Oral liquid compositions containing alendronate

 

(57) Abstract:

The invention relates to medicine. Disclosed a method for treatment and prevention of bone rarefaction patients through the introduction of a liquid composition of the alendronate, which is easily GLORIETTA. Also describes pharmaceutical dosage forms of alendronate in the form of syrup, aqueous solution, a solution obtained by diluting the powder, to implement the described therapeutic method. Song data can be entered for patients who have difficulty swallowing, and are more stable. 2 C. and 23 C.p. f-crystals.

The present invention relates mainly to the use of oral liquid compositions containing alendronate, i.e. trihydrate odnonatrieva salt 4-amino-1-hydroxybutylidene-1,1-biphosphonate acid to inhibit bone resorption in patients who have difficulty swallowing.

Background of the invention

Bones in the normal state are living tissue that is constantly undergoing resorption processes and accumulation of calcium, a common result of joint action of which is to maintain mineral balance. This dual process is known ketsa their resorption, whereas in the case of some pathological conditions the level of bone resorption exceeds the deposition that occurs, for example, in the malignant neoplasm or in primary hyperparathyroidism and in the case of osteoporosis. Other pathological conditions, however, may be a deposition of calcium in undesirable quantities and sites, resulting in ectopic calcification, osteoarthritis, formation of stones in the kidneys and bladder, to atherosclerosis and deforming otosu or Paget's disease, the development of which is a combination of abnormally high bone resorption with subsequent high levels of calcium deposits.

Alendronate - trihydrate odnonatrieva salt 4-amino-1-hydroxybutylidene-1,1-biphosphonate acid is a tool aimed at combating bone loss with bone diseases, including osteoporosis, which is described from the point of view of composition applied composition, method of use and synthesis together with other pharmaceutically acceptable salts in U.S. Patent 4922007 and 5019651 (both owned by Merck).

In some situations, in particular in the treatment of older women with alendronate regarding osteoporosis (bone rarefaction) or to the currently alendronate entered all patients orally in pill form. The only solid dosage forms for oral administration is a big inconvenience for those patients who are unable to easily swallow a pill. And such patients can be a significant part of the total number of patients receiving alendronate, because this tool is intended for that category of patients, which includes older women.

In such cases, the effective therapy for optimal therapeutic effects for this category of patients is desirable to have an improved oral composition to overcome the problems associated with swallowing.

Summary of the invention

The present invention relates to a method of treatment and/or prevention of depression of the bone in patients who have difficulty swallowing, through the introduction of referred patients pharmaceutically effective amount of alendronate in the form of liquid oral composition. Liquid oral composition may be in the form of syrup, aqueous solution or dissolved in an aqueous solution of the powder of alendronate and includes a buffer to maintain the pH of the solution and complexing agent to prevent the formation of insoluble the ia contains a pharmaceutically effective amount of alendronate in a liquid pharmaceutically acceptable carrier, i.e. in purified water, and the buffer, i.e., citrate, to maintain pH in the range from 2 to 8, preferably from 4 to 6, and a complexing agent, i.e., citrate or EDTA, for inhibiting the deposition of alendronate in the aquatic environment. Features also mentioned aqueous solution containing sugar in high concentrations, i.e., a syrup, which can also contain the necessary flavors to match market demands.

The invention relates also to pharmaceutical compositions that include to be production of a powder containing a pharmaceutically effective amount of alendronate in a pharmaceutically acceptable dry media, buffer, i.e., citrate, and suitable for the specified powder complexing agent, and the above-mentioned powder can be dissolved in water.

Detailed description of the invention and the preferred variants of its implementation

Oral solution alendronate in the form of a syrup, an aqueous solution or a diluted aqueous solution of the powder have an advantage of easy introduction, which makes them more acceptable for use by patients having difficulty swallowing in the case of solid oral dosage forms. Paroimia for storage space in hospitals pharmacies and warehouses. These compositions have the additional advantage that they allow chitravati the desired dose.

This method can be used to treat people, especially women in menopause, using effective osteogenic the number of alendronate order to inhibit bone resorption in need of such treatment. This need occurs locally in cases necrostudios fracture, bone defect, and so on, This need may also occur in systemic bone diseases such as osteoporosis, osteoarthritis, Paget's disease, osteomalacia, multiple myeloma and other types of cancer, steroid therapy and associated with age rarefaction of bone mass.

The term "inhibition of bone resorption in the context of the present description refers to the treatment and prevention of bone rarefaction, in particular to the inhibition of removal of existing bone mass or of mineral phases and/or phase organic basis through direct or indirect changes in education or activity osteoclast. Thus, the term "inhibitor of bone resorption in the context of the present description refers to agents that inhibit bit is there to increase bone mass in patients undergoing such therapy.

The term "effective osteogenic respect" in the context of the present description means the quantity that can affect the metabolism in Mature bone. In the context of the present description effective osteogenic relation to dose is also "pharmaceutically effective".

The term "treatment" or "therapy" in the context of the present description means (1) introduction to the patient alendronate in sufficient quantity to preventive actions to prevent the development of weakened and/or unhealthy condition, and/or (2) introduction to the patient alendronate sufficient to alleviate or eliminate the disease condition and/or symptoms of painful and/or weakened, and/or unhealthy condition.

The pharmaceutical compositions of the present invention, which include alendronate for administration to patients, include it in the quantity that is effective in osteogenic regard for the purposes of promoting growth of muscle mass, as well as pharmaceutically acceptable carrier. The songs are well produced in combination with dry inert fillers in powder form, such as sugars, including sucrose and lactose which their compositions are acceptable liquid excipients/carriers are purified water and brine.

Examples of other fillers and auxiliary additives:

The solvents.

ethanol

glycerine

propylene glycol

Stabilizers

EDTA (ethylenediaminetetraacetate)

Preservatives

sodium benzoate

sorbic acid

methyl-p-hydroxybenzoate

propyl-p-hydroxybenzoate

Tabularasa agents

citric acid/sodium citrate

tartrate of potassium, 1-substituted

the tartrate of sodium, 1-substituted

the potassium phthalate, 1-substituted

phthalate sodium, 1-substituted

potassium phosphate, 1-substituted

sodium phosphate, 2-substituted

Flavour

saccharin

lactose

sucrose

fructose

sorbitol

aspartame

Agents that increase the viscosity

derivatives of cellulose, including:

hydroxymethylcellulose

hydroxypropylcellulose

Dyes

FD & C Blue 2

FD & C Red 33

You also need the presence of a buffer to maintain the pH of the aqueous solution in the range of 2-8, and preferably 4-6.

The buffer system is typically a mixture of a weak acid and its soluble salts, such as sodium citrate/citric acid; or monocation or Duke is the atrium, 1-substituted, potassium phthalate, 1-substituted, potassium phosphate, 1-substituted and sodium phosphate, 2-substituted.

The number of used buffer system depends on (1) the magnitude of the desired pH value; and 2) the number of alendro-Nata. As a rule, use this amount of buffer that is placed in molar ratio with alendronate in the composition from 0.5 to 50:1 for the purpose of maintaining a pH in the range from 2 to 9, and is usually from 1 to 10 molar ratios of the buffer to the existing alendronate.

One of the used buffer is sodium citrate/citric acid containing sodium citrate in the range from 5 to 50 mg per ml and citric acid in the range from 1 to 15 mg per ml

In the composition there is also a complexing agent used to prevent deposition of alendronate via the formation of complex metal with dissolved metal ions, such as Ca, Mo, Fe, Al, Ba, which can vydeliajutsia glass container, rubber stoppers or simply be present in ordinary tap water. The specified agent acts as competitive for alendronate complexing agents, leading to the formation of soluble metal complexes, whereas alendronate usually the way as sauterelle/complexing agent, or EDTA. In the case of EDTA his take in the amount of from 0.005 to 0.1 wt.% from the composition and 0.005-2 parts by weight of EDTA per 1 weight part of alendronate, is preferred to apply the amount of EDTA is about 0.01 wt.% from the whole composition. The preferred situation is to use one of citrate buffer.

Below are examples of three oral dosage forms of alendronate:

Example 1:

Aqueous solution for oral administration

All the prepared amount of alendronate dissolved in water or a suitable co-solvent to obtain the desired concentration. Add the right amount of flavoring, coloring agents, agents that increase the viscosity, preservatives, stabilizers and tabularasa agents. This solution fill packaging disposable or reusable.

An aqueous solution is used directly from the bottle.

General preparative form

Alendronate - 0.5 to 10.0 mg

Sodium citrate - 5-50 mg

Citric acid 1-15 mg

Purified water up to a volume of 1 ml

The composition may also include additional agents, such as co-solvents, flavorings, dyes, preservatives, hundred the second form

Alendronate - 0.5 to 10.0 mg

Sodium citrate - 5 50 mg

Citric acid - 1 - 15 mg

Wild cherry (Wild Cherry)(powder)and- 10 - 200 mg

FDC red No. 33b- 0.1 - 1.0 mg

Sorbic acid - 0,05 - 0,2%

Saccharinin- 1 100 mg

The propylene - 5 - 20%

Purified water to 1 ml

where andYou can also use other flavorings, other than wild cherry (Wild Cherry)

bCan be selected other non-FD N 33 dyes to impart to the composition a specific taste.

inFor sweetening can be used as sucrose or aspartame.

Example 2:

Syrup for oral administration

All the prepared amount of alendronate administered sucrose solution (10-85%) to obtain a desired concentration. Type in the desired number of additional agents, such as glycerin, sorbitol, flavoring, colorants, agents that increase the viscosity, preservatives, stabilizers and tabularasa agents. The resulting solution fill packaging disposable or reusable.

The above syrup can be used directly from the bottle or added to small amounts of mg

Citric acid - 1 - 15 mg

Sodium citrate - 5 50 mg

Sucrose - 10 - 85%

Purified water up to a volume of 1 ml

The composition can also enter additional agents, such as glycerin, sorbitol, flavoring, colorants, preservatives, stabilizers and tabularasa agents, in accordance with the following words:

Specific preparative form

Alendronate - 0.5 to 10.0 mg

Citric acid - 1 - 15 mg

Sodium citrate - 5 50 mg

Glycerin - 5 - 25%

Sucrose - 10 - 40%

Sorbitol - 10 - 40%

Wild cherry (Wild Cherry) (powder)and- 10 - 200 mg

FDC red No. 33b- 0.1 - 1.0 mg

Sorbic acid - 0,05 - 0,2%

Purified water to 1 ml

whereandYou can also use other flavorings, other than wild cherry (Wild Cherry).

bCan be selected other non-FDC N 33 dyes to impart to the composition a specific taste.

Example 3:

Powder for subsequent breeding

All the prepared amount of alendronate mixed to a homogeneous state with one or more agents selected from flavours, colours, preservatives, stabilizers and specifically sautereau agents. The powder Obtained powder can be dissolved in ordinary tap water for cultivation of alendronate water solution.

The powder composition used for breeding

Quantity per container disposableg< / BR>
Alendronate - 2 50 mg

Saccharose - 100 - 1000 mg

Sodium citrate - 25 - 500 mg

Citric acid is 5 to 500 mg

wheregThe container may be a bottle (which can be added to water or a bag. Alternatively, the composition can be supplied in large volume in the container is reusable.

The exact dosage varies depending on age, weight, sex and condition of the patient, the nature of the disease and its severity and the other: so that the exact effective amount cannot be specified in advance and is determined in each case by the person providing care for the patient. However, as described below, an acceptable number can be defined in traditional experiments on animal models. In General, the effective dose of alendronate in any liquid compositions for oral administration is from 1.5 to 3000 µg/kg body weight and preferably from 10 μg/kg to about 200 μg/kg body weight.

Compositions and methods of use thereof described in the present invention, can be used for the treatment of fractures to the, osteoarthrit, Paget's disease, osteomalacia and bone loss, develops as a result of multiple myeloma and other types of cancer, bone loss that occur as side effects of other therapies (e.g., steroids), as well as the age rarefaction of bone mass.

1. Pharmaceutical composition for oral administration containing alendronate in an effective amount and a pharmaceutically acceptable carrier, characterized in that it further comprises a buffer system to maintain the pH in the range from 2 to 8 and a complexing agent or a buffer system, acting as a complexing agent, and the specified buffer is a mixture of a weak acid and its soluble salts or monocation, or vocational salt of the dibasic acid at a molar ratio of buffer/alendronate from 0.5 to 50/1.

2. The pharmaceutical composition under item 1, characterized in that it is liquid.

3. The pharmaceutical composition according to p. 2, characterized in that the said liquid is a syrup.

4. The pharmaceutical composition according to p. 2, characterized in that the said liquid is an aqueous solution.

5. Teasedale.

6. The pharmaceutical composition according to p. 5, characterized in that it is dissolved in water.

7. The pharmaceutical composition under item 1, characterized in that in the above-mentioned composition alendronate is contained in an amount of from 0.0005 to 0.5 g per gram of the composition.

8. The pharmaceutical composition under item 1, characterized in that the said pharmaceutically acceptable carrier is a purified water.

9. The pharmaceutical composition under item 1, characterized in that the said buffer is sodium citrate/citric acid, 1-substituted potassium tartrate, 1-substituted sodium tartrate, 1-substituted potassium phosphate, and 2-substituted sodium phosphate.

10. The pharmaceutical composition under item 1, characterized in that said buffer is present in an amount which corresponds to the molar ratio of buffer:alendronate from 0.5 to 50 mg.

11. The pharmaceutical composition under item 1, characterized in that the complexing agent is EDTA.

12. The pharmaceutical composition according to p. 11, wherein EDTA is present in a ratio of 0.005 to 2:1 weight. hours per weight part of alendronate.

13. The pharmaceutical composition according to claim what position on p. 3, characterized in that it is a syrup of the following composition:

Alendronate - 0.5 to 10.0 mg

Citric acid 1-15 mg

Sodium citrate - 5-50 mg

Sucrose - 10-85%

Purified water Up to a volume of 1 ml

15. The pharmaceutical composition according to p. 14, characterized in that it is a syrup of the following composition:

Alendronate - 0.5 to 10.0 mg

Citric acid 1-15 mg

Sodium citrate - 5-50 mg

Glycerin - 5-25%

Sucrose is 10-40%

Sorbitol is 10-40%

Wild cherry (Wild Cherry) (powder)and- 10-200 mg

FD red 33b- 0.1-1.0 mg

Sorbic acid - 0,05-0,2%

Purified water To 1 ml

16. The pharmaceutical composition according to p. 4, characterized in that it is an aqueous solution of the following composition:

Alendronate - 0.5 to 10.0 mg

Sodium citrate - 5-50 mg

Citric acid 1-15 mg

Purified water Up to a volume of 1 ml

17. The pharmaceutical composition according to p. 16, characterized in that it has the following composition:

Alendronate - 0.5 to 10.0 mg

Sodium citrate - 5-50 mg

Citric acid 1-15 mg

Wild cherry (Wild Cherry) (powder)and- 10-200 mg

FD red 33b- 0.1-1.0 mg

Sorbic acid - 0,05-0,2%

Saccharinin- 1-100 mg

Propylene glycol - 5-20%

Orasac for cultivation of the following composition:

Alendronate - 2-50 mg

Sucrose - 100-1000 mg

Sodium citrate - 25-500 mg

Citric acid - 5-500 mg

19. The method of treatment and/or prevention of bone rarefaction living objects who have difficulty swallowing, which includes oral administration of pharmaceutically effective dose of a liquid containing pharmaceutical composition of alendronate on p. 1.

20. The method according to p. 19, characterized in that the said living subject is a human.

21. The method according to p. 19, characterized in that the bone loss associated with osteoporosis and is determined by disease, age, or is related to treatment with steroids associated with rheumatoid diseases, Paget's disease or cancer.

22. The method according to p. 19, characterized in that the said treatment is prophylactic in nature.

23. The method according to method 19, characterized in that the said liquid is syrup.

24. The method according to p. 19, characterized in that the said liquid is an aqueous solution.

25. The method according to p. 19, characterized in that the said liquid is an aqueous solution obtained from a powder intended for breeding.

 

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