TW200816997A - Treatment of pain - Google Patents

Abstract

The invention relates to a new medicamentation for the treatment of pain, in particular fibromyalgia. The medicamentation comprises the administration of pramipexole and milnacipran. The medicamentation is a combination of pramipexole an milnacipran which may be used in a fixed dose combination as well as in a free dose combination. The invention further is related to the manufacture of a medicament for the treatment of pain, in particular fibromyalgia comprising said medicamentation and a method of treatment of pain, in particular fibromyalgia comprising said medicamentation.

Description

200816997 IX. INSTRUCTIONS: [Technical field to which the invention pertains] The t invention relates to a new drug therapy for treating pain, especially muscle fiber pain.兮 从 从, 成 music therapy including pramipexole and milnacipran = two drug therapy is a combination of pramipexole and milnacipran, which can be used in combination with solid-sigma and free-standing. The invention further relates to a method of making a medicament for the treatment of pain, especially muscle fiber pain, a drug therapy, and a method of treating pain, particularly muscle fiber pain, which comprises the drug therapy. _In the case of inventions, 'pain should be used as a collective term, and its complex sense of two senses, S perception, is characterized by the excitement of health sensation, and one perceives pain in an acute form. However, pain may develop into a chronic form that is itself recognized as a discrete disease. Pain is divided into at least one sub-dog. a.) 1⁄4 perceptive fork pain, which is transmitted to the CNS due to stimulation and shock of the pain receptor; b.) neuropathic pain, which is caused by tissue damage and/or injury / or peripheral or central (4) trauma, especially in the form of diabetes, by disease; c.) pain after dysfunction, such as migraine, back pain or physical and mental processes (pSych〇s〇matic. In the present invention In the case, the most significant form of pain is neuropathic pain, headache, especially migraine and/or muscle fiber pain. The most relevant form of disease associated with the present invention is muscle fibrillation pain. [Prior Art] Neuropathic Pain or Painful Periphery Neuropathy can be classified by the type of nerve that has been traumatized or injured. Basically 'differentiated into three types of nerves I22670.doc 200816997 The area affected by the neural, sensory, and autonomic systems. Known as a single neuropathy, if the right is far away from the disease, there are many neuropathies. There are many = domain affected, then the disease is called, and the cause of the disease can lead to neuropathy, such as diseases such as diabetes. Autoimmune disease, Bell's hemorrhoids Ρ _), cancer, summer ~ (Bells ... Chart 1 disease (Charc〇t-Marie-To〇th heart wase), carpal tunnel syndrome Hawthorn th failure; poisoning; μ spring ^ Lunar tissue diseases, causes of liver dysplasia, such as alcoholism, vitamin deficiency, etc. Painful and disabling paroxysmal form. Migraine pain ": Tian Shu is severe, pulsating or pulsating pain, Lord = often Accompanied by extreme sensitivity to light and sound... nausea and vomit: soil. == Sexual seizure warning money can be called "(four) ", manifested as flash or temporary = blind visual impairment. Migraine patients are prone to recurrence, the cause of which is Eating 戍 = sleep: foot, exposure to light or hormonal imbalance (female only). The cause can also be anxiety, stress or relaxation after relaxation (muscle fiber pain 俜, _ and illness, It is characterized by a large area of musculoskeletal pain and has a tender feeling at the special & tender point. In addition, muscle fiber pain suffers from hang-like symptoms such as fatigue, sleep disorders, headache or cognitive dysfunction. The College of Rheumatology

Rh: Umat〇1〇gy) defines muscle fiber pain as diffuse body pain and axial and monthly pain' and at least 11 of 18 tender points are painful. A large area of pain is present for at least three months. The point of tenderness (diagnostic sign of muscle fiber pain) is: See the sensation of the sensation of the sensation of the sensation of the sensitization. Compared with patients without pain, patients with muscle fiber pain have quantitative changes in pain thorns. 122670.doc 200816997, indicating that patients with muscle fiber pain treat sensory information in different ways, most likely due to central treatment of pain in the spine. Variety. ~ There can be a large area of pain throughout the body, which usually seems to appear in the muscles. The most common areas of pain include the neck, (4), shoulders, pelvis waist: and the hand 'but can include any body part. Pain changes with time. It does not show various strengths. It is extremely extreme, A area and chronic pain. The pain is described as deep muscle pain, dysmotility, twitching, pain and flash pain. Such as

Numbness, _ and burning pain patients often exist. Usually these pains and stiffness are strict: t & degrees are worse in the morning. Factors that contribute to increased pain include cold/wet climate, non-recovery sleep, physical and mental fatigue, excessive physical activity, lack of physical activity, anxiety, and stress. In addition to pain, patients often complain about fatigue in the form of a full $ debilitating form that hinders even the simplest daily activities. - The series of symptoms are feeling of physical exhaustion, sleep disturbance, memory loss, distraction, and varying degrees of anxiety and depression. In addition, certain other medical conditions are sometimes associated with muscle fiber pain, such as tension headaches, migraine headaches, large bowel urgency, overactive bladder, pelvic pain, premenstrual tension syndrome, cold intolerance, Dry eye and dry mouth, anxiety, depression, tinnitus, dizziness, vision problems and other conditions. Patients diagnosed with rheumatoid arthritis, lupus (SLE), and Sjogren's syndrome (Sjogren, syndrome) usually develop symptoms of muscle fiber pain during their illness. Milnacipran (disclosed in US 4,478,836) for use in the treatment of muscle fiber pain has been known from US69921 10, US660291 1 . Pramipexole (2-amino-6-n-propylamino-4-4,5,6,7-tetrahydrobenzothiazole, 122670.doc 200816997 preferred (a) enantiomer and its (hereinafter referred to as general The use of any of the pharmaceutically acceptable salts of the genus of Laxon in the manufacture of a remedy for the treatment of muscle fiber pain has been known from US Pat. No. 6,277,787. The present invention is directed to the present invention. #仑之组合, the use of drugs for the treatment of pain, the pain is more than = meat fiber pain or neuropathic pain or headache ', his life, sputum metastatic cancer. Better treatment of muscle fiber, quasi-pain It can be used in a free amount combination or a fixed amount combination. [Embodiment] = The invention is based on the principle of combination administration of pramipexole and milapura. The above various pains are treated by >J in treatment of pain. The effective amount or dose of life is in the range of about ! mg / day to gram / day. The preferred adult dosage is about 25 mg / ^ instrument mg / day 'better 50 mg / day to 1 mg / day In the case of patients with genital warts, the optimal dose must be responsible for the pain of the disease as usual: Consider the size of the patient, the other medications required by the patient, the persistence, and the severity of the patient and all other conditions of the patient. = That is preferably used only once or twice a day. Capsules, suspensions and the like are suitable. Form. Common prescriptions for medical scientists: Applicable. If there are reasons to administer drugs in other medical forms in special circumstances, it may be: he is effectively administered in the form of medicine, such as (but not limited to medicine A: liquid, accumulated injection) Suppositories, and the like, which are well known and understood. However, 'substantially, it is preferably administered or not, and the medical form is recommended. 122670.doc 200816997 The effective amount or dosage of pramipexole (especially in the form of the dihydrochloride monohydrate) of the oral pain is in the range of from about 0.1 mg/day to about 〇 mg/day. Preferred adult dosage system In the range of from about 02 mg/day to about 6 mg/day, and a better adult dosage is from about 4 mg/day to about 5 mg/day. For each patient, the optimal dose must be from the responsible condition. The physician considers the size of the patient, The other drugs required, the severity of persistent pain, and all other conditions of the patient are set. In the treatment of pain, especially chronic pain, (4) the release form of pramipexole, the appropriate pramipexole It is disclosed in the addition of 2嶋/〇15942 or · 2〇〇6/〇15943, both of which are incorporated herein by reference. Delayed release according to WO 2006/0! 5942 and suitable for use in the context of the present invention The keying agent is characterized in that the delayed release formulation comprises a base comprising at least one water swelling polymer, preferably not pregelatinized starch, or a pharmaceutically acceptable salt thereof. The substrate preferably comprises at least two = The polymer (preferably not pregelatinized) and at least one of the at least two polymers is an anionic polymer. Preferably, the anionic polymer is selected from the group consisting of avidin polymers, methacrylic polymers, alginates, and sulphate. The anionic polymer is a cross-linked propylene polymer: wherein the acrylic polymer is cross-linked in the matrix. From 5% by weight to about 25% by weight, and preferably from about 0.5% by weight to 15% by weight of scoop, and preferably from about 9% by weight to about 3% by weight. Depending on the product: 'At least one of the at least two polymers is a generally neutral aggregate: 'preferably not pre-gelatinized powdered powder" " good, this generally neutral polymerization 122670.doc 200816997 &amp ; from hydroxypropyl cellulose and hydroxypropyl medium # > n ^ soil methyl cellulose. More preferably, the polymer produced in the large version is hydroxypropyl^^^w#, emulsified cellulose, and wherein the amount of the 'propyl propyl methyl ketone in the matrix is about 10% by weight. Up to about 75% by weight, and more preferably from about 25% by weight to about 65% by weight. In one embodiment, the matrix comprises: from about 0.05 to 5% by weight, from about 0.25 to 25% by weight, from about 10 to 75% by weight, added to 1% by weight of (a) pramipexole or its salt (b) anion Swelling Polymer (c) Neutral Hydroxy Polymer, d) Other Excipients In one embodiment, the matrix comprises (4) at least one type of water-swelling polymer which is not pre-gelatinized powder and In case of excipients, the resulting lozenge provides non-pH dependent in vitro release characteristics in the range of pH d7.5, or (b) at least one water swelling anionic polymer and optionally excipients, the resulting binder It provides pH-dependent release characteristics with preferred faster release characteristics in the pH range of less than 4.5 and slower and more adequate pH-dependent release characteristics in the pH range of 4.5 to 7.5. The delayed release tablet may have a non-functional coating. Preferably, the tablet is administered once daily. A delayed release pellet formulation according to WO 2006/01 5943 and suitable for use in the context of the present invention is characterized in that it comprises an active ingredient selected from the group consisting of pramipexole and its pharmaceutically acceptable salts and at least one release-improving excipient. Preferably, the active ingredient is embedded in a matrix comprised of at least one release modifying excipient, preferably selected from the group consisting of lipids, waxes, and water insoluble polymers 122670.doc * 11 - 200816997. Preferably, the matrix comprises a core and a coating wherein at least one release modifying excipient is incorporated into the coating and the active ingredient is incorporated into the core as appropriate. The coating may comprise at least a first layer and a first layer encasing the first layer, wherein the first layer comprises an active ingredient, and wherein the second layer comprises at least one release modifying excipient, preferably selected from B Cellulose, cellulose acetate, polyvinyl acetate, polyacrylate, polymethacrylate, and ammonium methacrylate copolymer. The second layer may further comprise at least one water-soluble excipient, preferably selected from the group consisting of hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and polyethylene glycol. The second layer may further comprise an enteric/gluten coating t', preferably selected from the group consisting of methyl methacrylate copolymers A and B. In a consistent embodiment, the second layer comprises from about 0/about to about 85 weight percent of the enteric coating polymer and from about 5% by weight to about 75 weight percent. / 非 is a water-insoluble polymer. The core may comprise sugars such as sucrose; starch; cellulose and cellulose derivatives, preferably microcrystalline cellulose. • In one embodiment, the delayed release pill formulation comprises 'an inert pellet core; • a first layer as an active ingredient layer comprising pramipexole or a pharmaceutically acceptable salt thereof and optionally One or more wet adhesives and additional excipients; and a second layer provided on the first layer, the second layer being a delayed release coating comprising at least one of Non-water-soluble polymer and, optionally, a pore former, the pellet obtained has a pH-independent in vitro release profile or 122670.doc -12- 200816997 (8)=Dependent enteric coating polymer with PH-independent swelling A mixture of polymers, the resulting pellets have an in vitro release profile close to zero order at an acidic pH of up to 6.8, an accelerated release profile at pH 68, and a pH above 7.3. It has a more accelerated release characteristics. The inert pellet core may comprise multi-brew, cellulose, cellulose derivatives, powder and/or enamel. The inert pellet core may further comprise a fine sugar and/or microcrystalline cellulose' preferably comprising microcrystalline cellulose. The delayed release pellet formulation, which is more active with pramipexole-containing active pellets, can be prepared by wet or melt extrusion or melt granulation rather than by forming a drug layer on the inert pellet core. The water-insoluble polymer of the delayed release pellet may be selected from the group consisting of ethyl cellulose, cellulose acetate, acetic acid ethyl acetate, polyacrylic acid, and derivatives, such as a tetrabasic substituted acrylic acid polymer. Preferably, it is a methacrylic acid-based copolymer, a type B and an ethyl cellulose, and most preferably an ethyl cellulose. The pH-dependent enteric coating polymer may be an anionic ridiculous acrylic acid polymer, preferably a partially methylated methyl propyl phthalate polymer. When the pH is higher than 5.5, the pH is preferably higher. 7 It is soluble when it is dry. The non-pH dependent water swellable polymer may also be a quaternary substituted acrylic polymer, preferably an ammonium substituent comprising from about 5 weight percent to about 1 weight percent of the acrylic polymer.曰〇PH-dependent enteric coating polymer can be present in the coating (four)% to 5% by weight, and the non-pH-dependent swelling polymer is in the coating b 122670.doc 200816997 weight ° / It is present in an amount of up to 75% by weight. The delayed release coating may additionally comprise a pore forming component. The pore-forming component may be selected from the group consisting of propyl fluorene, fluorene, propyl sulfonate, polyvinylpyrrolidone and polyethyl hydrazide. A propyl cellulose selected from the group consisting of Khicel. A delayed release pellet formulation comprising an active ingredient selected from the group consisting of pramipexole and a pharmaceutically acceptable salt thereof can be burial by fine or squeezing granulation or granulation of Mf' using excipients without additional diffusion Membrane Achieving Delayed Release The pellets can be prepared in capsule form containing a sufficient amount of pellets to provide the daily dose administered. The extent to which any pharmaceutically active compound is disclosed or claimed is intended to include all active Hodgkin products produced in vivo, and right-in-combination of your milk with "enantiomeric, diastereomeric or inter-b ° When it is said that it is open, it is clear that all slaves include all enantiomers and non-living bodies. Obviously, the most grammatical, or tautomeric, is effective and the secondary works are better. Both of the compounds which are small isomers can be administered in the form of medicinal instructions in the form of medicinal herbs. As a target, each of the compounds of the target of the brothers and the moon includes (but is not limited to) , Hundreds, examples of sexual salts - acid or salt prepared. Because of the use of salt or neutral compounds in the combination of salt and chlorpheniramine, it is necessary to: = use, easy to use, can be used Properties of the sex and shelf life. = such as bio-acceptable acids including acetic acid, benzoate II, medicinal gossip, 4 formic acid, _ I22670.doc -14- 200816997 bromophenyl sulfonic acid, camphor Sulfonic acid, carbonic acid, citric acid, ethanesulfonic acid, fumaric acid Gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, decanesulfonic acid (methanesulfonate) , viscous acid, nitric acid, oxalic acid, bishydroxy acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Examples of pharmaceutically acceptable salts include (not limited to this) Acetate, benzoate, hydroxybutyrate, hydrogen sulphate, bisulfite, bromide, butyne-1 〆 diacid salt, hexanoate, chloride, chlorobenzoate, lemon Acid salt, dihydrogen phosphate, dinitrophenyl phthalate, fumarate, glycolate, heptanoate, hexyne-1,6-diate, hydroxybenzoate, iodide , lactate, maleate, malonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, mercaptobenzoate, hydrogen phosphate, naphthalene - 1-sulfonate, naphthalene-2-sulfonate, oxalate, phenylbutyrate, phenylpropionate, phosphate, phthalate, phenylacetate, propane sulfonate, C Acid salt, propionate, pyrophosphate, pyrosulfate, sebacate, suberate, succinate, sulfate, sulfite, sulfonate, tartrate, xylene sulfonate and Similar to the salt. The two active compounds (milapron and pramipexole) can be used as a single pharmaceutical formulation or they can be administered as discrete individual pharmaceutical formulations. The first variant has the advantage that the dosage is in the pharmaceutical formulation. The drug is fixed. In this case, the pharmaceutical formulation is referred to as a n fixed amount combination. An advantage of the second variant is that each compound can be used in a suitable free dosage form. If the dose of one of the two components of the combination therapy is reduced or increased relative to the other to enhance efficacy, the "free volume combination" allows for greater discretion depending on the patient. In the case of a combination of free amounts 122670.doc -15- 200816997, the two application forms (pramipexole form and milnacipran combination) can be in a short period of time (within 60 minutes, more preferably within 30 minutes) More preferably within ίο minutes) or within a long period of time, preferably within 12 hours, preferably within 6 hours and within 1 hour of the co-administration. Preferably, the two drugs are administered within 5 minutes. In the case of a fixed amount combination in the form of a delayed release formulation, the solid combination can be prepared based on the above-described delayed release formulation comprising pramipexole, in particular according to the formulation of WO 2006/015942 or WO 2006/015943. The features are listed above, and milnacipran can be added to the fixed amount combination at the appropriate dosage as listed in this specification. Where the king immediately releases a fixed amount of the combination of the formulation forms, the fixed amount combination can be prepared based on the immediate release formulation listed for each of the two combination ingredients in this specification. In the following, the invention will be described in the form of freely combinable formulations: Examples of pramipexole related formulations a.) Immediate release formulation: Tablets containing 0.125 mg or 0.25 mg or 〇·5 mg*! mg pram Solu-dihydrochloride-monohydrate, combined with mannitol, corn starch, highly dispersed cerium oxide, povidone, magnesium stearate. This formulation is known to be commercially available as a Sifrol^Mirapex® (immediate release formulation). b·) Delayed release formulation: ba•pramipexole delayed release drum ba.l 122670.doc » 16- 200816997 Ingredient mg/0.75 mg Lozenges pramussole-dihydrochloride monohydrate, peg-grinding 0.750 Hypromellose 2208 (Methocel K 15 Μ) 157.500 Corn starch 183.700 Carbomer 941 (Carbopol 8 71 G) 3.500 Colloidal cerium oxide 2.800 Magnesium stearate 1.750 Total 350.000 ba.2 Ingredient mg /0.75 mg Lozenges pramussole-dihydrochloride monohydrate, peg-milled 0.750 hydroxypropyl ketone cellulose 2208 (Methocel K 15 Μ) 157.500 corn starch 174.600 carbomer 941 (Carbopol® 71 G) 14.000 colloid Ceria 1.400 Magnesium stearate 1.750 Total 350.000 ba.3 Component mg/tablet pramipexole-dihydrochloride monohydrate, peg-milled 0.750 Hydroxypropylcellulose 2208 157.500 (Methocel K 100 Μ) Corn starch 187.900 122670.doc -17- 200816997 Colloidal cerium oxide 2.100 Magnesium stearate 1.750 Base lozenge Total weight 350.000 ba.4 Component mg/tablet pramipexole-dihydrochloride monohydrate, peg-grinding 0.750 hydroxypropyl hydrazine Cellulose 2208 175.000 (Methocel K 15 Μ) Carboxymethyl cellulose sodium 87.500 Lactose monohydrate (200 mesh) 52.500 Microcrystalline cellulose (ΡΗ 101 grade) 31.100 Colloidal cerium oxide 1.400 Magnesium stearate 1.750 Base lozenge total Weight 350.000 ba.5 mg/tablet pramipexole-dihydrochloride monohydrate, peg-milled 0.750 hydroxypropyl ketone cellulose 2208 175.000 (Methocel K 15 M) sodium carboxymethylcellulose 87.500 lactose single Hydrate (200 mesh) 52.500 microcrystalline cellulose (PH 101 grade) 27.600 Carbopol® 71 G 3,500 Colloidal cerium oxide 1.400 Magnesium stearate 1.750 Base lozenge Total weight 350.000 122670.doc -18- 200816997 ba.6 mg/tablet pramipexole-dihydrochloride monohydrate, peg-milled 0.750 hydroxypropylmethylcellulose 2208 175.000 (MethocelK 15M) sodium carboxymethylcellulose 87.500 lactose monohydrate ( 200 mesh) 45.500 microcrystalline cellulose (ΡΉ 101 grade) 24.100 carbomer ^l^Carbopo^Tl G) 14.000 colloidal cerium oxide 1.400 magnesium stearate 1.750 base tablet total weight 350.000 ba.7 component mg/ingot Pramipexole-dihydrochloride monohydrate Compound, peg-grinding 0.750 Carbopof 71 G 87.500 lactose monohydrate (200 mesh) 225.400 microcrystalline cellulose (pH 101) 33.200 colloidal cerium oxide 1.400 magnesium stearate 1.750 base tablet total Weight 350.000 ba.8 mg/tablet pramipexole-dihydrochloride monohydrate, peg-milled 0.750 carbomer 941 (Carbopol 8 71 G) 70.000 lactose monohydrate (200 mesh) 242.900 microcrystalline cellulose (pH 101) 33.200 Colloidal cerium oxide 1.400 122670.doc -19- 200816997 Magnesium stearate 1.750 Base lozenge Total weight 350.000 ba.9 Component mg/tablet pramipexole-dihydrochloride monohydrate, Peg-grinding 0.750 carbomer QdWCarbopol^Tl G) 70.000 lactose monohydrate (200 mesh) 140.000 dicalcium phosphate dihydrate 136.100 colloidal cerium oxide 1.400 magnesium stearate 1.750 base tablet total weight 350.000 ba.10 Mg/recorded: pramipexole-dihydrochloride monohydrate, peg-milled 0.750 carbomer 941 (Carbopol® 71 G) 52.500 lactose monohydrate (200 mesh) 140.000 dicalcium phosphate dihydrate 153.600 colloidal Cerium oxide 1.400 barium stearate 1.750 base tablet total weight 350.000 b a. 11 parts mg/tablet pramipexole-dihydrochloride monohydrate, peg-milled 0.750 hydroxypropyl ketone cellulose 2208 157.500 (Methocel K15M) corn starch 163.400 carbomer 941 (Carbopof 71 G) 24.500 Colloidal cerium oxide 2.100 Magnesium stearate 1.750 Base lozenge Total weight 350.000 122670.doc -20- 200816997 ba.12 Component mg/tablet pramipexole-dihydrochloride monohydrate , peg-milled 0.750 hydroxypropylmethylcellulose 2910 0.788 (Methocel E 5) corn starch 173.812 hydroxypropylmethylcellulose 2208 157.500 (Methocel K 15 M) Carbopof 941 (Carbopof 71 G) 14.000 colloidal cerium oxide 1.400 Magnesium stearate 1.750 Base lozenge Total weight 350.000 ba.13 Component mg/tablet pramipexole-dihydrochloride monohydrate, peg-milled 0.750 hydroxypropylmethylcellulose 2208 148.500 (Methocel K 15 Μ) Corn Starch 160.620 Carbopof 71 G 16.500 Colloidal Ceria 1.980 Magnesium Palmitate 1.650 Base Lozenge Total Weight 330.000 bb. Prambyline Delayed Release Capsule bb.l Ingredient mg/0.75 mg Capsule mg/0.75 mgThe capsular ER pellet consists of the following: 88.458 122670.doc -21 - 200816997 pramipexole-dihydrochloride monohydrate 0.750 microcrystalline cellulose pellets (Cellets 700) 73.980 hydroxypropylcellulose (KlucdEF) 0.150 Talc 0.495 mercapto-acrylic acid copolymer, type B (Eudragit S 100) 7.500 ammonium methacrylate copolymer, type B (Eudragit RS 100) 3.750 triacetin 1.833 ethanol (96%) 173.333* pure water 30.000* HPMC Capsules, size 3 46.000 Total 134.458 88.458 *Removed during processing, the final product does not contain this substance. Bb.2 Ingredient mg/0.75 mg Capsule mg/0.75 mg Capsule ER Pill consists of the following materials: 91.600 pramipexole-dihydrochloride monohydrate 0.750 microcrystalline cellulose pellets (Cellets 700) 73.980 Hydroxypropylcellulose (Klucel EF) 0.150 talc 0.578 122670.doc -22- 200816997 Mercaptoacrylic acid copolymer, type B (Eudragit S 100) 9.250 ammonium methacrylate copolymer, type B (Eudragit RS 100) 4.625 triacetin 2.267 Ethanol (96%) 214.167* Pure water 30.000* HPMC capsules, size 3 46.000 Total 137.600 91.600 *Removed during processing, the final product does not contain this substance. Bb.3

Ingredient mg/0.75 mg Capsule mg/0.75 mg Capsule ER Pill consists of the following: 80.063 pramipexole-dihydrochloride monohydrate 0.750 microcrystalline iron oxide pellets (Cellets 700) 73.980 propylcellulose ( KlucelEF) 0.150 Talc 0.495 Ethylcellulose (N14) 3.750 Macrogol 6000 0.938 Ethanol (96%) 49.167* Pure water 32.583* HPMC capsules, size 3 46.000 Total 126.063 80.063 *Removed during processing, the final product does not contain this material. 122670.doc -23- 200816997 bb.4 Ingredient mg/0.75 mg Capsule mg/0.75 mg Capsule ER Pill consists of the following: 82.088 pramipexole-dihydrochloride monohydrate 0.750 microcrystalline cellulose pellets (Cellets 700) 73.980 Hydroxypropylcellulose (Klucel EF) 0.150 Talc 0.645 Ethylcellulose (N14) 5.250 Macrogol 6000 1.313 Ethanol (96%) 68.333* Pure water 33.667* HPMC capsules, size 3 46.000 Total 128.088 82.088 *Processing shift Except that the final product does not contain this substance. Bb.5 Ingredient mg/0.75 mg Capsule mg/0.75 mg Capsules ER pellets consist of the following: 93.668 pramipexole-dihydrochloride monohydrate 0.750 microcrystalline cellulose pellets (Cellets 700) 73.980 Hydroxypropyl Cellulose (Klucel EF) 0.630 Talc 1.995 122670.doc -24- 200816997 Methacrylic acid copolymer, Type B (Eiidragit S 100) 9.000 Ammonium thiol acrylate copolymer, Type B (EudmgitRS 100) 4.500 Triethyl citrate Ester 2.813 Ethanol (96%) 250,200* Pure water 30.000* HPMC capsules, size 3 46.000 Total 139.668 93.668 *Removed during processing, the final product does not contain this substance. Bb.6 Pellet prepared by wet extrusion Example pramexole [g] microcrystalline cellulose [g] binder [g] 6 1 99 0 6a 0.5 99.5 0 6b 2 98 0 6c 1 98 1 (poly Vetidone K25) 6d 1 98 1 (propylcellulose) 6e 0.5 98.5 1 (mercapto cellulose) bb.7 Pill prepared by melt extrusion with a hydrophilic excipient

To achieve sufficient homogeneity of the contents, 9 g of polyethylene glycol 6000 (PEG) was mixed with 1 g of pramipexole. Subsequently, the mixture was mixed with 50 g of PEG 6000 and 40 g of poloxamer 1 88 (poloxamer 1 88). The mixture was extruded in a twin-screw extruder at a temperature of 54 ° C with a mold diameter of 0.7 mm, and a face cut granulator was used to obtain pieces of about 1 mm. The pieces were rolled into a circle at 400 rpm in a spheronizer at 41 ° C 122670.doc -25-200816997. The pellets were sieved and the fraction of 〇·8-1·1 mm was used for the delay as described in the previous examples. Example of melt extrusion: Example No. pramexole [g] PEG 6000fgl Poloxamer 188fgl 7 1 59 40 7a 0.5 59.5 40 7b 2 58 40 7c 0.5 69.5 30 bb.8 Pellets prepared by melt extrusion

In order to achieve sufficient homogeneity of the contents, 9 g of stearyl alcohol was mixed with 丨prramexole. Subsequently, the mixture was mixed with 90 g of stearyl alcohol. The mixture was extruded in a twin-screw extruder at 5 rc with a die diameter of Q 7 mm, using a string-cutting granulator to obtain pieces of about 1 mm. The chips were rolled into a circle at 4G0 rpm in a spheron pellet machine. The pellets were sieved, part of nun. for delay as described in the previous examples. Table Η & Some additional examples for melt extrusion. Melt extrusion example:

122670.doc •26- 200816997 Delayed release pellets prepared by wet extrusion To achieve sufficient uniformity of the contents, 9 g of microcrystalline cellulose was mixed with 1 g of pramipexole. Subsequently, the mixture was mixed with 60 g of microcrystalline cellulose and 30 g of carbomer 971P. The mixture was extruded in a twin-screw extruder with a sufficient amount of water (or binder solution) with a mold diameter of 0.7 mm. The resulting extrudate was rolled into a circle at 400 rpm in a spheron pelletizer. After drying, the pellets were sieved and a portion of 0·8-1 · 1 mm was filled into the capsules.

Example: pramipexole [g] microcrystalline cellulose [g] delayed release excipient [g] 9 1 69 30 carbomer 971P 9a 0.5 69.5 30 carbomer 971P 9b 2 68 30 carbomer 971P 9 c 1 69 30 Eudragit S 9d 2 58 40 Eudragit S 9e 1 44 30 Eudragit S 25 Carbomer 971P bb.10 Delayed release pellets prepared by melt extrusion to achieve sufficient uniformity of the contents, 9 g of hydrogenated castor oil with 1 g pramexole mix. Subsequently, the mixture was mixed with 60 g of hydrogenated castor oil and 30 g of basking palm wax. The mixture was extruded in a twin-screw extruder with a sufficient amount of water (or binder solution) with a mold diameter of 0.7 mm. The resulting extrudate was rolled into a circle at 400 rpm in a spheron pelletizer. The pellet was sieved and a portion of 0.8-l.lmm was filled into the capsule. 122670.doc -27- 200816997

Delayed release pellets prepared by hot melt granulation/melt granulation In this process, the adhesion of the active ingredient to the excipient is promoted by the addition of a low scent, lipophilic binder, such as mash, fat Fatty acids, fatty acid alcohols, and more water soluble polymers, such as poloxamers or polyethyl acrylates, are typically added to other components in powder form. The binder is liquefied by the friction generated during the mixing stage or by the heat generated by the heating jacket. Suitable excipients are, for example, lactose, microcrystalline cellulose and dicalcium phosphate. After the material has been fused and granulated, the resulting material is cooled, screened and processed into tablets as an additional excipient' or spheronized into pellets which may be additionally coated and filled into capsules. Example: pramipexole [%] lactose octadecyl alcohol [%] carnauba wax "%1 11 0.9 74.1 15 10 11a 1.4 58.6 15 25 lib 0.9 79.1 15 5 milnacipran-related formulation: capsule contains 50 mg Milnacipran _ hydrochloride. 122670.doc -28>

Claims (1)

200816997 X. The scope of the patent application ····, the painful effective pramipexole and the analgesic effective amount of milnacipran for the preparation of a medicament for the treatment of pain. The use of the monthly claim 1 is characterized in that the pain is muscle fiber pain. The use of the long term 1 is characterized in that the pain is migraine. .4 The use of claim 1, characterized in that the pain is chronic pain. 5. The use of claim 1 'characterized by the pain being neuropathic pain. 6. The use of any one of clauses 1 to 5, characterized in that the medicament consists of a set of kits. One set is a pharmaceutical composition comprising at least pramipexole and the other component is - Single sheet, the sheet indicating - preferably selected from the indications of the indications of the request, to 5, the administration of a shoulder containing a pramipexole, and the administration of the formulation comprising the pramipexole Timely. Use the instructions for recommendations containing medicinal formulations of milnacipran. 7. The use of any of claims 1 to 5, characterized in that the medicament consists of a set of kits, wherein one set is a pharmaceutical composition comprising at least pramipexole, and one set consists of at least one meter. The pharmaceutical composition of Naprelon and the other component is a single sheet, the sheet indicating an indication that is preferably selected from the indications of any one of the items 2 to 5, and a blend containing pramipexole Instructions for administration of the substance and instructions for administration of a pharmaceutical formulation comprising milnacipran. The use of any of claims 1 to 5, characterized in that the pramipexole is in a delayed release formulation. 9. A pharmaceutical composition comprising an analgesic effective amount of pramipexole and analgesia 122670.doc 200816997 An effective amount of milnacipran. 10. The pharmaceutical composition of claim 9 which is characterized in that it is an immediate release formulation. 11. A pharmaceutical composition according to claim 9 which is characterized in that it is a delayed release blending of poplar. 122670.doc 200816997 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: (none) 122670.doc