Pharmaceutical composition of methisoprinol for oral administration

FIELD: medicine.

SUBSTANCE: declared is a pharmaceutical composition for oral administration, containing methisoprinol, methyl n-hydroxybenzoate, propyl-n-hydroxybenzoate, saccharose or maltose, glycerol, citrus flavouring and purified water.

EFFECT: composition has a pleasant flavour and storage-stable.

2 ex, 1 tbl, 5 dwg

 

The invention relates to the field of medicine and chemical-pharmaceutical industries.

Acute respiratory infectious diseases are the most common infectious diseases in children and adults. In recent years there have been significant changes in the structure of respiratory infections. If in previous years in the diagnosis of acute respiratory infection was assumed, first of all, well-studied and well-known pathogens such as influenza, parainfluenza, adenovirus, respiratory syncytial virus, rhinovirus, in recent years, an increasing proportion of herpes viruses and atypical pathogens. In addition, at the present time attaches importance to the persistence of viruses and other pathogens in different parts of the respiratory tract, which leads to changes in the reactivity and proves the feasibility of the use of drugs combined with immunomodulatory and antiviral effects. One of such preparations is Methisoprinol (Isoprinosine, Inosine pranobex, Propriety) - Inosine (hypoxanthine-ribozid): pair-acetylaminobenzoic acid (acidosis): M,M-dimethylamino-2-propanol(timepanel)=1:3:3 complex. The complex has immunostimulating activity and nonspecific antiviral effect. Restores the functions of the lymph�of cítov in conditions of immunosuppression, increases blastogenic in the population of monocytic cells, stimulates the expression of membrane receptors on the surface of T-helper cells, prevents the decrease in the activity of lymphocytic cells under the influence of corticosteroids, normalizes the inclusion of thymidine. Has a stimulating effect on the activity of cytotoxic T lymphocytes and natural killer cells, the function of T-suppressors and T-helper cells, promotes the production of immunoglobulin (Ig) G, interferon-gamma, IL-1 and IL-2, reduces the formation of Pro-inflammatory cytokines - IL-4 and IL-10 potentiates chemotaxis of neutrophils, monocytes and macrophages. The drug has antiviral activity in vivo against Herpes simplex virus, cytomegalovirus and measles virus, virus T-cell lymphoma human type III, polioviruses, influenza viruses A and b, echo virus (enterocystoplasty virus), virus encephalomyocarditis and equine encephalitis. The antiviral mechanism of action is associated with inhibition of viral RNA and the enzyme dihydropteridine involved in the replication of some viruses, increased suppressed virus mRNA synthesis of lymphocytes, which is accompanied by suppression of the biosynthesis of viral RNA and translation of viral proteins, increased production by lymphocytes interferons-alpha and-gamma, which has antiviral properties.

The drug approved for treatment of influenza and ARVI n� Russia including children 3 years of age (Registration certificate P # 15167/01 dated 29.04.2011 issued by the Federal service on surveillance in healthcare and social development). To date the drug is used mainly in the form of tablets (http://medi.ru/doc/l499.htm). However, for children with a range of pathological conditions more appropriate to use are liquid dosage forms.

When you create liquid forms of methisoprinol developers are faced with certain difficulties. In particular, it is known that the solution of methisoprinol has a bitter taste and is unstable during storage. Therefore requires the creation of new, deprived of these disadvantages dosage forms of methisoprinol.

The prior art discloses a veterinary drug is in the form of a solution suitable for oral administration, is effective against skin tags. The product contains up to 30% by weight of methisoprinol, polyhydric alcohol such as propylene glycol or sorbitol, as well as auxiliary substances and additional ingredients (WO 2010/019059 (A1) - 18.02.2010). The drug has limited use.

Also known composition of Isoprinosine syrup Syrup containing 250 mg per 5 ml syrup inosine, aadobe timepanel, and as excipients Sucrose, Methyl p-hydroxybenzoate, Propyl-p-hydroxybenzoate, sodium hydroxide, aromatic�citator plum, Mononitrate sodium and water http://www.medicines.ie/printfriendlydocument.aspx?documentid=5788&compayid=107). This composition can be specified as the closest analogue. Known syrup does not provide significant stability. For prolonged storage, impurities are formed.

The object of the present invention is to provide an effective pharmaceutical composition for oral administration.

The problem is solved by a composition comprising methisoprinol, sucrose or maltose, glycerine, Methyl p-hydroxybenzoate, Propyl p-hydroxybenzoate, citrus flavor, and purified water with the following content of components, mg/ml:

Methisoprinol47,5-52,5 mg/ml
Sucrose or maltose585-715 mg/ml
Glycerin47,5-52,5 mg/ml
Methyl p-hydroxybenzoate1.62 V-1.98 mg/ml
Propyl p-hydroxybenzoate0,18-0,22 mg/ml
Citrus flavor4.5 to 5.5 mg/ml
Purified waterelse

The technical result of the drug long-term �Brazul impurities during storage of the components of the complex and almost has no unpleasant taste. Citrus flavor - natural food flavoring, such as Orange, Lemon and Grapefruit, preferably is a lemon flavour (Lemon Flavour), containing propylene glycol, ethanol, limonene, linalool, citral, n-decyl aldehyde.

This liquid composition, if necessary, can be obtained well-known in the field of pharmacy, the drug is in the form of dry syrup. The product is easily restored without losing their properties and stability.

Example 1

A method of obtaining a pharmaceutical composition

1) preparing a preservative solution

In a mixer for fluids poured about 90% of the total volume of purified water at 80°C, was added methyl p-hydroxybenzoate and propyl p-hydroxybenzoate, stirred until complete dissolution.

2) the Addition of sucrose or maltose and mixing until complete dissolution, then cooled to 30°C.

3) the Addition of glycerol and stirring until complete dissolution

4) Add methisoprinol and stirring until complete dissolution

5) added citrus flavoring such as lemon flavoring, and mixing to obtain a homogeneous solution

6) Adding the remaining portion of purified water. The stirring for 30-50 minutes, preferably for 40 minutes.

P�overca pH and relative density.

d20=1,255-1,275

preferably pH=5,8-6,8

If necessary, adjust pH by adding sodium bicarbonate or acid food.

7) Filtering using a filter of 20 micron

8) Filling bottles and capping

Filling the bottles with the filtered solution by means of an automatic system for filling liquids/closing lids with the protection of children.

9) Final packing

The vials are labeled and placed in a cardboard box along with a leaflet on the packing line, consisting of labeling machines and machines for packaging and packing.

Test data from groups of patients with SARS showed not only the high efficiency of the drug, but also a significant preventive effect. In particular, after applying the liquid form, the number of patients undergoing primary and repeated episodes of respiratory infection, decreased 3.8 times compared with the same indicator in the control group.

Example 2

Assessment of the content of impurities during storage

- determination of inosine using HPLC

- salt content 4-acetamidobenzoic acid HPLC

- potentiometric titration of N,N-dimethylamino-2-propanol.

Conditions: chromatograms of a solution of formative and placebo no peaks that overlap the peak methisoprinol on the chromatogram ready �product.

In comparative tests under conditions of prolonged storage, it was found that in the inventive drug impurity a (hypoxanthine) to be < 0.5%, impurity B (4-aminobenzene acid) ≤0,2%. For known syrup 1% and 0.5% respectively.

The results shown in the figures.

Figure 1 - chromatogram of placebo

Figure 2 - chromatogram of the claimed composition of example

Figure 3 - chromatogram restored finished product

Figure 4 - chromatogram of the composition without glycerin mixed with a (hypoxanthine)

Figure 5 - chromatogram of the composition without glycerin mixed with (4-aminobenzene acid).

Pharmaceutical composition for oral administration comprising methisoprinol, methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, flavoring and water, characterized in that it further comprises sucrose or maltose, glycerin, and fragrance - citrus flavor at the following content of components, mg/ml:

Methisoprinol47,5-52,5 mg/ml
Sucrose or maltose585-715 mg/ml
Glycerin47,5-52,5 mg/ml
Methyl p-hydroxybenzoate 1.62 V-1.98 mg/ml
Propyl p-hydroxybenzoate0,18-0,22 mg/ml
Citrus flavor4.5 to 5.5 mg/ml
Purified waterelse



 

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