Zolmitriptan-containing pharmaceutical composition

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to pharmaceutical composition for intranasal administration contains zolmitriptan that is agonist of 5-HT1-receptor and pharmaceutically acceptable carrier. The composition has pH value less 6.0. The composition can be used for treatment of migraine and related disorders. The composition shows the improved stability in storage and provides effective relief for patients suffering with migraine.

EFFECT: improved and valuable medicinal properties of composition.

11 cl, 1 tbl, 9 ex

 

This invention relates to new pharmaceutical compositions, their reception and their use in the treatment of disease. In particular, this invention relates to pharmaceutical compositions drugs against migraine zolmitriptan for insertion into the nose.

Zolmitriptan has the chemical name (S)-4-{[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]methyl}-2-oxazolidinone. Zolmitriptan is a selective agonist NT-receptor. NT-receptor mediates vasoconstriction and thus modifies the blood flow to the carotid vascular bed. The 5HT1 agonist-receptor useful in the treatment (including prevention) of pathological States in which the detected vasoconstriction in the carotid vascular bed, such as migraines, repetitive heavy monolateral, orbitotemporal headache and headache associated with vascular disorders, collectively called “migraine”. Zolmitriptan was developed for the acute treatment of migraine in the form of tablets 2.5 mg and 5 mg, designed to receive a maximum of 15 mg per day.

Although zolmitriptan is a successful drug, bringing significant relief to those suffering from migraines, there is a continuing need for alternative methods for direct treatment of migraine and prevention of migraine headaches. In the lastnosti, patients suffering from migraine or migraine attack, need a quick easing their suffering.

Zolmitriptan is a member of the class of drugs known as triptan, for example sumatriptan, naratriptan and rizatriptan that prescribed for the treatment of migraine. Leading the sale is sumatriptan, which was sold as an oral composition. Was also developed subcutaneous composition; it was more effective (P. Tfelt-Hansen, Cephalalgia 1998, vol. 18(8), page 532-8) and gave a more rapid onset of action, but was not particularly acceptable to the patient. Was developed intranasal spray (for insertion into the nose). He was more acceptable to the consumer than subcutaneous injection, but was reportedly less effective in reducing the symptoms of migraine attacks (Dahlof C., Cephalalgia 1998; 18(5): 278-282). In addition, many patients have reported unpleasant bitter taste after using the nasal spray.

The authors of this invention was to find the composition of zolmitriptan, which would give a quick calming while maintaining high efficiency. They also were looking for a song that would be more acceptable way of introduction to a broad range of patients than subcutaneous injection. It is clear that the idea of subcutaneous injection may deter many patients from taking appropriate and neobhodimosti. In addition, the authors present invention was looking for a song that would be convenient, effective and acceptable to the patient and not cause unnecessary irritation or side effects.

In U.S. patent USP5466699 describes a class of chemical compounds for the treatment and prevention of migraine. In U.S. patent USP5466699 describes that this class of compounds can be prepared for oral, sublingual, buccal, parenteral (e.g. subcutaneous, intramuscular or intravenous), rectal, local, and intranasal, and describes examples of possible compositions, including, for example, intranasal composition. Intranasal composition comprises the active ingredient, methylhydroxybenzoate (0,2%), propylhydroxybenzoate (0,02%) citrate buffer and sufficient hydrochloric acid to reach pH 7.

The authors of this invention have proposed intranasal composition of zolmitriptan, which could provide an effective and improved quick relief for patients suffering from migraine. Although the inventors do not wish to be bound by any theory, they believe that it is a relief, at least partly due to direct absorption through mucous membrane of a significant proportion of zolmitriptan entered in the nose (intranasal).

In addition, research the intranasal composition of zolmitriptan, having a pH above 7.0 and at pH 7.4 showed that the stability of this composition was not acceptable for extended periods of time.

The authors of the present invention has provided an improved rapid onset of action using stable intranasal composition of zolmitriptan having a pH lower than 7.0. In addition, this arrangement was acceptable to the patient population and did not cause unnecessary irritation or side effects.

Thus, the authors of the present invention provide a pharmaceutical composition suitable for intranasal, which contains zolmitriptan and a pharmaceutically acceptable carrier, and the pH of this composition is less than 7,0.

The composition of zolmitriptan intranasal usually prepared in the form of an aqueous composition and usually sautereau. Suitable bufferedio agents include citric acid, phosphates, such as centripetal (for example, dodecahedral, heptahydrate, dihydrate and anhydrous forms) or sodium phosphate and mixtures thereof (for example, McIlvaine buffer, which is a mixture of citric acid and dinatriumfosfaatti).

In a particular aspect, the pH of the pharmaceutical composition zolmitriptan is below 6.0, for example in the range of 3.5 to 5.5, and, in particular, in the range of 4.5 to 5.5. In a particular aspect, the pH of this composition is approximately equal to 5.0.

In addition to b is Fehr composition of zolmitriptan may contain other ingredients, generally present in the intranasal compositions, such as antioxidants such as sodium metabisulfite, taste masking agents, such as menthol, and sweetening agents such as dextrose, glycerol, saccharin and sorbitol.

In another aspect, the invention provides an aqueous solution of zolmitriptan in buffer at pH less than 7.0, in particular at pH below 6.0, for example, in the range of 3.5 to 5.5 and, in particular, in the range of 4.5 to 5.5, for example, at approximately a 5.0. In particular, this invention provides an aqueous solution of zolmitriptan in the buffer of citric acid and phosphate at pH less than 7.0, in particular at pH below 6.0, for example, in the range of 3.5 to 5.5, in particular in the range of 4.5 to 5.5, for example, at approximately 5,0.

The pharmaceutical composition of this invention can be administered, together (simultaneously or sequentially) with one or more pharmaceutical agents useful in the treatment of migraine or related pathological conditions.

The pharmaceutical compositions of this invention should generally be administered to the people in such a way that a single dose in an amount of about 0.5 mg to 15 mg (for example, 0.5 mg, 1.0 mg, 2.5 mg, 5.0 mg and 10 mg) zolmitriptan delivered to a patient in need of this treatment. Concentration and volume of the composition can vary, as is known for insertion through the nose, usually enter the amount of 50-250 m is l, for example, a 50 µl or 100 µl (one spray or two sprays 50 ál - one for each nostril). The exact deliver the dose depends on various factors known in the field, including weight, age and sex of the patient to be treated, and the specific status of the disease (migraine), subject to treatment. This unit dose can be taken at any stage when a migraine attack or during a migraine attack. This unit dose can be taken if necessary, usually from 1 to 3 times a day.

The pharmaceutical compositions of this invention can be prepared by dissolving zolmitriptan in an acidic medium, such as aqueous citric acid, with the formation of nitrate salts zolmitriptan and bringing the pH to the desired value by addition of a suitable agent, such as phosphate. Received buffered solution is usually prepared with a guarantee that it has a low biological seeding, or with the guarantee that he is sterile. Usually this solution is sterilized, for example, by passing through a sterile filter (for example, 0.2 μm) or by autoclaving. Preferably, the solution is rinsed with nitrogen and placed under nitrogen in primary packaging to minimize the possibility of degradation. An alternative may use a different inert gas, such as argon. Thus, in another aspect the the invention provides a sterile pharmaceutical composition, suitable for intranasal, which contains zolmitriptan and a pharmaceutically acceptable carrier, and the pH of the composition is lower than 7.0.

The pharmaceutical compositions of the present invention is usually placed in a suitable device for introducing capable of delivering zolmitriptan in the number of unit doses to a patient in need of this treatment. Such devices for introduction include commercially available devices and device described in industrial design UK Registered Design 2071555. Thus, in another aspect, the invention provides a device for intranasal containing zolmitriptan and a pharmaceutically acceptable carrier, and the pH of the composition below 7,0.

Filled device for intranasal can be Packed to protect from light. Thus, in another aspect, the invention provides a device for intranasal containing zolmitriptan and a pharmaceutically acceptable carrier in a light-proof packaging, such as foil packs. In an alternative aspect, the device itself has a dark color to protect from light, for example, has a dark blue color.

Thus, in this aspect, the invention provides a pharmaceutical composition suitable for intranasal enter the tion, which contains zolmitriptan and a pharmaceutically acceptable carrier, and the pH of the composition is lower than 7.0, for use in a method of therapeutic treatment of the human or animal.

In another aspect, the invention provides a method of treating a pathological state in which useful agonism NT receptors, involving the administration of an effective amount of a pharmaceutical composition suitable for intranasal, and the pH of the composition is lower than 7.0. This invention also provides the use of zolmitriptan and a pharmaceutically acceptable carrier in the preparation of pharmaceutical compositions suitable for intranasal, and the pH of the composition is lower than 7.0.

Zolmitriptan used in the compositions of this invention may be obtained in accordance with the descriptions WO 91/18897 and WO 97/06162.

Examples 1-4

Zolmitriptan is dissolved in aqueous citric acid solution, add 0.4 M dodecahydrate of dinatriumfosfaatti to pH 5.0 and add water for injection to the desired volume. Thus can be obtained solutions with concentrations of zolmitriptan 5 mg/ml, 10 mg/ml, 25 mg/ml and 50 mg/ml Solution is filtered through a sterilizing filter (0.2 μm) and placed in glass vials USP/Ph Eur Type 1 (nominal volume spray 100 ml), which close chlorotoluene plugs

Table 1
Activity nasal spray0, 5 mg1 mg2.5 mg5 mg
The concentration of the solution5 mg/ml10 mg/ml25 mg/ml50 mg/ml
Zolmitriptan0,51,02,55,0
Citric acid anhydrous USP/Ph Eur1,111,291,792,60
Dodecahydrate disodiumqs toqs toqs toqs to
phosphate USP/Ph Eur*pH 5.0pH 5.0pH 5.0pH 5.0
Water for injectiontotototo
USP/Ph Eur0.1 ml0.1 ml0.1 ml0.1 ml
* Added a 0.4 M solution dodecahydrate of dinatriumfosfaatti USP/Ph Eur, diluted with purified water USP/Ph Eur.

The bottles were collected in a device for spraying nasal drugs in unit doses described in UK Registered Design 2071555. This device contains a holder for bottles, a device to bring in on the op perate and the protective cover. The assembled device may be used to deliver a single dose zolmitriptan 0.5 mg, 1.0 mg, 2.5 mg or 5.0 mg with an introduction. Filled device for nasal sprays are packaged in a plastic tray and placed inside a cardboard carton to protect from light.

Examples 5-8

Zolmitriptan is dissolved in aqueous citric acid solution, add 0.4 M centripetal to pH 5.0 and add water for injection to the desired volume. Thus can be obtained solutions with concentrations of zolmitriptan 5 mg/ml, 10 mg/ml, 25 mg/ml and 50 mg/ml Solution is filtered and placed in glass vials USP/Ph Eur Type 1 (nominal volume spray 100 ml), which close chlorotoluene tubes.

Table 2
Activity nasal spray0.5 mg1 mg2, 5 mg5 mg
The concentration of the solution5 mg/ml10 mg/ml25 mg/ml50 mg/ml
Zolmitriptan0,51,02,55,0
Citric acid anhydrous USP/Ph Eur1,111,291,792,60
Centripetal USP/Ph Eur*qs to pH 5.0s to pH 5.0 qs to pH 5.0qs to pH 5.0
Water for injection USP/Ph Eurto

0.1 ml
to 0.1 mlto 0.1 mlto 0.1 ml
* Added a 0.4 M solution of dinatriumfosfaatti USP/Ph Eur, diluted with purified water USP/Ph Eur.

The bottles are autoclaved at 121°C for 15 minutes. Then they were assembled in a device for spraying nasal drugs in unit doses described in UK Registered Design 2071555. This device contains a holder for bottles, a device for actuation and the protective cover. The assembled device may be used to deliver a single dose zolmitriptan 0.5 mg, 1.0 mg, 2.5 mg or 5.0 mg with an introduction. Filled device for nasal sprays are packaged in a plastic tray and placed inside a cardboard carton to protect from light.

Example 9

The patient removes the pack from the device to spray nasal drugs and then remove the protective cover. The patient then inserts the nozzle of the device into the nostril and makes it work for the introduction of a single dose.

1. Pharmaceutical composition suitable for intranasal, which contains zolmitriptan and a pharmaceutically acceptable carrier, and the pH of the composition is below 6.0.

2. The pharmaceutical is Skye composition according to claim 1, where the pH of the composition is in the range of 4.5 to 5.5.

3. The pharmaceutical composition according to claim 1 or 2, where the composition is buffered.

4. The pharmaceutical composition according to claim 3, where the buffer is a mixture of citric acid and dinatriumfosfaatti.

5. The pharmaceutical composition according to any one of claims 1 to 4, which is sterile.

6. Method of preparation of sterile pharmaceutical composition according to claim 5, providing for autoclaving.

7. A method of treating a pathological state in which useful agonism NT receptors, involving the administration of an effective amount of the pharmaceutical composition according to any one of claims 1 to 5.

8. Device for intranasal containing pharmaceutical composition according to any one of claims 1 to 5.

9. Device for intranasal containing pharmaceutical composition according to any one of claims 1 to 5, Packed to protect from light.

10. An aqueous solution of zolmitriptan in buffer at pH below 6.0.

11. An aqueous solution of zolmitriptan in buffer at pH in the range of 4.5 to 5.5.



 

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