WO2014074017A1 - Nouvelle composition médicamenteuse pour traiter le syndrome de douleurs lors de spasmes de muscles lisses - Google Patents

Nouvelle composition médicamenteuse pour traiter le syndrome de douleurs lors de spasmes de muscles lisses Download PDF

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Publication number
WO2014074017A1
WO2014074017A1 PCT/RU2013/000932 RU2013000932W WO2014074017A1 WO 2014074017 A1 WO2014074017 A1 WO 2014074017A1 RU 2013000932 W RU2013000932 W RU 2013000932W WO 2014074017 A1 WO2014074017 A1 WO 2014074017A1
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WIPO (PCT)
Prior art keywords
diclofenac
hyoscine
butyl bromide
drug composition
smooth muscle
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PCT/RU2013/000932
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English (en)
Russian (ru)
Inventor
Максим Эдуардович ЗАПОЛЬСКИЙ
Аллан Герович БЕНИАШВИЛИ
Маргарита Алексеевна МОРОЗОВА
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Zapolsky Maxim Eduardovich
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Publication of WO2014074017A1 publication Critical patent/WO2014074017A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to the field of pharmaceuticals and medicine, namely to the means used to treat pain with smooth muscle spasm, in particular, in such conditions as:
  • spasm The basis of such spastic conditions is spasm of smooth muscle of organs. It may be due to increased the level of response to irritation due to disturbances in the functioning of the links of the corresponding neuro-reflex arc. In addition, spasm can occur as a result of impaired functioning of the neuromuscular synapse with a change in the electrical potential of muscle cells or metabolic processes in individual muscle elements.
  • dyskinesia of the biliary tract and gallbladder is a functional disorder of the motor function of the gallbladder and extrahepatic ducts, i.e. literally "traffic violation".
  • traffic violation we are talking about a violation of the agreed contractions of the gallbladder and sphincters, allowing bile to exit from the gallbladder into the duodenum.
  • gallstones The most common cause of biliary colic in adults is gallstones.
  • the formation of gallstones occurs mainly in the gallbladder and is associated with metabolic disorders in which the chemical composition of bile is impaired. Such conditions can threaten, according to statistics, 5-10% of the population of any developed country.
  • Renal colic is a syndrome observed in a number of kidney diseases, the main manifestation of which is acute pain in the lumbar region.
  • the most common causes of renal colic are kidney stones, hydronephrosis, nephroptosis are conditions in which urodynamics in the upper urinary tract are disturbed.
  • IBS Irritable bowel syndrome
  • antispasmodics are traditionally used for the treatment of pain in such spastic conditions. Usually they are used in a short course, until the pain is completely stopped, including in combination with painkillers.
  • HUB C was most prevalent, including the following groups of drugs:
  • salicylates acetylsalicylic acid (aspirin), diflunisal, lysine monoacetylsalicylate.
  • - pyrazolidines phenyl butazone.
  • Indole acetic acid derivatives indomethacin, sulindac, etodolac.
  • piroxicam tenoxicam, lornoxicam, meloxicam.
  • ibuprofen ibuprofen, naproxen, flurbiprofen, ketoprofen, thiaprofenic acid.
  • Antispasmodics are medicines that reduce the tone and motor activity of smooth muscles and are used to prevent or eliminate spasms of smooth muscle organs. Examples of clinically significant effects of these drugs are: the elimination of pain caused by spasms of the muscles of the abdominal cavity organs, improved ventilation of the lungs due to expansion of the bronchi during bronchospasm, decreased blood pressure and increased blood flow in the peripheral vessels as a result of a decrease in vascular wall tone.
  • Myotropic S. s. reduce the tone of smooth muscle organs by directly affecting the biochemical processes taking place in smooth muscle cells. In experiments on isolated organs, they lower the tone of smooth muscles, blood vessels, bronchi, intestines, urinary and biliary tract and others. In the conditions of the whole organism separate groups of myotropic S. with. exhibit unequal tropism to various smooth muscle organs and, therefore, are used mainly for certain indications.
  • Dicetel pinaveria bromide
  • Duspatalin mebeverine hydrochloride
  • Otilonia bromide Spasmomen
  • spastic pain and dyskinesias hyperkinetic type with esophagitis, gastritis, duodenitis, enteritis, irritable bowel syndrome, as well as other products (gimecromon, benzene , drotaverine hydrochloride, etc.
  • Hyoscine butyl bromide was created in Germany in 1951.
  • Hyoscine ⁇ -butyl bromide is a derivative of the nitrogen alkaloid hyoscine (scopolamine).
  • hyoscine is a quaternary ammonium compound that is poorly absorbed when taken orally and does not pass the blood-brain barrier.
  • hyoscine ⁇ -butyl bromide reduces the tone of smooth muscles, as a result of which it has been used in the treatment of abdominal pain caused by spasms of the gastrointestinal tract, including irritable bowel syndrome, and biliary and urinary tract spasms.
  • Hyoscine ⁇ -butyl bromide exerts its effect due to the blockade of M-cholinergic receptors located in the intestinal muscles; its use is not associated with systemic side effects characteristic of other M-cholinergic blockers.
  • Ml and MH subtypes of receptors which are most found in the upper regions gastrointestinal tract, gall bladder and biliary ducts, which determines its frequent use in this pathology.
  • RF patent 2424793 relates to a pharmaceutical composition in the form of a food film for oral administration, where the food film includes diclofenac in the form of free acid or diclofenac resinate in an amount of 10 to 50 wt.% And a film-forming polymer in an amount of 10 to 80 wt.%, Calculated on the dry weight of the resulting food film.
  • the composition contains from 10 to 50 mg of diclofenac in a dissolved or uniformly dispersed state, while the food film has a thickness of 20-250 microns.
  • the invention provides for the rapid decomposition of food film in the patient's oral cavity in less than 20 seconds.
  • Patent RU 2242968 C2 is known, which relates to a fast-dispersing solid dosage form which dissolves in the oral cavity within sixty (60), more preferably thirty (30), most preferably ten (10) seconds. Modified starch was used as the matrix, and hyoscine butyl bromide could be selected as the active substance.
  • Levsin sublingual tablets containing belladonna alkaloids as active principle and lactose, magnesium stearate, stearic acid, mannitol, starch and dye, which can be used in various spastic conditions, as auxiliary agents. conditions, including those with irritable bowel syndrome (http://www.medapharma.us/products/pi/LevsinSLTablets_PI.pdf). It does not have a sufficiently effective effect to relieve intense pain.
  • the orodispersible tablet disintegrates into easily swallowed small particles within a few tens of seconds after ingestion.
  • oral dispersion provides faster absorption by the body compared with swallowed forms due to the increase in the area of exchange with physiological fluids.
  • the patent of the Russian Federation 2317812 is known, which discloses an orodisperse solid dosage form containing homogeneous granules of lactose and starch obtained by drying by co-spraying.
  • a variety of pharmacologically active substances can be included as an active principle.
  • these excipients may have a negative effect when used with irritable bowel syndrome.
  • Another approach to creating more effective pain relievers for smooth muscle spasms is to combine well-known drugs.
  • diclofenac for example, a combination of diclofenac and pitophenone is known, which can be used for pain, for colic of the intestines, gall bladder and ureters (Modulatory effect of diclofenac on antispasmodic effect of pitofenone in cholinergic spasm, Kulkarni, SK, Indian Journal of Experimental Biology, Volume 42, Issue 6, June 2004, Pages 567-569).
  • Novigan in the form of tablets may be indicated, including NSAIDs, which is Ibuprofen, in combination with the antispasmodic Pitofenon and the anticholinergic antifriction agent Fenpiverinia bromide (http://www.rlsnet.ru/tn_index_id_2346.htm).
  • NSAIDs which is Ibuprofen
  • Fenpiverinia bromide http://www.rlsnet.ru/tn_index_id_2346.htm
  • the present invention is to develop a more effective dosage form, which may be used to reduce pain in various spastic conditions of smooth muscles.
  • a new drug composition in the form of an orodispersed tablet for the treatment of pain in case of smooth muscle spasm containing hyoscine butyl bromide and non-steroidal anti-inflammatory drug (NSAIDs) in therapeutically effective amounts and pharmaceutically acceptable excipients as active components.
  • NSAIDs non-steroidal anti-inflammatory drug
  • the drug composition is effective, for example, for the treatment of spastic dyskinesia of the biliary tract and gall bladder, biliary colic, cholecystitis, intestinal colic, renal colic, pylorospasm, algomenorrhea, irritable bowel syndrome.
  • NSAIDs for example, acetylsalicylic acid (aspirin), diflunisal, phenylbutazone, lysine monoacetylsalicylate, indolacetic acid derivatives (indomethacin, sulindac, ethodolac), phenylacetic acid derivatives, diclofencofenac (diclofencofenac), can be used lornoxicam, meloxicam), propionic acid derivatives (ibuprofen, naproxen, flurbiprofen, ketoprofen, thiaprofenic acid).
  • One of the preferred alternatives is a combination of hyoscine butyl bromide and diclofenac or its sodium salt.
  • NSAIDs NSAIDs
  • pains of weak and moderate intensity which are localized in muscles, joints, tendons, nerve trunks, as well as with headache or toothache, to a lesser extent, with severe visceral pain.
  • the potentiating effect of this group on the effect of hyoscine butyl bromide was found even when drugs with a NSAID group weaker in analgesic effect were used.
  • the combination can be used for both moderate and intense pain.
  • NSAIDs show their pharmacological effect in high doses, which is due to the presence of a number of side effects.
  • the main negative property of all NSAIDs is a high risk of developing adverse reactions from the gastrointestinal tract. Therefore, the possibility of reducing them is an important task in the development of new drugs based on them. It was found that due to the introduction of hyoscine butyl bromide, the destruction of the cells of the gastric mucosa induced by NSAIDs is significantly reduced.
  • composition according to the invention includes active substances in therapeutically effective doses.
  • the indicated doses depend on the disease, the intensity of the pain, age and weight of the patient. On average, they make up -1-50 mg for butyl bromide hyoscine and from 1 to 1000 mg for NSAIDs. Doses of NSAIDs are approved for use and are known from the prior art, including from the FS. However, in the present invention, they can be reduced to 10% due to the synergy with hyoscine butyl bromide.
  • Another aspect of the invention is a form for administering a drug composition.
  • the proposed medicinal composition is made in the form of an orodispersed tablet, which allows not only to reduce ulcerogenic the action of NSAIDs, but also solve the problem of bioavailability and variability of the action of hyoscine butyl bromide.
  • Sugars such as lactose, sucrose can be used to create an orodispersible tablet; sugar alcohols, in particular mannitol, sorbitol, xylitol; silicon dioxide, stearic acid and its pharmaceutically acceptable salts, polyvinylpyrrolidone, microcrystalline cellulose, modified starches, sweeteners, flavoring and aromatic additives, etc.
  • a drug composition in the form of an orodispersed tablet containing a combination of hyoscine butyl bromide and NSAIDs, the carrier of which is a composition of Mannitol, Aspartame, Crospovidone, Polyvinylpyrrolidone K 30, Flavoring additive, silicon dioxide, colloidal anhydrous.
  • One of the special cases of the invention are tablets containing hyoscine butyl bromide and diclofenac or its sodium salt with potassium polacrilin, with a ratio of diclofenac or its sodium salt with potassium polacrilin (1: 2) in the following components, wt.%: Hyoscine butyl bromide 3.7-4.3
  • Flavoring additive 2.83-3.57
  • Orodispersed tablets are white, round, uncovered, flat tablets with a beveled edge.
  • Potassium Polacrillin (PP) is a monofunctional minimally cross-linked carboxylic acid exchange resin obtained by co-polymerization of methacrylic acid with divinylbenzene and subsequently neutralized with potassium hydroxide:
  • PP is an effective disintegrating agent in low concentrations in various tablet formulations, including many hydrophobic formulations, where standard disintegrating agents are not very effective.
  • the claimed composition it can be used to obtain a complex with diclofenac or its diclofenac sodium salt resinate.
  • Mannitol has an additional stabilizing effect on the composition.
  • Aspartame sugar substitute is used in this form as a digestible low-calorie sweetener, providing acceptable palatability in combination with other ingredients.
  • the optimal combination of two types of polyvinylpyrrolidone-Crospovidone and Polyvinylpyrrolidone K 30 was also selected. This combination provides the required compressibility, stability, and also affects the taste of the tablets.
  • flavoring additive you can enter food acceptable additives, such as lemon, tangerine, blueberry, peppermint, etc., preferably dry mint.
  • Colloidal silicon dioxide is introduced into the composition as an antifriction and dispersing component.
  • anhydrous, for example, Aerosil 200 brand dioxide can be used.
  • a method of producing tablets is as follows:
  • Mannitol is mixed, anhydrous colloidal silicon dioxide, a 20% solution of polyvinylpyrrolidone K 30, and the mixture is granulated by spraying in a fluidized bed.
  • the previously prepared diclofenac or diclofenac sodium complex is mixed with potassium polacrilin (Diclofenac resinate or sodium diclofenac resinate) taken at a ratio of 1: 2 with hyoscine butyl bromide, crospovidone, aspartame and a flavoring.
  • the mixture is tabletted by the compression method in two stages: preliminary compression with a force of 2-3 kN and final compression with a force of 8-10 kN.
  • the hardness of the tablets is 25-44 N.
  • All suspended material is sieved through a 40 mesh strainer.
  • the fluidized bed granulator is preheated before filling the mixture and before spraying the solution of the sprayed material to begin to flow the mixture of Mannitol and Aerosil 200 for at least 3 minutes.
  • Stage B obtaining the Complex Diclofenac Sodium Resinate
  • Potassium Polacrillin (42.0 kg). Sifted Potassium Polacrillin is slowly added to warm purified distilled water (temperature from 35 ° C to 40 ° C) to the aforementioned distilled water with stirring and stirring is continued for 2 hours. Slowly add Diclofenac Sodium to the above resin solution with stirring. The pH of the solution of Diclofenac Sodium - Resin should be 5-6.
  • the resin will stabilize, and a pop-up liquid will be present on the top layer of the paste. Drain pop-up liquid.
  • the paste is dried at a temperature of 60 ° C for 30 minutes or until the loss upon drying is NMT 3.0%.
  • Crospovidone (6.08 kg)
  • the method used to obtain compression tablets is a rotary tablet press SMART Kilian 250. Compression is carried out in two stages: pre-compression and final compression. Conditions: the main compression force is 8-10 kN, the preliminary compression force is 2-3 kN. The hardness of the tablets is 40 N.
  • mice 80 mice in total were divided into groups of 10 animals each. Test solutions of substances were encrypted by the study leader. The experiments were conducted by a researcher who did not know what substance was injected into mice (blind method). The groups of animals were decrypted after all the data were received.
  • mice 1 group, 10 mice. Animals in this group received 1% starch paste.
  • mice 10 mice. Animals of this group received diclofenac 10 mg / kg.
  • mice Animals of this group received diclofenac 2.5 mg / kg
  • mice 10 mice. Animals of this group received diclofenac 10 mg / kg + hyoscine ⁇ -butyl bromide 2 mg / kg.
  • mice Animals of this group received diclofenac 2.5 mg / kg + hyoscine ⁇ -butyl bromide 2 mg / kg 6 group, 10 mice. Animals of this group received hyoscine ⁇ -butyl bromide 2 mg / kg
  • mice All substances were injected into mice into the stomach using a metal probe for mice (FTSS-20S-38) from Salomon Scientific (USA) in a volume of 0.2 ml per 10 g of body weight.
  • the control group was administered 1: starch paste in the same volume.
  • mice were injected intraperitoneally with a 0.75% solution of acetic acid at the rate of 0.1 ml per 10 g of animal body weight and the number of writhing in each animal was counted over 15 minutes.
  • Hyoscine ⁇ -butyl bromide at a dose of 2 mg / kg also exerted a depressing effect (p ⁇ 0.001, Student's t-test) on cramps caused by acetic acid in mice.
  • the next step in the analysis was to compare the efficacy of the diclofenac + hyoscine ⁇ Economics-butyl bromide combination with the action of the separately administered diclofenac. For this, a two-way analysis of variance was used where one factor was “substance” and another factor was “dose”.
  • the next step was to compare the strength of the combination of diclofenac + hyoscine ⁇ -butyl bromide with separately administered hyoscine ⁇ -butyl bromide. Since hyoscine N-butyl bromide was studied in only one dose, a one-way analysis of variance was used in which the effect of the combination was compared with the action of hyoscine.
  • FIG. 1 summarizes a comparison of the effects of substances on the strength of the inhibitory effect on cramps.
  • cramps caused by acetic acid in the control group are taken as 100% and the effect of substances and their combinations is expressed as a percentage of the control.
  • Data are presented as a percentage of control taken as 100%.
  • Each group consisted of 10 mice.
  • Diclofenac 10 mg / kg + briefly-butyl bromide hyoscine 2 mg / kg> Diclofenac 10 mg / kg hyoscine ⁇ -butyl bromide 2 mg / kg diclofenac 2.5 mg / kg + ssen-butyl bromide hyoscine 2 mg / kg> Diclofenac 2, 5 mg / kg.
  • the invention is applicable in the field of pharmaceuticals and medicine, namely, it relates to agents used in the treatment of various spastic conditions of smooth muscles, especially with irritable bowel syndrome (IBS).
  • IBS irritable bowel syndrome

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Abstract

L'invention se rapporte au domaine de l'industrie pharmaceutique et de la médecine, et concerne notamment des agents utilisés pour différents états spasmodiques des muscles lisses, notamment dans le cas du syndrome du côlon irritable. Cette composition médicamenteuse se présente sous forme de comprimés dispersibles oralement afin de traiter le syndrome de la douleur des muscles lisses, et se caractérise en ce qu'elle comprend une combinaison de butylbromure d'hyoscine et d'un agent anti-inflammatoire non stéroïdien (AINS) dans des quantités thérapeutiquement efficaces en qualité de composants actifs, ainsi que des substances auxiliaires pharmaceutiquement acceptables. Ces comprimés ont une plus grande efficacité et une meilleure biodisponibilité du principe actif.
PCT/RU2013/000932 2012-11-07 2013-10-21 Nouvelle composition médicamenteuse pour traiter le syndrome de douleurs lors de spasmes de muscles lisses WO2014074017A1 (fr)

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RU2012147216 2012-11-07
RU2012147216/15A RU2497505C1 (ru) 2012-11-07 2012-11-07 Новая лекарственная композиция для лечения болевого синдрома при спазме гладкой мускулатуры

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020157484A1 (fr) * 2019-01-28 2020-08-06 Reckitt Benckiser Health Limited Comprimé orodispersible

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RU2657803C1 (ru) * 2017-03-21 2018-06-15 федеральное государственное бюджетное образовательное учреждение высшего образования "Алтайский государственный университет" Средство, обладающее противовоспалительным и анальгезирующим действием

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RU2242968C2 (ru) * 1999-01-27 2004-12-27 Ар.Пи.Шерер Корпорейшн Быстродиспергирующаяся лекарственная форма, не содержащая желатин
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NOVIGAN: "Instruktsiya po primeneniju, protivopokazaniya, sostav i tsena, 3D-upakovka.", SPRAVOCHNIK LEKARSTV RLS. N. P N008846, 28 April 2006 (2006-04-28), Retrieved from the Internet <URL:http://www.rlsnet.ru/tn_index_id_2346.htm> [retrieved on 20140313] *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020157484A1 (fr) * 2019-01-28 2020-08-06 Reckitt Benckiser Health Limited Comprimé orodispersible

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