TW520298B - Oral morphine multiparticulate formulation - Google Patents

Abstract

An oral morphine multiparticulate formulation for once-daily administration to a patient, comprising sustained release particles each having a core containing water soluble morphine and an osmotic agent, the core being coated with a rate-controlling polymer coat comprised of ammonio methacrylate copolymers in an amount sufficient to achieve therapeutically effective plasma levels of morphine over at least 24 hours in the patient.

Description

520298 A7 ________________________ B7 ~ L · "—, > · _ I-,-, M | __ _ V. Description of the Invention (i) TECHNICAL FIELD The present invention relates to an oral morphine formulation suitable for taking once a day, 'may_ Less risk of side effects caused by fluctuations in morphine concentration in plasma. Technical Background Morphine is often used in the treatment of morphine sulfate or its hydrate. Morphine sulfate is a class of opium compounds, and /, (5 and / C The specific affinity of the receiving device. The main effect of its therapeutic value is pain and quietness, and the detailed mechanism of the analgesic effect is unknown. It is known that the specific opioid receptor is located in the brain and spinal cord and may play a role of analgesic effect. Department · ?-Xiaof: After oral administration of morphine in combination with ii, the final absorbed amount is not limited to the original compound. Morphine is eliminated (metabolized in the intestinal wall and liver) before systemic circulation, so only 4 0% of the dose reached systemic circulation. Finally all morphine was converted into morphine-3 -glucuronic acid compound (concentration is high but inactive) and morphine-6 -A glucuronic acid metabolite of glucuronic acid compounds. Many animal experiments have proven that morphine-6-glucuronic acid compounds are an effective opioid agonist with the potential to promote the analgesic response of morphine. Morphine first passes through the liver Morphine-6-glucose \ uronic acid compounds are formed after metabolism. Approximately 90% of the dose of morphine is mainly excreted in the urine as its conjugate or morphine-3-glucuronic acid compound, while the rest is excreted in the bile. Morphine Sulfate is often used to reduce moderate to severe pain, especially Shu-»· _ ~----· · · ·---I I ^»-^ One ... ~ One, Xiao • One t, , _— 丨 I | 丨 The paper scale Chengzhou '1 ^ 丨 乂 家 柃 彳 ((' to) eight 4 see the core (210 > < " 297 公 #) -4- 520298 A7 B7 V. Invention 1 Yun Ming (2 minus care, surgery and myocardial infarction, so tend to use in patients who need to be repeated over a period of time to effectively opioid analgesia. Different slow / sustained release morphine formulations have been developed and described in the literature. Extended release of oral morphine sulfate Preparations are considered clinically important because they impart analgesics better than immediate release and reduce side effects that may be associated with morphine. Bd dosage forms such as MS ContinTM tablets (N app) are currently available Morphine sulfate is obtained at active doses of 10 mg, 30 mg, 60 mg, 100 mg, and 200 mg per unit dose. Pain specialists have pointed out that to prevent post-interrupted pain, a once-daily extended-release preparation is Required. The currently available daily morphine products are those sold under the MST Continus hong and kapanol trademarks. In addition to prolonging the duration of sustained release, in order to achieve a true therapeutic effect, a sustained-release morphine formulation must achieve a therapeutically effective plasma morphine concentration and minimum fluctuations in plasma morphine concentration for at least 24 hours. ^^ v I read first I read L read back I | | h

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Elimination 1ν Notice ii ϋ India Morphine-related side effects are a feature of morphine treatment. These side effects include nausea and vomiting, constipation, quietness, confusion and loss of appetite. In addition to their convenience and ability to provide sustained pain relief, the use of modified-release morphine formulations also requires a lower incidence of severe morphine-related side effects. (Gourlay, G.K. et al., Pain (1 997) 69, 295-302) ° Described in US Patent No. 5,47 8 '5 7 7: Application for a paper according to the scale mg: 心 M (' NS) Eight-four gauge (210X 297 male f) -5- 520298 A7 B7 V. Description of the invention (3) Method for providing effective treatment of human pain for about 24 hours' use of a controlled release, solid oral dosage form Morphine opioids relieve pain. After taking this dosage form, the concentration of opioids in plasma will be increased very quickly at first. These peak plasma concentrations appear for about 2 to 8 hours, even after repeated doses, there will be large peak fluctuations. These large spikes are expected to increase the concomitant morphine-related side effects. For cancer patients with long-term pain experience, morphine-related side effects are a significant disadvantage and increase patient suffering. To reduce this side effect, patients need a formulation that exhibits the smallest peaks and minimal sag fluctuations; that is, a formulation that essentially exhibits a stable plasma concentration during the dose period. A further requirement for a therapeutically sustained sustained-release morphine formulation is the ability to maintain high morphine concentrations in plasma over a period of dose. The peak plasma concentration in the aforementioned U.S. Patent Nos. 5,4,7,5,7 appears about 2 to 8 hours after administration. The morphine formulation disclosed by Ep 6 31 and 7 81 has been prolonged controlled release, so that the peak plasma concentration in vitro experiments appears about 2 to 6 hours after taking. Read first I read I

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-少 'Xiao fc combined 1ί r: Similarly' ΕΡ 6 3 6, 3 7 0 revealed a sustained release of morphine formula, the peak plasma concentration in vivo experiments appeared quite early after taking, ie after taking 1 · 〇 to 6 hours, and its w 5 〇 between 4 and 12 hours is a parameter, defined as the time of 50% cmax plasma concentration; for example, the period when the plasma concentration is equal to or greater than 50% of the peak plasma concentration . Ε P 6 0 9, 9 6 1 reveals the components of sustained release, including wood and paper scales. Chuanxiong (('NS) Λ4 gauge straw (210X2 ^ T ^ Ty -6- 520298 A7 B7) V. Description of the invention (7 ) Acrylic acid copolymer type A and amino methacrylic acid ester type B ', as described in USP / NF, at a ratio of 15:85 to 1:99, and save fc A 1 1, and even 1 is about 5: 9 5. This copolymer is manufactured and sold by Rohm, Gmblt, Darmstadt, Germany. The speed-regulating polymer outer film preferably contains a 5: 9 5 Eudragit RL: Eudragit SL mixture, most particularly Eudragit RL 12.5: Eudragit RS 12.5. The penetrant according to the present invention refers to a pharmaceutically acceptable substance that can improve the solubility of water-soluble morphine through the outer membrane of a speed-regulating polymer or through the gastrointestinal tract (GIT) tissue. Without being limited to any particular theoretical mechanism, this penetrant The absorption of water-soluble morphine can be enhanced by creating a regional environment or chemical potential environment. The penetrant is preferably an organic acid, a pharmaceutically acceptable hydrochloric acid, a gastrointestinal absorption enhancer, or a combination thereof. . Suitable penetrants include, but are not limited to Adipic acid, ascorbic acid, citric acid, malic acid, succinic acid, tartaric acid, lactic acid, monopotassium citrate, potassium tartrate, sodium trans-butenoate, sodium dihydrogen phosphate, sodium hydrogen sulfate, hydrogen metasulfate Sodium or a combination thereof. Furthermore, the penetrant is preferably an organic acid selected from the group consisting of trans-butenedioic acid, adipic acid, ascorbic acid, citric acid, malic acid, tartaric acid, lactic acid, and succinic acid. -Butenedioic acid. It is better that the water-soluble morphine and the penetrant are present in the core at a ratio of 2.5 · 1 to 1: 2 · 5, preferably about 1: 1. I £ I Read 1 Read · Back I and I Zhi I Noteί

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-10- 520298

! Fi s ’) A7 B7 Drugs such as binders, surfactants and lubricants are aggregated in a non-reactive core and are formulated. The non-reactive core is preferably a sugar-coated granule, with an average diameter of about 0.4 mm, more mainly 0.3-0.8 mm, and most mainly 0.5-0.6 mm. Morphine active agents, penetrants, and, if necessary, pharmaceutically acceptable adjuvants are mixed to form a homogeneous powder, the active mixture referred to herein. This mixture is then applied to the inactive core as a coating solution. This mixture can be selectively sieved through a suitable sieve using a mill. When coating with a conventional coating pan, multiple layers of coating solution and powder are applied to the central inactive core to form a multi-layered core. When using an automatic coating system, the coating solution and powder are applied simultaneously, as is conventional. So traditional automated coating systems include a CF granulator or other suitable liquid-based layer-based system. The coating solution contains one or more binders dissolved or suspended in a suitable solvent or solvent mixture. Suitable binders include polyvinylpyrrolidone, starch and gelatin. Polyvinylpyrrolidone is a preferred binder. It is best to use the relevant inhomogeneous powder in the central inactive core of sections 5 and 50. The complete core preferably has an average diameter in the range of 0.4 mm to 1.8 mm, and more preferably 0.7 mm to 1.5 mm. Pharmaceutically acceptable adjuvants can be uniformly mixed with water-soluble morphine to form an active mixture. These substances contain components known as lubricants and surfactants. Typical adjuvants include: microcrystalline cellulose (sold under the AVICEL trademark), silicon dioxide (sold under the AERSIL trademark), lactose, talose, powder, sorbus '' ~ ~ _____________.... ........ ...... ·. —-· &Quot; One ― —-. 丨 _ Paper size iiUiH '(' Anti) Λ4 Regulations (210X297 Male f) -12- 13 · 520298 A7 ___ B7 V. Description of the invention (10) Sugar alcohol, sodium lauryl sulfate and cyclodextrin, these can be used alone or in combination with each other. The main adjuvants are talose and sodium lauryl sulfate. Sustained release particles are beads coated with an outer film formed by the speed-regulating polymer outer film of an aminomethacrylate copolymer sold under the EUDRAGIT trademark. EUDRAGIT polymer is a natural lacquer material based on acrylate and / or methacrylate. This polymerizable substance is sold under the trademarks of EUDRAGIT RL and EUDRAGIT RS, and includes acrylic resins containing copolymers of acrylic acid and methacrylic acid esters of low quaternary ammonium groups, which are described in Messis · Rohm Pharma GmbH (1 9 8 4) ', EUDRAGIT's brochure, with detailed physical and chemical data of this product. The ammonium group appears as a salt type and produces the permeability of natural paint films. EUDRAGIT RL and R S are free permeability (R L) and micro permeability (R S), respectively, and do not change due to p Η 値. The speed-regulating polymer outer membrane may be formed by coating a multilayer polymer solution or suspension outer membrane to the core, which is described later in this article. The polymer solution or suspension contains the dissolved polymer or suspended polymer, respectively, in a suitable aqueous solution or an organic solvent or solvent mixture, optionally in a lubricant. Suitable lubricants are talc, stearic acid, magnesium stearate and sodium stearate. The best lubricant is talc. The polymer solution or suspension may optionally include a plasticizer. Suitable plasticizers include polyethylene glycol, propylene glycol, glycerol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, butyl citrate, lemon Ethyl Ester, Ethyl Ethyl Citrate, Ramie Oil, and Different Percentages of this Paper Size Sugawa Shigou l, \ Un (('NS) Λ4 Regulations (210x 297 cm)) (Fill in this page again)

520298 A7 B7.-. --1 ----~~ ^. — * _ »-___ _-_ _ __________________ V. Description of the invention (13) Manufactured as follows: Coating small ¥ (IR beads) will Morphine sulfate (49.38% w / w), maleic acid (49.38% w / w), talc (0. 98 8% w / w) and sodium lauryl sulfate ( 0 · 2 5%) (aggregation active mixture) put into a rolling mixer to mix and honed into powder. Using a suitable binder, such as polyvinylpyrrolidone; a suitable organic acid or aqueous solution, such as isopropanol, is applied to the sugar-coated particles in a suitable liquid layer system. The synthesized immediate-release beads were dried at 55 ° C for 20 hours to obtain a moisture content of 3-6%. The dried beads are then sieved and the applicable portion is left for further processing. The formation of the coated beads comes from: Active mixture 7 5 · 3% Polyketene solution (solid) 6.1% Sugar-coated particles 1 8 · 6% Sustained release beads (SR beads) Before coating The coated beads (immediate release) are placed on a drying tray and exposed to the surrounding environment to balance the sex content of the coated beads. It contains 6.2% 5% EudragitRS (9 5% weight / weight) and Eudragit RL (5% weight / weight) 'and is dissolved in isoacetone / propan-16- 520298 A7 B7 5. Description of the invention (14) The coating solution is sprayed onto the liquefied layer and applied to the coating beads (IR). At the same time, talcum powder is added through the screw drill material supply device to prevent the material from agglomerating. The resulting product includes a core (coated beads) outer covering a speed-regulating polymer outer film, and each gram of coated beads contains 30.1 g of polymer outer film. Dry the coated beads in an oven at 3 5 ° C for 20 hours to remove the remaining solvent, and then place the outer film beads on a drying dish and expose to the week 1¾ environment 9 6 hours to reach the moisture balance. . As such, the materials used for the S R beads are coated beads 8 1 · 8%: Eudragit RS / RL coating solution (solid): 2.5% and talc: 15.7%. Fill the capsules (9 5% SR beads / 10% l R beads) Using a rolling mixer, reduce the morphine sulfate coated beads (10% weight / weight) and polymer outer film Beads (90% w / w of potency) were mixed. The above mixture beads were put into gelatin capsules to achieve a strength of 60 mg per capsule. Example 2 60 mg morphine capsules

i3 Xiao A Morphine Sulfate Capsule contains a mixture of two groups of SR beads and IR beads. It has the following composition: 1 Paper size Hong KW family sample (('NS) ^ Regulations (210X 297))- 17- 520298 A7 B7 V. Invention i See 15 Ingredients mg / capsule mg / g 1 Active substance morphine sulfate 60 309.6 Adjuvant sugar ball 30 154.8 Trans-butenedioic acid 60 309.6 Talc powder 29.1 150.2 Sodium lauryl sulfate 0.30 1.5 Polyvinylpyrrolidone (Kollidon 30) 9.8 50.6 Amino methacrylate copolymer type A (Eudragit RL) 0.22 1.1 Amino methacrylate copolymer type B (Eudragit RS) 4.15 21.4 Diethyl phthalate 0.22 1.1 Isopropanol — — Acetone + — — Read first and read the precautions before writing this page. U Βη 消 ίί * Used in the processing process, the final product appears only in trace quantities. Manufactured as follows: \ The coating beads are prepared as in Example 1 Coated beads. Continuous release beads (SR beads) Prepare two SR components. The SR component 1 is used in Example 18-520298 A7 V. Description of the invention (16) 1 45% is poured into the capsule. The preparation method of the second SR composition can be compared with the preparation method of the first SR. However, there are several differences below! 1 · The polymer coating solution contains 10% plasticizer (diethyl phthalate). Solution formulation (solid main component)

Eudragit RS 8 6-3 6%

Eudragit RL 4.55% diethyl phthalate 9.09% and 2. Place the coated beads in an oven and bake at 5 5 ° C for 20 hours to remove residual solvent, and then place on a drying pan and expose to the surrounding environment 9 6 + Riji & reach moisture balance. As such, used in S beads: 8 1 · 6%;

: 1 5 · 7%. _ · 2 · 7% and talc: 1 into a capsule (4 5% and 1 SR composition;

s R composition; and 10% IR 5% and other lf®SR composition; 4 5% second >% 蒌 毚 / weight) 0 weight 笾 / weight) and 1 / m) such as Fan Yifeng every Capsules contain morphine sulfate-coated beads (10% of the potency _, the first SR component bead (45% of the potency reads the second SR component bead (45% of the potency) / The method of Example 1 was mixed and poured into gelatin capsules to achieve a medicinal strength of 60 mg. -19- This paper is a standard ((, NS) regulation (210X 297 male f)

I 520298 A7 B7 V. Description of the invention (17) Example 3 60 mg of morphine sulfate, capsules mg / capsule mg / g 1 active morphine sulfate 60 310.0 adjuvant sugar ball 30 155.0 trans-butenedioic acid 60 310.0 Talc powder 29.1 150.3 Sodium lauryl sulfate 0.30 1.5 Polyvinylpyrrolidone (Kollidon 30) 9.8 50.6 Amino methacrylate copolymer type A (Eudragit RL) 0.22 1.1 Amino methacrylate copolymer type B (Eudragit RS) 4.15 21.4 Iso Propanol $ 1 — Acetone # 1 — Read First Read Back

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13 A + was used in the process, and only a small amount of the final product was produced as follows: Coated beads (IR beads) 'The coated beads were prepared in the same manner as in Example 1. Sustained Release Recipe Beads (SR beads) Prepare two sustained release components. s R component 1 (formulation effect -20- 520298 A7 V. Description of the invention (22 Table 3: Details of the processing of morphine sulfate SR beads # Coating beads Bead Eudragit RL 12.5 Eudragit RS 12.5 Amount of isopropanol talc ( Kg) 0.500 0.010 0.190 0.200 0.150 Coating solution Eudragit RS 1 2.5: Eudragit RL12.5 is 95: 5; content is 6.25% w / w dissolved in isopropanol Solution flow rate g / TC 6 Talc powder g / TC 4 _Outer membrane accumulation 50% 75% 100% Coating polymer mg / g 18.8 mg / g 28.1 mg / g 3? · 5 mg / g / IR Coating solution weight (kg 0.200 0.125 0.125 talc powder weight (kg) 0.150 0.100 0.100 Drying temperature ° C 50 50 50 Time (hours) 22 20.67 1ί Read the precautions before writing this page on iA) Order / 297g f) 25- 520298 A7 B7 V. The description of the invention (25) is 硏To investigate the effect of food on the bioavailability of the formulation of the present invention, 12 male subjects (18 to 37 sides) weighing between 60 and 94 kilograms were fed and fasted. Give a film similar to 100% of the weight of the target 60 mg morphine sulfate formulation of polymer SR beads / coated bead formula capsules. The interval between treatments was 7 days as a scoop. During each treatment period, subjects were required to fast overnight before the dose was given. At least 10 hours, and the fasting condition treatment group fasted 4 hours after dosing. Subjects receiving the drug under the feeding condition received a standard high-fat breakfast 30 minutes before the dose, and the breakfast was complete Give the dose within 5 minutes after the end. Collect 7 ml of venous blood samples at the following times: 0 (pre-dose), 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 16 After 18, 20, 24, 30, and 36 hours of administration, the concentrations of morphine and its metabolites (3-glucuronic acid compound and 6-glucuronic acid compound) in plasma were measured by liquid chromatography. As a result, no significant food effect was observed, and the feeding / fasting treatment ratio 値 was AUC (0-36) was 0 · 95, AUC (inf) was 0 · 9, and the original compound Cmax was 1 · 〇 4. ifi 先 I Reading Bupi i || --Note

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Example 5 60 mg of morphine sulfate capsules Morphine sulfate capsules are manufactured as follows: Anti-fc coated beads (IR beads) As in the procedure of Example 4, the coated beads are made of the following components: -28- 520298 A7 V. Description of the invention (28) Formulation range of B7 ingredients (60 mg capsules) mg / g 1 morphine sulfate 60 281-346 sugar balls (sugar-containing granules) 30 141-173 trans-butenedioic acid 60 281- 346 Talc powder 14-41 80-193 sodium lauryl sulfate 0.30 1.4-1.7 polyvinylpyrrolidone 7-15 36-85 (Kollidon 30) aminomethacrylate copolymer type A 0.1-0.3 0.6-1.5 (Eudragit RL) ammonia Methacrylate copolymer type B 1.9-5.9 10.9-27.9 (Eudragit RS) Isopropanol # 1 — Acetone $ — — — Only used in the process, and only a small amount of reading and reading should be followed.

Formulation B Formulation B (unit strength of 60 mg capsules) contains a mixture of 90% sustained-release beads and 10% immediate-release beads a. All other intensities are proportional to the figures cited. This paper scales this state vl KK Heart Right 彳 (('NS) Λ4 Regulation (210X 297 ^ f) -31- 520298 Parts s Xiao A A India A7 V. Description of the invention (29) Component J Unit formula (60 mg capsules ) Formulation range mg / g morphine sulfate 60 288-349 sugar spheres (sugar-containing granules) 30 144-175 trans-butenedioic acid 60 288-349 talc 13-37 73-179 sodium lauryl sulfate 0.30 1.4-1.7 Polyvinylpyrrolidone 7-15 36-86 (Kollidon 30) Aminomethacrylate copolymer type A 0.1-0.3 0.5-1.4 (Eudragit RL) Aminomethacrylate copolymer type B 1.7-5.4 9.8-25.8 (Eudragit RS ) Isopropanol # a — acetone $ — —

$ Only used in the process, and only a small amount of formula C Formula C (60 mg capsule unit dose strong special) contains 90% as the active agent of sustained release beads, and 10% is applied to the sustained The immediate release portion of the active is released on the bead. Dimensions of this paper.) 彳 H. 1¾¾¾. Sample (('NS) Λ4 gauge (210X297mm f) (邡 Read the precautions on the back before writing this page)

-32 · 520298 R beads) it eliminate /, \\ A7 B7 V. Description of the invention 30 groups of ingredients unit formula range I (60 mg capsules) mg / g morphine sulfate 60 292-355 sugar balls (sugar granules) 27 131-160 trans-butenedioic acid 60 292-355 talc 13-37 74-182 sodium lauryl sulfate 0.30 1.5-1.8 polyvinylpyrrolidone 7-15 37-87 (Kollidon 30) aminomethacrylate copolymer Type A 0.1-0.3 0.5-1.4 (Eudragit RL) Amino methacrylate copolymer Type B 1.7-5.4 10-26.1 (Eudragit RS) Isopropanol # — — Acetone + — — Only used in processing and only Appears trace coating beads using polyvinylpyrrolidone solution (weight / weight dissolved in isopropanol) as a binding agent, will there be morphine sulfate (49 · 383% weight / weight) ), Paper scraps of trans-butenedioic acid (49.383% w / w), talc (0.988% w / w), and sodium lauryl sulfate (0. 25% w / w) Sichuan small KK family sample 家 ((NS) Λ 4 gauge straw (210x 297 mm) (1A first read the back and pay attention Then write trivial items on this page)

-33- 34-520298 A7 ___________ B7 ------- — -----— '" —— »' — V. Description of the invention (31) The mixture is applied to sugar balls (0 · 5-0 · 6 mm). This treatment is performed using a liquid coating machine. The obtained IR beads were dried in an oven at 40 to 50 ° C > 30 to 60% relative humidity (R)) for 10 to 20 hours to remove residual solvents (isopropanol) and The moisture content is 3 -6%. The dried beads were sieved with sieve openings of 0.7 mm and 1.5 mm, and the portion between 0.7 mm and 1.5 mm was collected for further processing. The coated beads contain: Active mixture (as above) 7 5.3 9% Polyketene solution * (solid) 6% non-sugar particles (0 · 5-0 · 6 mm) 18.6% * Polyvinylpyrrolidone is allowed to be used in a range of 4 · 5% to 9 · 6% Release beads (SR beads) The polymer solution is preferably composed of Eudragit RS / Eudragit RL in a weight / weight 95: 5 ratio and isopropanol / acetone in a suitable solvent of 6.25% weight / weight solution and sprayed onto On a liquefied layer containing IR beads. At the same time, talc is added to prevent coagulation to improve the coating process. The coating material used to coat the beads is as follows: Coating solution 3 g / min / kg IR beads talc: 1.2 g / min / kg IR beads polymer after coating, at 40-50 ° C / 3 〇- 60 %% R Drying under the temperature for 1 〇-20 hours, execute until the desired separation speed is reached. Paper size Chengchuan Shi 1¾ (('N: S) Μ standard straw (2〗 〇χ 297 (Mm) (Read the first note and then write down this page)

520298 A7 ___________—__ ____——__— ΒΊ V. Description of the invention (33) Time (hours) 1 Schedule range% release 1 * No more than 2 5 2 No more than 2 5 3 No more than 2 5 4 5-30 6 15-40 9 2 5-60 1 2 3 5-70 2 4 ^ Not less than 7 0 Ν Μ = Not more than * NL Τ: Not less than (¾ Read the precautions on the back before writing this page j Example 7 A single dose study was conducted with healthy volunteers to compare the relative bioavailability of the ^ _2_JB_ 3 product with the reference product. This study was designed to study the pharmacokinetic properties of these 4 morphine formulations' Investigate the possibility of morphine absorption from these formulations in the lower gastrointestinal tract. The results show that the release sequence in vitro is also reflected in vivo. The products of Examples 1 and 2 show sustained release of morphine for more than 36 hours, and so on Confirmed absorption of morphine from the lower gastrointestinal tract. The relative availability of morphine from the slower products was> 100% compared to the reference product. The reference product used in this study is similar to the capsules in Example 4 SR beads / coating with a weight of 100% of the polymer outer film Bead Recipe -36- This paper rule waste test knife 丨 Ten 丨 Θ 丨 Today Decent Purine (('NS) Correction Straw (210 X 297 male f) 520298 Part-彳 而 U 5 Elimination ^ μ · ^' μ} ^: A7 B7 V. Description of the invention (40) Table 8: Pharmacokinetic parameters of the average morphine stationary state without conversion! (mean soil standard deviation, 12 subjects) Parameter treatment method A treatment method B treatment method CA Example 1 Example 2 Reference group Cmaxss 18.18 ± 7.00 17.22 Soil 6.37 19.66 Soil 4,49 tmax 7.83 ± 4.53 6 · 83 Soil 4.60 8.09 Soil 8.07 AUCss 268.28 ± 79.35 276.07 ± 58.40 278.80 ± 62.34 Tmin 16.00 Soil 10.23 · 10.00 Soil 11.25 8.00 ± 6.93 Thalf 22.02 ± 46.40 18.23 ± 29.59 10.22 ± 6.74 kel 0.02 ± 0.02 0.02 ± 0.03 0.09 ± 0.04 Cmin 6.86 ± 2.37 7.82 ± 2.64 " 6.61 ± 2.15 Cav 11.18 ± 3.31 11.50 soil 2.43 11.62 ± 2.60 Cmax / C24 2.87 Soil 2.85 2.31 ± 1.99 2.25 ± 0.82 Cm ax-Cmin 11.32 ± 7.09 9 · 40 ± 6 · 99 13.04 ± 3.85 Cmax / Cmin 3.12 Soil 2.75 2.57 ± 2.04 3.14 Soil 0.84 Cmax-Cmin / Cmin 2 · 12 ± 2 · 75 1.57 soil 2.04 2.14 ± 0.84 Cmax- Cmin / Cav 1. 05 soil 0 · 75 0.86 soil 0.73 1.14 soil 0.29 Fss 0.98 ± 0.18 1 · 01 ± 0.21 — (For the precautions for reading first, then write this page) ^ / n (ϋ — ^ ϋ —ϋ ml-^ 1 ϋϋ I -I--i-· —I— · 0 5Comparison of treatment method A with reference group · 0 5 Comparison of treatment method B with reference group a = 1 1 person who completed treatment method C Degree CNS) Λ4 fresh orange (210X 297 male f) -43 · -45-520298 A7 B7 V. Description of the invention (42) 50% peak plasma concentration exceeded the complete 24 hour dose period. Furthermore, the products of Examples 1 and 2 show that τ 7 5 s is greater than or equal to 12 hours, and the result shows β table 10. Table 1 0: Steady-state administration parameters Example 1 Example 2 Τ 5 0 2 4 2 4 Τ 7 5 17 15 Example 1 1 After comparing the formulas of Examples 1 and 2 with the available one-time morphine formula once a single dose Compare the formulations of Examples 1 and 2 with two other once-a-day products currently available in Germany (trademark MSTContinus Long) and products elsewhere (trademark kapanol). Treatment: A: Formula of Example 1, single dose, fasting (12 subjects) B: Formula of Example 2, single dose, fasting (12 subjects C ·· 20 mg kapanol capsules (X3), single dose, fasting (20 subjects) (Faulding) (reference group 1) D: 60 mg MSTContinus Long capsule, single dose, fasting (20 subjects) (Mundi Pharma) (Reference group 2). The paper size of this paper) 丨 Η. ΚΡϋϋ1 (('NS) / \ 4 梠 (210X 297 公 f) (Read the precautions on the back before filling in this page

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Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 520298 1 v-i A8 * i B8 ,, 丨 C8 _i. 一 —… — ”_ ^ _____ 々, Annex IV (A): 87 1 17680 Amendments to the scope of patent applications for Chinese patent applications Q1 11-8…, · Amendment 1 November 8, 1991 1 · An oral morphine multiparticulate formulation for patients, including water-soluble morphine and penetrant The core sustained release particles. The core is coated with an effective amount of an aminomethacrylate copolymer. The outer membrane of the speed-regulating polymer can make the patient's plasma morphine concentration reach an effective therapeutic amount for at least 24 hours. The penetrant is an organic acid. 2. The formulation according to item 1 of the patent application scope, in which a part or all of the sustained-release particles of the speed-regulating polymer outer film are further coated with an immediate-release outer film containing water-soluble morphine. 3. The formulation according to item 1 of the patent application, wherein one step includes a part of the sustained-release particles containing a water-soluble morphine core. 4. The formulation according to any one of items 1 to 3 of the scope of patent application, including at least two kinds of sustained-release particles with different in vitro dissolution profiles. 5 · As stated in the patent 轫 轫 轫 中 1-3 of any one of the ~ ~ * formulations, morphine is released within 20 hours or more than 20 hours after a single dose in vivo, making plasma morphine Concentration · A plasma concentration peak of 50% or more. 6 • If the formulation of item 5 of the patent application scope, the period is 24 hours or more. 7 · If the application item in the scope of the patent application is No. 5, the period is the paper size applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling this page) 520298 8 8 8 8 ABCD " ττ, patent application for 30 hours or more. (Please read the precautions on the back before filling out this page) 8 · If the formulation of any of the items 1 to 3 of the scope of patent application, release a single dose in vivo within 6 hours or more than 6 hours Morphine peaks plasma concentrations of morphine equal to or greater than 75%. 9 _If the formulation in the scope of patent application item 8, the period is 12 hours or more. 10. The formulation according to item 8 of the scope of patent application, wherein the period is 18 hours or more. 1 1 · If the formulation according to any one of item 113 of the patent application scope, release morphine in a steady state in vivo, so that the plasma morphine concentration is equal to or greater than 50%. The peak plasma concentration exceeds 24 hours during the dose period. . 1 2 · If the formulation according to any one of the claims 1 to 3 of the scope of patent application, release morphine in a stable state in vivo, so that the plasma morphine concentration is equal to or greater than 75% of the plasma during a dose period exceeding 24 hours The peak concentration is 12 hours or more. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1 3 · If the product is applied to any of the items 1 to 13 in the scope of patent application, it will provide a curve of the amount of dissolution in the aqueous medium, which will release about 3% after 1 hour- 25% water-soluble morphine, about 5%-35% water-soluble morphine released after 4 hours, about 2.5%-65% water-soluble morphine released after 9 hours, and about 35%-12 hours later 75% of water-soluble morphine, and about 24% of water-soluble morphine released after 24 hours. 1 4 · If the formulation of any one of item 113 of the scope of patent application, provide a curve of the amount of dissolution in the water medium, about 1 hour after the release of this paper, the Chinese national standard (CNS) Α4 specifications (210X 297 public funds) _ 2 _ 520 298 A8 B8 C8 D8, patent application range 10%-15% water-soluble morphine, about 15%-30% water-soluble morphine will be released after 4 hours, about 9 hours after release 35%-water-soluble morphine, about 45%-65% of morphine released after 12 hours, and about 80% of water solubility released after 24 hours. Sex morphine. The formulation of any one of clauses, wherein more than 80% of the formulation consists of sustained release particles. 1 6 · The formulation as described in any one of the claims 1 to 3 of the scope of the application, propionic acid, wherein the speed-regulating polymer outer film contains amino methacrylic acid in a ratio of 5: 9 5 as described in USP / NF Ester copolymer type A and aminomethacrylate copolymer type B. 7. The formulation according to item 1 of the scope of patent application, wherein the organic is selected from the group consisting of fumaric acid, adipic acid, ascorbic acid, citric acid, tartaric acid, lactic acid, malic acid or succinic acid. 18 • The formulation according to item 17 in the scope of patent application, wherein the organic acid is fumaric acid. For example, the proportion of the water-soluble morphine and penetrant in any of the items 1 to 3 in the scope of the patent application is in the printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Core Economy 20. The water-soluble morphine in the formulation according to any one of 3 items is morphine sulfate or a hydrate thereof. 2 1 · The formulation according to item 1 of the scope of patent application has a moisture content of about 3-6% by weight. .If any one of the scope of the patent application, the core of the sustained-release particles is coated with the compound of the speed-regulating polymer compound outer film (Please read the precautions on the back before filling this page) ^ 20298 A8 B8 C8 D8, before the scope of patent application ‘First balance with the surrounding environment or dry under wet conditions to get a moisture content of about 3-6%. 2 3. The sustained-release particles in the formulation according to any one of claims 1 to 13 of the scope of the patent application, after being coated with a speed-regulating polymer outer film, 'at a temperature of 4 0-50 ° C and 3 0-6 Dry at 0% relative humidity. 2 4 · The formulation according to any one of the claims 1 to 3 of the patent application 'contains 10 mg to 200 mg of morphine sulfate or an equivalent amount of water-soluble morphine. 2 5 · The formulation according to any one of the claims 1 to 3 of the scope of patent application ′ is contained in a capsule. (Please read the precautions on the back before filling out this page} Printed by the Consumers and Cooperatives of the Ministry of Economic Affairs and the Ministry of Economic Affairs and Intellectual Property, printed sheet-paper quasi-standard bidder i. 87117680 Patent Application Chinese Schematic Correction Page 1 9U 0 sl · KH 8L 96 L -_-_-_- ^ §.0 .§04 -§ · inch §.9_ Leak 蜃 §.0- oocm § · Η §m §m rn