in the range from 70/30 to 30/70, preferably in the range of 60/40 to 40/60, and more preferably 50/50. For maximum stability of the active ingredient during the stage of granulation and storage process, it is preferable to select an alcoholic solvent, in particular ethanol.

The mass ratio of solvent granulation to the amount of the granulated mixture can be in the range from 8 to 20%, preferably in the range from 10 to 25%. Oblastnoy thus the mixture is stirred and mixed before you start graining, i.e. enlargement of the ingredients with the formation of granules.

Granulares is nnow the mixture is then subjected to stage drying to obtain dry grain, that is, having a humidity of about the same as it was with the mixture prior to granulation. Drying can be carried out inside of the mixer-granulator / dryer connection vacuum in order to avoid the use of high temperatures, unfavorable for the stability of the active ingredient. Alternatively, the granulated mixture can be dried in the oven, to which may be connected a vacuum, or dried in the fluidized layer.

According to the private version of the method, the obtained granules are calibrated to the size ranging from 100 to 250 microns, preferably about 200 microns.

Such granules obtained using a wet method, can be added to the external phase, which includes baking powder and/or agent, providing fluidity. The whole mass is thoroughly mixed in the mixer, such as a drum mixer.

Then in the mixer always add a lubricating agent to obtain lubricated granules.

Lubricated granules can be placed in gelatin capsules or compressed on a tablet press according to technologies known to specialists in this field.

In the case of preparation by dry granulation, the active ingredient is thoroughly mixed with the diluent, with the addition of a bonding agent, in the mixer used in the pharmaceutical industry the items. The mixture is then granularit by granulation without added solvent, such as briquetting or compacting, for example, roller compaction. The resulting agglomerates can be stage grinding/calibration to reduce the size and obtain granules.

According to the private version of the method, the obtained granules are calibrated to the size ranging from 100 to 250 microns, preferably about 200 microns.

As mentioned earlier, these granules can be added to the external phase comprising an agent that provides fluidity, and/or baking powder.

Thus obtained granules are mixed with lubricating agent within the time required to obtain uniform distribution of the lubricating agent on the granules.

Lubricated granules can be obtained in the same manner as previously described, can be placed in gelatin capsules or tablets on a tablet press, in accordance with technology well known to specialists in this field of technology.

Alternatively, the compositions according to the present invention can be obtained by direct dry mixing, i.e. direct thorough mixing the active ingredient with a diluent and a possible baking powder.

A lubricating agent and a possible agent, providing fluidity, in conclusion, add in the rates of mixing before distribution in gelatin capsules or before pressing into tablets.

In particular, the invention therefore relates to stable pharmaceutical compositions comprising a water-soluble salt of vinorelbine and at least one diluent and one lubricating agent, characterized in that it is represented in solid form intended for oral administration.

In the context of the present invention means that the composition, which is called "stable", is a composition in which after storage, optionally in an inert atmosphere, for 24 months at a temperature in the range from 0 to 10C, preferably from 2C to 8C, the content of impurities is less than 2%, preferably less than 1%, and even more preferably less than 0.5%.

The term "diluent" in the context of the present invention means a substance which the amount of the pharmaceutical composition can be increased to ensure the homogeneity of the bulk product and content uniformity of the active ingredient in the final dosage form, tablet or gelatin capsule. The diluents also provide during the manufacturing processes appropriate for the mixture in case of active ingredients which usually do not flow properly. In addition, they allow for ease of extrusion during manufacture of the tablets.

The term "smatyvayus the agent" in the context of the present invention means a substance reducing friction between the various components of the mixture of excipients in powder form, and may contain the active ingredient. In addition, they provide a reduction in the adhesion of the powder to the die and the punch. Lubricating agents also offer better transmission of forces pressing. However, taken in excess, they reduce the cohesion of the tablets.

The term "binder" in the context of the present invention is meant a substance capable of strengthening ties between the particles. Using binders it is possible to reduce the pressing force required to obtain tablets. Some binders, such as cellulose derivatives, create engagement between aglomerirovanie particles. Others have a fairly low melting point and a temperature increase occurring during compression, is able to form bridges between particles.

The term "agent, providing fluidity" in the context of the present invention is meant a substance capable of improving the fluidity of the solid mixture by improving the fluidity of the powder and, thus, promote the regular filling of the compression chamber.

The term "baking powder" in the context of the present invention refers to a substance that enables a solid dosage form to dissolve in presets is under fluid for example, in the stomach or in contact with digestive fluids, thereby releasing the active ingredient.

By "film-forming agent" in the context of the present invention means a substance, most often, a polymeric substance capable of coating tablets, granules or even gelatin capsule shell made of a thin film. It can play the role of a dye or used for taste masking or odor. In addition, the shell can protect the patient or medical personnel manual and the buccal-pharyngeal level of toxicity of the active ingredient. It can also be gastro-resistant or cause dialysis. In this case, the film-forming agent is called a covering agent, since the deposited amount more.

By "adjuvant of film formation in the context of the present invention are plasticizers, preventing excessive fragility of the covering film. They can also help reduce the temperature in the formation of the film.

The diluent is preferably selected from a sugar, preferably sucrose, fructose, glucose, polyols, preferably mannitol, xylitol, sorbitol, maldita, lactate, polysaccharides, preferably native or pregelatinized starch, maltodextrins, cyclodextrins, mineral soy is ineni, preferably dehydraton or anhydrous dicalcium or tricalciumphosphate, derivatives of cellulose, preferably microcrystalline cellulose, monohydrate or anhydrous lactose, and mixtures thereof, and more preferably selected from the dihydrate of dicalcium phosphate, mannitol, Pregelatinised maize starch, microcrystalline cellulose and mixtures thereof.

Lubricating agent is preferably selected from salts of fatty acids, preferably magnesium stearate, aluminum stearate, calcium stearate, sodium stearate, servicestart, zinc stearate, esters of fatty acids, preferably of behenate of glycerol, monostearate of glycerol, palmitostearate glycerin, stearic acid, stearyl alcohol, castor oils, hydrogenated or dehydrogenation, hydrogenated vegetable oils, corn oil, sodium benzoate, talc, sodium fumarate, triglycerides of fatty acids, polyethylene glycol and its derivatives, and mixtures thereof, preferred is magnesium stearate.

The diluent preferably consists of a mixture of microcrystalline cellulose and a component selected from D-mannitol, maize starch and dihydrate of dicalcium phosphate.

The proportion of diluent preferably is in the range from 20 to 80% by weight of the total composition, more predpochtite the flax is from 30 to 60%, more preferably equal to approximately 56%.

The proportion of a lubricating agent preferably ranges from 0.5 to 10% by weight of the total composition, preferably from 1% to 5%, and even more preferably equal to approximately 0.5%.

The composition according to the invention may contain a binder.

The binder may be selected from cellulose derivatives, preferably hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethyl cellulose, methylcellulose, cellulose, polyvinylpyrrolidone, gums, preferably the guar gum, tragacanth gum, Arabia gum, xanthan gum, sugars, sucrose or glucose, gelatin, polyethylene glycol or a copolymer of vinylpyrrolidone and vinyl acetate, and mixtures thereof, more preferred is polyvidone C.

The proportion of binder preferably is in the range from 1 to 10% by weight of the total composition, preferably equal to approximately 2.5%.

The composition according to the invention may include baking powder.

Baking powder may preferably be selected from croscarmellose sodium, carmellose sodium, carmellose calcium, cellulose derivatives, starch, preferably carboxymethyl amylum, Pregelatinised starches, native starches, polyvinylpyrrolidone derivatives, pre is respectful of crosspovidone or copovidone, and mixtures thereof, with the preferred are crosspovidone, sodium carboximetilkrahmal or croscarmellose sodium, and even more preferred is croscarmellose sodium.

The proportion of baking powder is in the range from 1 to 10% by weight of the total composition, preferably from 2 to 8%, and more preferably equal to approximately 5%.

The composition according to the invention may include an agent that provides fluidity.

Agent, providing fluidity, preferably selected from hydrophilic or hydrophobic colloidal silica, hydrate or anhydrous, it is preferred hydrophilic colloid dowolny silicon dioxide.

The overall proportion of agent, providing fluidity, and/or lubricating agent preferably ranges from 0.2 to 5% by weight of the total composition, preferably approximately equal to 0.75%.

According to a preferred variant of the invention, the composition includes:

approximately 56 wt.% diluent, preferably about 22 wt.% microcrystalline cellulose and about 34 wt.% Pregelatinised maize starch, or dihydrate of dicalcium phosphate or D-mannitol;

- approximately 2.5 wt.% binder, preferably of polyvidone C;

approximately 5 wt.% baking powder,preferably croscarmellose sodium;

approximately 0.25 wt.% agent, providing fluidity, preferably colloidal dowolnego silicon dioxide;

approximately 0.5 wt.% lubricating agent, preferably magnesium stearate.

The composition according to the invention can be presented in the form of a powder or as granules.

Or, the composition according to the invention can be compressed into a tablet.

The composition according to the invention in the form of powder or granules can be distributed in the polymer gelatin capsule, preferably selected from gelatin, hydroxypropylmethylcellulose and pullulan.

Gelatin capsule, in addition, may further include a dye, preferably selected from pigments and oxides, and mixtures thereof, more preferably selected from oxides of titanium and iron oxides, and mixtures thereof.

Gelatin capsule preferably comprises gelatin, iron oxides and titanium dioxide.

On the surface of the tablets may be coated film-forming agent.

Film-forming agent is preferably selected from cellulose derivatives, preferably hydroxypropylmethylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, methyl cellulose, ethyl cellulose, cellulose acetate, carmellose sodium, acrylic derivatives, preferably polybutylmethacrylate is the poly-2-methylaminoacetaldehyde, polymethylmethacrylate, politicalit, chloride trimethylenetrinitramine, cetyl alcohol, behenate glycerol, waxes, preferably beeswax, Carnauba wax, gelatin, shellac, coconut oil, hydrogenated castor oil, polyvinyl alcohol, polivinilovogo ether, polyvinyl acetate, and mixtures thereof.

The proportion of film-forming agent preferably ranges from 0.1 to 20% by weight of the total tablet, preferably from 0.5 to 10%.

The composition may further contain at least one adjuvant of film formation.

Adjuvant of film formation is preferably selected from polyoxyethylene and alilovic esters, plasticizers, preferably of triethylcitrate, dibutylsebacate, dibutyl phthalate, miglioli, triacetin, fillers, preferably talc, silica, titanium dioxide, dyes, and mixtures thereof.

Share adjuvant of film formation is in the range from 0.01 to 5% by weight of the total tablet.

According to a preferred variant of the invention, the composition includes approximately to 0.19 wt.% poly (ethylene glycol), 0.81 wt.% titanium dioxide, 0.01 wt.% yellow quinoline dye and 0.01 wt.% red iron oxide.

The composition according to the invention preferably is holding from 5 to 80 wt.%, preferably from 20 to 60 wt.% the water-soluble salts of vinorelbine.

If the composition according to the invention is obtained by granulation, it preferably comprises from 30 to 50 wt.% soluble salts vinorelbine, even more preferably about 35 wt.%.

If the composition according to the invention is obtained by dry mixing, it preferably contains from 35 to 55 wt.% soluble salts vinorelbine, even more preferably about 50 wt.%.

Water-soluble salt, preferably vinorelbine is ditartrate vinorelbine.

In order to increase the stability of the composition according to the invention preferably can be stored in an airtight container.

The composition according to the invention, compressed into tablets, or distributed in a gelatin capsule, can, thus, be stored in an airtight container, preferably in termoformowania blister covered with air - and water-resistant aluminized laminate or laminate in accordance with technology known to specialists in this field.

Further, the invention is a non-limiting manner illustrated in the following examples.

Produced tablets and gelatin capsules in accordance with the invention. Determined their stability and dissolution rate.

the example 1

Using wet granulation was prepared mixture with 35% concentration ditartrate vinorelbine, then added to the external phase (croscarmellose sodium, colloidal dowolny silicon dioxide), followed by a stage of lubrication and distribution in gelatin capsules. The resulting capsules were dosed out per 30 mg base vinorelbine.

The main diluent was Pregelatinised maize starch.

1.1. The composition of the granules (per dose and per cent)

ComponentsThe dose of 30 mg base
Weight in mg%
Ditartrate vinorelbine41,5535,00
Pregelatinised maize starch40,4234,05
Microcrystalline cellulose26,9422,70
Polyvidone C2,972,50
Croscarmellose sodium5,945,00
Colloidal dowolny silicon dioxide0,300,25
Magnesium stearate0,590,50
Total:118,71100,000
Gelatin capsule of size 31 gelatin capsule/

1.2. Test for stability at 5C in a sealed package after 6 and 12 months

Compositions in the form of gelatin capsules were placed in a sealed package (t0) and kept at 5C and the external humidity 20%. Next, we determined the content of impurities (% by weight of the total composition) after 6 and 12 months (T6 and T12, respectively) and compared with the contents of the impurities that are defined in advance in t0. The difference between the percentage in T6 and t0, and then in T12 and t0, shows the change in impurity content.

The results were compared with those obtained for dried ditartrate vinorelbine kept in the same conditions.

The results are presented in the table below. This procedure was used in the following examples 2 through 5.

On the vinorelbine tartrate Gelatin capsules
Change contentFrom t0 to T6: +0,5
impurities tFrom t0 to T12: +0,79From t0 to T12: +0,06

1.3. Test the solubility in t0

The amount of dissolved active ingredient was measured in accordance with standard European Pharmacopoeia in 1 liter of 0,1N HCl for gelatin capsules at a temperature of 37C and a stirring speed of 75 rpm the Results are presented in the table below. This procedure was used in the following examples 2 through 5.

Time (min)0510153045
The amount of dissolved active ingredient (%)08694949595

To assess the bioavailability ditartrate vinorelbine in oral form according to the invention, the following kinetics races is of its commercial soft gelatin capsules of the type Navelbine Oral (WO 03/101383), containing solution ditartrate vinorelbine (identical conditions, the mixing speed of 50 rpm).

Time (min)0510153045
The amount of dissolved active ingredient (%)0690959698

Example 2

Using wet granulation was prepared mixture with 35% concentration ditartrate vinorelbine, then added to the external phase (croscarmellose sodium, colloidal dowolny silicon dioxide), followed by a stage of lubrication and distribution in gelatin capsules. The resulting capsules were dosed out per 30 mg base vinorelbine.

The main diluent was the dicalcium phosphate dihydrate.

2.1. Composition (per dose and per cent)

ComponentsThe dose of 30 mg base
Weight in mg%
Ditartrate vinorelbine41,5535,00
The dicalcium phosphate dihydrate40,4234,05
Microcrystalline cellulose26,9422,70
Polyvidone C2,972,50
Croscarmellose sodium5,945,00
Colloidal dowolny silicon dioxide0,300,25
Magnesium stearate0,590,50
Total:118,71100,000
Gelatin capsules of size 31 gelatin capsule/

2.2. Test for stability at 5C in a sealed package after 6 and 12 months

The change of total impurities
From t0 to T6: +0,18
From t0 to T12: +0,07

2.3. Test the solubility

Time (min)0510153045
The amount of dissolved active ingredient (%)05585949595

Example 3

Using wet granulation was prepared mixture with 35% concentration ditartrate vinorelbine, then added to the external phase (croscarmellose sodium, colloidal dowolny silicon dioxide), followed by a stage of lubrication and distribution in gelatin capsules. The resulting capsules were dosed out per 30 mg base vinorelbine.

The main diluent was D-mannitol.

3.1. The percentage composition per dose

tr>
ComponentsThe dose of 30 mg base
Weight in mg%
Ditartrate vinorelbine41,5535,00
D-mannitol40,4234,05
Microcrystalline cellulose26,9422,70
Polyvidone C2,972,50
Croscarmellose sodium5,945,00
Colloidal dowolny silicon dioxide0,300,25
Magnesium stearate0,590,50
Total:118,71100,000
Gelatin capsule of size 31 gelatin capsule/

3.2. Test for stability at 5C in a sealed package after 6 and 12 months

The change of total impurities
From t0 to T6: +0,25
Ott to T12: +0,12

3.3. Test the solubility in t0

Time (min)0510153045
The amount of dissolved active ingredient (%)08494949595

Example 4

With a dry mixture was prepared mixture with 35% concentration ditartrate vinorelbine followed by a stage of lubrication and distribution in gelatin capsules. The resulting capsules were dosed out per 30 mg base vinorelbine.

The main diluent was Pregelatinised maize starch.

4.1. The percentage composition per dose

ComponentsThe dose of 30 mg base
Weight in mg%
Dutartre the vinorelbine 41,5535,00
Pregelatinised maize starch40,4234,05
Microcrystalline cellulose26,9422,70
Polyvidone K302,972,50
Croscarmellose sodium5,945,00
Colloidal dowolny silicon dioxide0,300,25
Magnesium stearate0,590,50
Total:118,71100,000
Gelatin capsule of size 31 gelatin capsule/

4.2. Test for stability at 5C in a sealed package after 6 and 12 months

The change of total impurities
From t0 to T6: +0,08
From t0 kt: +0,12

4.3. Test the solubility in t0

Time (min)0510153045
The amount of dissolved active ingredient (%)077100100100100

Example 5

Using wet granulation was prepared mixture with 35% concentration ditartrate vinorelbine, after which was added to the external phase (croscarmellose sodium, colloidal dowolny silicon dioxide), followed by a stage of lubrication and tablet pressing. The resulting capsules were dosed out per 30 mg base vinorelbine.

The main diluent was Pregelatinised maize starch.

5.1. The percentage composition per dose

ComponentsThe dose of 30 mg base
Weight in mg %
Ditartrate vinorelbine41,5535,00
Pregelatinised maize starch40,4234,05
Microcrystalline cellulose26,9422,70
Polyvidone K302,972,50
Croscarmellose sodium5,945,00
Colloidal dowolny silicon dioxide0,300,25
Magnesium stearate0,590,50
Total:118,71100,000

The above experiments show that the composition according to the invention is stable at a temperature of 5C in an airtight container for at least 12 months. Thus, with sufficient grounds for compositions expected shelf life of 24 months at 5C.

These experiments show that in the case of compositions according to the invention, more than 80% with the of ergasias active ingredient can be released in vitro in less than 30 minutes.

The results of the experiments on the study of the dissolution of the compositions according to the invention show that after 30 minutes the amount of dissolved ditartrate vinorelbine is identical to the number marked in the case of soft capsules commercial Navelbine Oral (described in the patent document WO 03/101383). Thus, for both these dosage forms may be expected to receive the same bioavailability ditartrate vinorelbine after 30 minutes.

Example 6

By dry mixing the cooked mixture with 35% concentration ditartrate vinorelbine followed by a stage of lubrication and distribution in gelatin capsules.

Ditartrate vinorelbine add to the diluents (Pregelatinised maize starch and microcrystalline cellulose), baking powder (croscarmellose sodium) and the agent providing fluidity (colloidal duvignau to silicon dioxide), in a mixer, preferably a drum mixer. The main diluent is Pregelatinised maize starch. To obtain a homogeneous mixture of the various components is stirred for some time, the duration of mixing is preferably 10 minutes. After the stage of mixing conduct phase lubrication, which is carried out in the same mixer with the use of magnesium stearate as a lubricating agent. Duration e the stage for optimal lubrication of the mixture is preferably 5 minutes. By stage lubrication should stage distribution of the mixture in gelatin capsules. The resulting capsules were dosed out per 30 mg base vinorelbine.

6.1. The percentage composition per dose

ComponentsThe dose of 30 mg base
Weight in mgWeight in mg
Ditartrate vinorelbine41,5535,00
Pregelatinised maize starch43,3936,55
Microcrystalline cellulose26,9422,70
Croscarmellose sodium5,945,00
Colloidal dowolny silicon dioxide0,300,25
Magnesium stearate0,590,50
Total:118,71100,000
1 gelatin capsule/

1. Stable pharmaceutical composition for treating cancer, comprising a water-soluble salt of vinorelbine, characterized in that it is represented in solid form intended for oral administration, and includes:
approximately 56 wt.% diluent, preferably about 22 wt.% microcrystalline cellulose and about 34 wt.% Pregelatinised maize starch or dihydrate of dicalcium phosphate or D-mannitol;
- approximately 2.5 wt.% binder, preferably of polyvidone C;
approximately 5 wt.% baking powder, preferably croscarmellose sodium;
- approximately 0.25 wt.% agent, providing fluidity, preferably colloidal dowolnego silicon dioxide;
- approximately 0.5 wt.% lubricating agent, preferably magnesium stearate.

2. The composition according to claim 1, characterized in that it presents in the form of powder or granules.

3. The composition according to claim 1, characterized in that compressed into a tablet.

4. The composition according to item 15, wherein the distributed in the polymer gelatin capsule, preferably selected from gelatin, hydroxypropylmethylcellulose and pullulan.

5. The composition according to claim 1, characterized in that the water-soluble salt Viorel is on is ditartrate vinorelbine.



 

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3 cl, 14 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention describes a method for stabilising a sensitive ingredient for biological absorption in the oral intake in a therapeutic composition involving the stages of combining pregelatinised starch with at least one sensitive ingredient, and mixing the sensitive ingredient with pregelatinised starch. Pregelatinised starch is used in the amount of 5% to 80% of composition weight. The sensitive ingredient is specified in vitamin C, phenylephrine and their combinations. The sensitive ingredient is used in the amount of 0.1% to 20% of composition weight. Said sensitive ingredient is uniformly distributed in pregelatinised starch and adsorbed on pregelatinised starch.

EFFECT: stability of said sensitive ingredients and maintenance of their activity and availability for biological absorption in the oral intake of the therapeutic composition.

17 cl, 15 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns a pharmaceutical composition containing cholest-4-en-3-one oxime and oil specified in sesame oil, olive oil, soya oil, cottonseed oil or mixed medium-chain triglycerides (ESTASAN, MYGLIOL) or mixed oils, preferentially sesame oil, olive oil and soya oil, more preferentially sesame oil.

EFFECT: invention ensures chemical stability of the dosage form, higher concentration of the solubilised active ingredients, higher biological availability of the active ingredient.

6 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a stable pharmaceutical composition for treating cancer containing a water-soluble salt of vinflunine ditartrate and at least one diluent, one binding substance, one aerating agent and one lubricating agent wherein the composition is presented in a solid form for oral application wherein: the content of the water-soluble salt of vinflunine ditartrate makes 5 to 80 wt %, the content of the diluent makes 20 to 80 wt % of total weight of the composition, the content of the binding substance makes 1 to 10 wt % of total weight of the composition, the content of the lubricating agent makes 0.5 to 10 wt % of total weight of the composition, the content of the aerating agent makes 1 to 10 wt % of total weight of the composition.

EFFECT: invention provides storage stability at 5C for 24 months in a sealed package.

19 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a solid dispersion wherein revaprazan particles are surface-modified by a water-soluble polymer, a water-soluble saccharide, a surfactant or their mixture wherein the water-soluble polymer is specified in a group consisting of polyvinylpyrrolidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyethylene glycol, a water-soluble polyacrylic acid copolymer, polyvinyl alcohol or their mixture, and wherein the water-soluble saccharide is specified in a group consisting of lactose, white sugar, saccharose, mannitol, sorbitol, xylitol, trehalose, maltitol, dulcitol, inositol, dextrin, cyclodextrin and their mixture. The invention also refers to a method for preparing said solid dispersion. The present invention also presents a pharmaceutical composition containing the solid dispersion, and the method for producing the pharmaceutical composition.

EFFECT: invention provides improved solubility of revaprazan and reduced adhesion and agglutination properties.

16 cl, 4 dwg, 7 tbl, 55 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and medicine. A composition represents a powder of a substance containing a consortium of immunoglobulins IgA, IgG and IgM and target additives able to form a stable foam structure, specified in: polyethylene glycol, albumin, gelatine, pectin, casein, caseinate, casein hydrolysate, hydroxypropyl cellulose, polyglucin, dextrin, tragacanth, aerosil, glycine, L-lysine monohydrochloride, L-arginine monohydrochloride, glucose, maltose, mannitol, lactose or their mixtures; it is characterised by porous structure and fragility, has a relative disintegration shrinkage at least 10 %, equivalent pore diameter 10-110 mcm at particle size no more than 100 mcm and a resting angle less than 50 and represented in the form of a solid capsule in the following proportions in 1.0 g of the composition: the consortium of immunoglobulins IgA, IgG and IgM 0.05-0.95 g; target additives - the rest with the capsule coated with a layer of a enterosoluble substance specified in: shellac, oleic acid, hydroxypropyl cellulose, cellulose acetate phthalate, bee wax, Tween-20, Tween-80, castor oil, polyethylene oxide or their mixture.

EFFECT: invention provides the isotropic filling of the 100% preset volume of the solid capsules that exceeds the effect of a similar composition by 5%, the maximum isotropic filling of the solid capsules ensures precise dosages of the consortium of immunoglobulins.

4 cl, 4 ex

FIELD: process engineering.

SUBSTANCE: invention relates to capsule comprising hollow tubular case 2 and cap 3. Said case and cap define volume there between and are furnished with complementary latches 12, 21 to lock cap 3 on case 2 in completely closed position. Said latches 12, 21 comprises lock ring 12 arranged on case 2 and ledge 21 arranged on cap 3. There is, at least one air vent hole 14 made up of axial recess on case outer surface to allow communication of fluids between inner volume and atmosphere. Capsule is used for dispensing fluids.

EFFECT: fluids communicated between inner volume and atmosphere.

10 cl, 8 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry, particularly a technology of a new dosage form of 3,31-diindolylmethane. A method consists in mixing 3,31-diindolylmethane and a liquid fatty excipient and adding a wedding agent. In mixing, the prepared mixture is heated to 35-45C to prepare a solution. Then the prepared solution is cooled to 21-23C to fill gelatine capsules in the following proportions, g/capsule: 3,31-diindolylmethane - 0.01-0.1, the liquid fatty excipient - 0.05-0.1, the wedding agent 0.4-0.45. The prepared drug in the form of soft gelatine capsules containing 3,31-diindolylmethane in the form of the solution enables higher bioavailability of the active substance.

EFFECT: prepared drug is non-toxic, safe in prolonged introduction, has no local irritant action, no toxic effect on the immune and reproductive systems.

4 cl, 4 dwg, 7 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to pharmacology and medicine. The group of inventions involves pharmaceutical compositions containing 5-azacytidine for the oral introduction wherein the compositions release a cytidine analogue substantially in stomach, a method of treating an individual suffering a disease associated with abnormal cell proliferation which involves the oral introduction of the pharmaceutical composition into the individual, using 5-azacytidine for preparing the pharmaceutical composition for treating the disease associated with abnormal cell proliferation.

EFFECT: invention provides higher clinical effectiveness.

9 tbl, 9 ex, 23 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: pharmaceutical composition applicable for oral administration contains an S1P receptor agonist and mannitol with the composition representing a solid dosage form. Mannitol has a particle specific surface area 1 to 7 m2/g, and the S1P receptor agonist is specified from 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol (FTY720), its pharmaceutically acceptable salt and FTY720-phosphate.

EFFECT: compositions under the invention are characterised by a high level of distribution uniformity of said S1P receptor agonist, and applicable for oral administration in the solid dosage form, eg in the form of a tablet or a capsule.

14 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: method for preparing a pharmaceutical composition consists in mixing an S1P receptor agonist - 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt with sugar alcohols; the mixture is milled and/or granulated, and then mixed with an oil agent. The method under invention is implemented on high-speed automated equipment and enables producing the compositions with high-level distribution uniformity of 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

EFFECT: preparing the pharmaceutically acceptable salt in the composition applicable for oral administration of said S1P receptor agonist.

15 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for treating and/or preventing depressions. The pharmaceutical composition contains an active substance presented by a selective serotonin reuptake inhibitor (SSRI) specified in a group of fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine differing by the fact that as an active substance, it additionally contains N-acetyl-5-methoxytryptamine (melatonin) in the following proportions, mg: selective serotonin reuptake inhibitor (SSRI) - 10-30 mg, melatonin - 3-8 mg. The pharmaceutical composition may be presented by a solid dosage form - a tablet, a film-coated tablet, a capsule, by a soft dosage form - a rectal suppository.

EFFECT: pharmaceutical composition provides treating depressions and has a number of additional therapeutic properties: easing falling asleep and relieving sleeping disorders, recovering circadian rhythm and seasonal rhythm with reducing a risk of side effects of SSRI.

3 cl, 14 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention relates to pharmaceutical and nutriceutical tablets. Composition for tabletting contains matrix with lubricant, which is included into its composition. Said matrix with lubricant included into its composition consists of oily liquid, finely dispersed in oil-insoluble material. Said matrix constitutes from 0.3 to 8.8% of composition and composition does not contain stearate. Claimed is method of manufacturing composition for tabletting and tablet, manufactured by tabletting said composition.

EFFECT: invention makes it possible to improve lubrication of dry nutriceutical and/or pharmaceutical compositions during tabletting.

24 cl, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: composition of a solid quick-disintegrating tablet of low frangibility contains 1 to 20 wt % of ethyl cellulose as a binding agent and 2 to 15 wt % of a disintegrating agent. The ethoxy group content in ethyl cellulose is found within the range of 44 % to 54.9%. Viscosity of 5% ethyl cellulose makes a value within the range of 3 sP to 200 sP as mixed with solvents toluene/ethanol, 80:20. The disintegrating agent is specified in a group consisting of crossed-linked povidone, croscarmellose sodium salt (crossed-linked carboxymethyl cellulose sodium salt), starch glycolate sodium salt, low-substituted hydroxypropyl cellulose and guar gum. The composition may additionally contain an active pharmaceutical ingredient. What is also described is a method for preparing the quick-disintegrating tablet of low frangibility by direct compression.

EFFECT: invention provides creating the quick-disintegrating mechanically solid tablet of low frangibility for fast and effective delivery of the active ingredient into the nasal cavity.

27 cl, 8 tbl, 6 ex

Pressed tablets // 2472491

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a pressed tablet containing a pressed non-chewable base and a volatile active agent, preferentially menthol or eucalyptol included in a spray-dried granule additionally containing a starch carrier and a polyol granulating agent. The pressed tablet may be a two-layer tablet containing a sparkling layer and a non-sparkling layer with the spray-dried granule included in the sparkling layer. The tablets in the present application are effective to provide decongestant effects in a nasal cavity.

EFFECT: invention additionally refers to the use of starch for increasing release rate of the volatile active agent from the pressed tablet and improving its disintegration smoothness.

12 cl, 3 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents an oral tableted pharmaceutical composition used for oral administration and containing dexamethasone as an active ingredient, and the excipients: lactose, povidone, magnesium stearate, and differing by the fact that additionally contains the excipients: croscarmellose sodium, microcrystalline cellulose; lactose is lactose monohydrate with the ingredients taken in certain proportions, mg per one tablet.

EFFECT: invention provides high transportation durability and storage stability, and also enables reducing a number of tablets taken and side effects caused by prolonged treatment.

2 cl, 4 ex

FIELD: food industry.

SUBSTANCE: invention relates to a composition for direct pressing, to a method for production of the said composition for direct pressing by way of compression and subsequent granulation and to methods for production of pharmaceutical pressing or food product compositions in the form of dextrose pellet for direct pressing. Additionally the invention relates to pharmaceutical compositions or food product compositions containing dextrose composition for direct pressing and to application of dextrose composition for direct pressing for production of pharmaceutical compositions or food product compositions. The dry granulation method for production of dextrose composition for direct pressing involves production of the initial dextrose composition in a powder form where the initial dextrose composition contains 50-100 wt % of dextrose, the initial dextrose composition compaction (by way of rolling compaction using a rolling compactor to produce flakes or by way of briquetting using a one-hole tablet press or a rotary tablet press to produce briquettes), the flakes or briquettes milling to produce granules and the granules sieving to produce dextrose composition for direct pressing with preset distribution of granules size.

EFFECT: invention allows to produce a dextrose composition with excellent flowability and tablets strength that is suitable for usage as an ingredient in pharmaceutical compositions or food product compositions and is produced by a simple, cost effective and reproducible method.

12 cl, 3 dwg, 2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: pharmaceutical composition in a pressed tableted form contains parathyroid hormone (PTH), 5-CNAC or its salt, a disintegrant and a solvent. A disintegration time of the composition makes no more than 6 min, while solubility more than 90% takes place for 20 min.

EFFECT: group of inventions provides effective PHT delivery; a tablet is rapidly disintegrated or dissolved, and the active ingredient has a therapeutic effect.

10 cl, 7 ex, 5 dwg

FIELD: medicine.

SUBSTANCE: invention refers to medicine and concerns a conjugate for drug delivery. The invention also concerns a pharmaceutical composition for eliminating a pathogen population in a host animal, containing said compound; as well as a method for eliminating the pathogen population in the host animal.

EFFECT: invention provides higher activity of the declared conjugate as compared with those known by the present technology.

3 cl, 14 ex

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