RU2166937C1 - Paracetamol-base drug - Google Patents

Abstract

FIELD: medicine, pharmacy. SUBSTANCE: invention relates to paracetamol-base drug containing antioxidant in therapeutic doses. Drug has [poly-(2,5-dihydroxy-phenylene)] -4-thiosulfoacid sodium salt or ascorbic acid as an antioxidant. Drug has paracetamol, ascorbic acid, phenylephrine hydrochloride, sucrose or glucose, polyvinylpyrrolidone, sweetening agent, aromatic principle with food dye taken in the definite ratio. Agent can be made as tablet, powder, capsule, dragee, granule, syrup, solution or suppository. Agent exhibits additional useful properties. EFFECT: enhanced effectiveness of drug. 4 cl, 2 ex

Description

 The invention relates to medicine and relates to medicines based on paracetamol.

 Currently, paracetamol, which by its chemical structure is paraacetaminophenol and also known as acetaminophen, acetophene, alfedol, apamide, dolamine, calpol, mexalen, panadol, prozol, tylenol, efferalgan, etc., is considered one of the most popular drugs that have an antipyretic and analgesic effect, and is actively used for pain syndromes of different genesis, for fever accompanying infectious and inflammatory diseases, with poor tolerance of acetylside derivatives itsilovoy acid. Paracetamol is available in many manufacturers, mainly in the form of tablets containing 200 mg or 500 mg of active principle, as well as in the form of syrup, oral solution, capsules and rectal suppositories.

 An important advantage of paracetamol is its compatibility with a wide range of drugs of different pharmacological groups, which leads to its widespread use in combined dosage forms.

 The average single therapeutic dose of paracetamol is 500-1000 mg [Russian Drug Register. Encyclopedia of drugs. Seventh Edition. M .: "RLS-2000", 2000, p. 704].

 Numerous combined medicines are described that contain, in addition to paracetamol, other therapeutic drugs of various pharmacological orientations.

 US Pat. No. 5,773,031 (1998) teaches the possibility of combining paracetamol with antacid, anti-inflammatory, vasodilator, anti-infective, psychotropic, stimulant, antihistamine, laxative, decongestant, vitamin, gastrointestinal, anti-diarrhea, anti-hypertensive, anti-hypertensive, anti-hypertensive , analgesic, antipyretic, hypnotics, sedatives, antiemetics, anticonvulsants, hyperglycemic, hypoglycemic, thyroid, antithyroids GOVERNMENTAL, diuretic, anticonvulsant, uterine, anaboliticheskimi, antiasthmatic, expectorants, antitussives, with means of migraine, with means for weight loss, with the means of seasickness with erythropoietin with bronchodilators, mineral and nutritional additives.

 Paracetamol-based liquid compositions are known that include antioxidants as stabilizers [French Patent 2.751.875, 1998].

 As an analgesic, a combination of acetylsalicylic acid, paracetamol, caffeine, diazepam, hydroxyzine and codeine was used [Romanian Patent 113.712, 1998].

 An anti-inflammatory antipyretic agent is proposed containing paracetamol (0.18-0.58 mg), ascorbic acid (0.08-0.22 mg), calcium gluconate or lactate (0.08-0.22 mg), and / or diphenhydramine (0.018-0.058 mg), and / or rutin ( 0.018 - 0.058 mg) [Application of the Russian Federation for the invention 98.100.919, 1998].

 Known anti-inflammatory, analgesic and antipyretic drug, consisting of aspirin, paracetamol, caffeine and excipients (starch, talc, citric acid, calcium stearate, polyvinylpyrrolidone, cocoa, milk sugar) [RF Patent 2.034.533, 1995].

 Received a medicinal product in a dosage form with controlled release of active substances containing paracetamol, pseudoephedrine, dexbrompheniramine [US Patent 4.777.050, 1988].

 A pharmaceutical composition has been patented with analgesic and antipyretic properties, which contains paracetamol, as well as ascorbic acid in an amount that is sufficient to prevent the toxic effects of paracetamol on the liver. This composition may contain 250-1000 mg of paracetamol in a single dose of the drug and, accordingly, 300-1000 mg of ascorbic acid. In this case, ascorbic acid is in the immobilized state of the drug and is released gradually [US Patent 4,292,298, 1981].

 A medicinal composition has been created for the prevention and treatment of influenza and acute respiratory viral infections, which includes paracetamol (200-500 mg), ascorbic acid (50-100 mg), antihistamine (0.5-25.0 mg), immunocorrector (0.5-6.0 mg), as well as glucose (300-500 mg). As an antihistamine, tavegil or suprastin can be used, and as an immunocorrector - gangliin, molokin or hepalin [RF Patent 2.110.254, 1998].

 In the composition of the drug, to improve sleep, use (per day) 100 - 1000 mg of paracetamol (acetaminophen), 1 - 10 mg of phenylephrine hydrochloride (mesatone), 5-30 mg of phenylpropanolamine, 5-30 mg of phenyltoloxamine and 50-1000 mg of ammonium chloride. Instead of ammonium chloride, ascorbic acid in an amount of 20 mg can be used [US Patent 4,493,827, 1985].

 The known composition for oral administration with a coating may contain paracetamol and phenylephrine as the main active principles [Application of the Russian Federation for the invention 95121.769, 1998].

 Widespread paracetamol-based drugs are Efferalgan with Vitamin C, tablets of which contain 330 mg of paracetamol and 200 mg of ascorbic acid, and Fervex, produced in the form of a granular powder for the preparation of an oral solution, the packet (1 dose) of which contains pheniramine maleate 25 mg, paracetamol 500 mg and ascorbic acid 200 mg.

 A series of medicines is being produced under the common name Coldrex, some of which include paracetamol and phenylephrine hydrochloride.

 So, the Coldrex drug, which has an antipyretic, analgesic, decongestant, and expectorant effect, contains 500 mg of paracetamol, 5 mg of phenylephrine hydrochloride, 25 mg of caffeine, 20 mg of terpinghydrate, 30 mg of ascorbic acid in 1 tablet. Coldrex Night has the form of a syrup containing 1 g of paracetamol, 20 mg of promethazine hydrochloride and 15 mg of dextromethorphan hydrobromide per 20 ml of syrup, and has an antipyretic, analgesic, antitussive and antihistamine effect.

 The closest to the proposed composition can be recognized as the Coldrex Hotrem drug, which is available in bags containing 5 g of powder for making hot drink with lemon or blackcurrant flavor. Each packet contains 750 mg of paracetamol, 10 mg of phenylephrine hydrochloride and 60 mg of ascorbic acid as active principles. This drug has an analgesic, antipyretic and decongestant effect [Russian Drug Register. Encyclopedia of drugs. Seventh Edition. M .: "RLS-2000", 2000, p. 452-453].

 The main objective of the present invention was to increase the effectiveness of paracetamol-based drugs by giving them additional beneficial qualities that expand the possibilities of their therapeutic use. This goal was achieved as a result of the joint use in the composition of the proposed medicinal product, at least paracetamol and antihypoxant.

 The essence of the applicant's proposal is as follows. The composition of the medicinal product containing paracetamol further includes an antihypoxic drug. In this case, the concepts of “antihypoxant” and “antihypoxic action” drug can be understood as a drug assigned to the pharmacological group of antihypoxic drugs, and a drug of another pharmacological group that exhibits antihypoxic activity, and in combination with the main nature of the pharmacological properties of paracetamol and with the nature of its mission.

 In this case, a single dose of the proposed drug should contain therapeutic doses of paracetamol and antihypoxant. Preferably, the average therapeutic dose of the proposed agent contains an average therapeutic dose of paracetamol ranging from 200 mg to 1000 mg, and an average therapeutic dose of an antihypoxic drug, regardless of which non-injection dosage form they are present in.

 Under the "single dose" of the drug in this case and hereinafter refers to the lump sum prescribed to the patient the amount of this drug. A single dose of the drug may be contained, for example, in one tablet, in one powder, in one tablespoon of the solution. However, it can be achieved with a single dose of two tablets, half a tablet, one teaspoon of the solution, depending on the content of the active principle in the corresponding dosage form.

 Previously, only Oliphene, which is the sodium salt of [poly- (2,5-dihydroxy-phenylene)] -4-thiosulfonic acid, now referred to as Hypoxene, and the combined drug Actovegin [Russian Medicines Register] were classified as antihypoxants. Encyclopedia of drugs. Sixth Edition. M., "RLS-2000", 1999, p. 415]. At present, apart from Olifen and Actovegin, butylhydroxytoluene, Levocarnitine (Karniten), Mildronate, Solcoseryl, Trimetazine, Cytochrome C, Emoxipine are also included in the drug group of antihypoxants [Drug Register of Russia. Encyclopedia of drugs. Seventh Edition. M., "RLS-2000", 2000, p. 1160]. The presence of antihypoxic effect is also noted in Dibunol, Mexidol, Tocopherol acetate [Mashkovsky M. D. Medicines: T. 2, 14th ed., Revised., Rev. and add. - M.: Publishing House New Wave LLC, 2000, p. 182-187].

 In ascorbic acid, as a drug, the presence of antihypoxic activity was not previously noted. (The Register of Medicinal Products of Russia. Encyclopedia of Medicines. Sixth Edition. M., 1999, p. 843).

 However, as was established by experimental studies, ascorbic acid may exhibit an antihypoxic effect [P. Hochochka, J. Somoro. Biochemical adaptation. M .: Mir, 1988, 568 p.].

 Moreover, studies conducted at the Institute of Biophysics of the Russian Academy of Sciences, it was found that ascorbic acid has a pronounced antihypoxic effect at a dosage of at least 300 mg. (unpublished data).

 In the composition of the proposed product as a component with antihypoxic effect, it is fundamentally permissible to use any of the listed drugs in the dosage in which an antihypoxic effect is manifested when administered orally, provided that it is suitable for the manufacture of the specific dosage form required. However, it is most preferable to use Hypoxen as the most active antihypoxicant, as well as ascorbic acid, which is the most affordable antihypoxant as an antihypoxant. In this case, the optimal content of Hypoxene in the average therapeutic dose of the proposed drug can be 300-500 mg, and the most acceptable content of ascorbic acid is from 300 to 1000 mg.

 To date, sufficient material has been accumulated that indicates that many diseases and pathological conditions are generated or accompanied by hypoxia of the corresponding tissue, which, in particular, is indicated by the high effectiveness of the most active antihypoxant Hypoxene in a wide range of pathologies. In particular, the sodium salt of [poly- (2,5-dihydroxyphenylene)] - 4-thiosulfonic acid has been patented as a therapeutic drug for the correction of pathological conditions associated with metabolic disorders [RF Patent 2.124.888, 1999]. This compound has been shown to be effective in the treatment of multiple sclerosis [Description of the invention to application 94-037.731, 1996], chronic non-specific lung diseases [RF Patent 2.043.765, 1995], acute destructive pancreatitis [RF Patent 2.139.048, 1999 g.] and in other cases.

 All this gives reason to believe that other antihypoxants can be equally useful in the treatment of many diseases.

 In this regard, the combination of paracetamol and an antihypoxic drug provides an increase in the activity of the total drug: against the background of normalization of the functional state of cells in the pathological focus using an antihypoxant, the antipyretic and analgesic effects of paracetamol are more pronounced.

 In addition, a similar total preparation may be indicated for use in more cases than paracetamol per se, i.e. in cases where, along with pain and with febrile conditions, hypoxic effects occur. On the other hand, the total drug has certain advantages over the actual antihypoxic drug, since it eliminates the manifestations of the pain syndrome, often accompanying hypoxic conditions.

 This total drug, therefore, can affect both the causes of the disease and its symptoms and consequences, which is not achieved with the separate use of the individual components of the total drug. Especially rational is the use of such a remedy for influenza, acute respiratory and colds.

 The proposed complex preparation, including at least therapeutic doses of paracetamol and antihypoxant, may exist, depending on the specific purposes of its use, in the form of various non-injection dosage forms - tablets, granules, powders, dragees, capsules, syrups, solutions, suppositories and etc. It can be prepared in the form of effervescent tablets or powders; It can be supplemented at will or need with flavorings, flavors, food colors. The preparation of the proposed drug can be carried out in a traditional way using known auxiliary substances and does not have any specific features. The composition of the proposed drug can be introduced and other drugs that expand and enhance its pharmacological activity.

 In particular, the proposed drug containing paracetamol and antihypoxic drug may be supplemented with phenylephrine hydrochloride in an amount of 1 to 20 mg per single dose.

 Phenylephrine hydrochloride is an adrenergic agonist, and it stimulates mainly α-adrenoreceptors and causes narrowing of peripheral blood vessels, increasing blood pressure. Due to the peculiarities of the chemical structure (the presence of one hydroxyl group in the phenyl radical), it undergoes relatively little enzymatic inactivation and has a significantly longer vasoconstrictor and pressor effect compared with adrenaline and norepinephrine.

 Compared with the drug Coldrex Hotrem containing paracetamol, phenylephrine hydrochloride and ascorbic acid in a relatively low concentration, the proposed drug containing paracetamol, phenylephrine and antihypoxant has a more pronounced pharmacological activity and is shown with a wider range of pathologies, as it is contained in the composition of Coldrex, the amount of ascorbic acid did not give it the antihypoxic activity that the proposed drug possesses.

 Other medications used for infectious and inflammatory diseases can also be additionally introduced into the composition of the proposed paracetamol-based agent.

 The following examples illustrate the invention and should not be limiting.

Example 1. The composition (powder granular, metered, 5.0 g), mg:
Paracetamol - 750
Hypoxene - 300
Phenylephrine hydrochloride - 10
Glucose - 3740
Polyvinylpyrrolidone - 25
Sweetener - 100
Food Coloring Fragrance - 75
Paracetamol (750 g, 50 μm), Hypoxene (300 g, 100 μm), phenylephrine hydrochloride (10 g, 50 μm) and aspartame (100 g, 50 μm) are mixed in a paddle mixer for 5 minutes. Then an equal amount of glucose (1160 g, 750 μm) is introduced into the mixer and mixing is carried out for 10 minutes. Next, the remaining amount of glucose (2580 g) is added and mixing is carried out for another 10 minutes.

The resulting dry mixture is subjected to "wet" granulation by wetting it with a granulating solution taken in a volume of 156 ml and forcing it through a granulator sieve with a mesh size of 2.0 mm; then the wet granulate is dried in a tray dryer at a temperature of 50 ^o C for 5 hours (residual moisture content of the product is less than 0.5%).

 Granulating solution: 25 g of polyvinylpyrrolidone - 35000 is dissolved in 131 ml of water with vigorous stirring until completely dissolved. The volume of the finished solution is 156 ml.

 Then, “dry” granulation of the product is carried out by forcing it through a granulator sieve with a mesh size of 1.0 mm. The resulting dry granulate is mixed with flavoring with food coloring (50 g, 80 μm) in a paddle mixer for 20 minutes (mixing - dusting).

 The finished dosage form in the form of a granular product is Packed in bags / sachet / 5.0 g.

Example 2. The composition (powder granular, metered, 5.0 g), mg:
Paracetamol - 750
Ascorbic acid - 300
Phenylephrine hydrochloride - 10
Sucrose - 3790
Polyvinylpyrrolidone - 25
Sweetener - 75
Food Coloring Fragrance - 50
Paracetamol (750 g, 50 μm), ascorbic acid (300 g, 50 μm), phenylephrine hydrochloride (10 g, 50 μm) and aspartame (75 g, 50 μm) are mixed in a paddle mixer for 5 minutes. Then an equal amount of sugar / sucrose (1135 g, 750 μm) is introduced into the mixer and mixing is carried out for 10 minutes. Next, the remaining sugar / sucrose (2655 g) is added and mixing is continued for another 10 minutes.

The resulting dry mixture is subjected to "wet" granulation by wetting it with a granulating solution taken in a volume of 156 ml and forcing it through a granulator sieve with a mesh size of 1.0 mm; then the wet granulate is dried in a tray dryer at a temperature of 50 ^o C for 5 hours (residual moisture content of the product is less than 0.5%).

 Granulating solution: 25 g of polyvinylpyrrolidone - 35000 is dissolved in 131 ml of water with vigorous stirring until completely dissolved. The volume of the finished solution is 156 ml.

 Then the product is "dry" granulated by forcing it through a granulator sieve with a mesh size of 2.0 mm. The resulting dry granulate is mixed with flavoring with food coloring (50 g, 80 μm) in a paddle mixer for 20 minutes (mixing - dusting).

 The finished dosage form in the form of a granular product is Packed in bags / sachet / 5.0 g.

Claims (3)

 1. A drug based on paracetamol, characterized in that it further comprises an antihypoxant in therapeutic doses.  2. The drug according to claim 1, characterized in that as the antihypoxant contains the sodium salt of [poly- (2,5-dihydroxy-phenylene)] - 4-thiosulfonic acid. 3. The drug according to claim 1, characterized in that it further comprises phenylephrine hydrochloride, sucrose or glucose, sweetener, flavoring, food coloring, polyvinylpyrrolidone, and ascorbic acid as an antihypoxant in the following ratio of components per unit dose, mg:
Paracetamol - 100 - 1000
Ascorbic acid - 300 - 1000
Phenylephrine hydrochloride - 1 - 20
Sucrose or glucose - 900 - 4000
Sweetener - 10 - 100
Flavoring and food coloring - 10 - 100
Polyvinylpyrrolidone - 25 - 100
4. A medicine according to any one of claims 1 to 3, characterized in that it is prepared in the form of tablets, powders, capsules, dragees, granules, syrups, solutions or suppositories.