TWI284043B - Ion-strength independent sustained release pharmaceutical formulation - Google Patents

Abstract

The present invention is related to an optionally coated pharmaceutical hydrophilic gel forming matrix formulation comprising one or more active substances and having a prolonged release of said one or more active substances upon exposure to gastrointestinal fluids, characterized in that said release is substantially ion-strength independent. The invention is further related to a method of preparing this formulation which can be used in the administration of active substances for the treatment of a large number of disorders.

Description

1284043 A7 B7 V. INSTRUCTIONS (1) The present invention relates to a pharmaceutical formulation having a substantially delayed release profile which is independent of the ionic strength of a dissolution medium such as a gastrointestinal digestive juice, and has a delayed release up to sixteen Hours of time. The dosage form combines one or more active materials with a hydrophilic polymeric carrier to result in a gel-forming masterbatch formulation. The hydrophilic gel-forming parent material preparation is a dosage form well known to control the dissolution performance of an active substance. The release of the active material begins to hydrate with the surface of the dosage form to form a gel structure. At the same time, the surfactant surfactant is dissolved in the dissolution medium. A stationary phase in which the dissolution medium continuously penetrates the gel structure to allow the gel to swell. The active substance is dissolved in the dissolution medium and transported to the outer layer of the gel. At the same time, the outer layer of the gel is dissolved. Finally, the release layer is not released due to a decrease in the concentration gradient of the dissolution medium in the formulation and the infiltrated dissolution medium. This type of machine belongs to prior art such as Manford Robinson, Chapter 14 of the second edition of Industrial Pharmaceutical Theory and Practice: "Continuous Action Formulation". The hydrophilic polymer used in the above formulation is mostly a polysaccharide carrier such as a cellulose derivative, hydroxypropyl decyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC). ), carboxymethyl cellulose (NaCMC) or a combination of such cellulose derivatives. These types of formulating agents are described in numerous patents and patent applications such as U.S. Patent No. 4,871,548 and EP-A-0,923,934. No. 4,871,548 discloses a controlled release dosage form comprising an active compound and at least one low viscosity cellulose ether in a mixture of a high viscosity cellulose ether. EP-A-0923934 discloses modified release masterbatch formulations for cefaclor and cephalexin, containing 5-35% different grades -4 - This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) 1284043 A7 , __ B7 V. INSTRUCTION DESCRIPTION (2) Hydrophilic polymer mixture in which the hydrophilic polymer comprises from about 0.1% to about 20% by weight of medium viscosity hydroxypropyl methylcellulose and about Ο· 〗 〖% to about 20% low viscosity hydroxypropyl cellulose. While the foregoing formulation is generally described as a sustained release formulation, such sustained release occurs only at the salt concentration of the dissolution medium, in other words, when the ionic strength is low. The release rate of the active substance from the aforementioned formulation is substantially affected by the ion intensity. High ionic strength may even lead to so-called dose dumping effects. In this case, the total amount of active substance is released in a very short time, which may result in an undesired and even dangerous high active substance blood concentration. High ionic strength often occurs after a meal. Since the patient often takes the drug after a meal, the formulation which is affected by the strength of the ion may cause an undesired rapid release of the active substance without a high risk of scheduled sustained release. W0 98/47491 describes a sustained release formulation in which the release control of the active substance is based on a combination of two so-called "smart" polymers having opposite wetting properties, one polymer exhibiting a strong hydrophobic tendency while the other polymer Shows a strong hydrophilic tendency. In such a formulation, the dose dumping effect can be prevented by the coating. It is an object of the present invention to provide a sustained release formulation which is substantially free of a dissolution medium which is generally a gastrointestinal digestive solution, even when the formulation is not coated. It is obvious to those skilled in the art that the formula also meets the normal physical and medical requirements of the industry. For example, the powder has good fluidity when the key is pressed. The crushing strength of the shrink key is up to the art *3 〇 Newton, and the friability is 10 to the compressive force. It is less than 1% at 40 kN, and the content is uniform and stable. It is further required that the formulating agent can be prepared using general formulating procedures and equipment, so that it is not necessary to use ______ -5- This paper scale is suitable for the price of @S家标准(CNS) Α4 specification (four) X tearing public love) " -- 1284043 A7 B7 Five invention description ( 3

A lot of investment costs. This object is achieved according to the invention via a pharmaceutical hydrophilic gel-forming masterbatch formulation which, when exposed to a gastrointestinal tract digestive juice, can release one or more active substances for a prolonged period of time, characterized in that the release is substantially Not affected by ionic strength. Long-term release is defined as the release of the active substance from the dosage form over a period of 45 minutes or more (suddenly). This period of time usually begins with the administration of the dosage form or begins with the beginning of the in-tube dissolution test (the moment the dosage form contacts the dissolution medium). The term "substantially unaffected by ionic strength" means that when the ionic strength (1) varies between 〇〇5 and 〇45 m/L, the release rate side plot of the active substance does not change significantly (according to the general section 711 · USP 24) , physical test and determination (10% soil content). The ionic strength (1) is defined as 1 = 1/2 CZi2, where c is the concentration of different ions in the solution, 'for their respective charge numbers (Chemical and Physical Surgery 71, 〇 & 乂 1 (111.1^(1〇, 2-18 pages, Boston, €11 (: Publishing Company, 1990-1991). Although the coating is not necessary to achieve ionic strength, the formulation may be coated with the coating material to achieve another predetermined effect. For example, masking or coloring is masked. Suitable coating materials are known in the art such as HPMC, acrylics, ethylcellulose (see Graham Cole, Ed., Pharmaceutical Coating Technology, London, Taylor &Francis; 1995). The resulting parent material has a lozenge dosage form or a multiparticulate dosage form, preferably containing at least two hydrophilic high viscosity fibrous history ether mixtures. Although hydrophobic polymeric ethers such as ethyl cellulose are present, generally there is no adverse effect on the release properties of the formulation. However, it is preferred that there is no such solid hydrophobic cellulose ether. The actual size of the paper is applicable to the SS standard (CNS) Ai^ (21Gx297 public) 1284043 A7 B7 V. Description of invention (4) Quality Hydrophobic The vegan ether indicates that the amount exceeds 20% of the total weight of the gel-forming polymer. Cellulose ether is well known in the art and can be obtained at a pharmaceutical grade with different average molecular weights, resulting in obtaining different viscosities of the cellulose ether solution. For the purposes of this patent application, the hydrophilic polymer is characterized by its viscosity in a 2% w/w aqueous solution divided into a low viscosity (less than about 1000 millipascals), a medium viscosity (about 1000 to about 10,000 millipascals), and High viscosity (approximately 10,000 millipascals). Hydrophobic hydroxypropyl methylcellulose polymers (HPMC's) that can be used in the present invention are available from Dow Chemical Company under the trade name Methocel® at different viscosity grades. And under the trade name Metolose® from New Vietnam Chemical Co., Ltd. Low viscosity polymers such as Messo E5®, Messo E-15LV®, Messo E50LV®, Messo K100LV ® and Messo F50LV8, their 2% aqueous solutions have viscosity 5, 15, 50, 100 and 50 millipascals at 25 ° C. The medium viscosity HPMC's are for example Messo E4M® and Messo K4M, 2 % aqueous solution has a viscosity of 4,000 millipascals at 25 ° C High-viscosity HPMC's are, for example, Messo K15M® and Messo K100M® with a 2% aqueous solution having a viscosity of 15,000 and 100,000 millipascals at 25 C. * Hydrophilic hydroxyethyl-based cellulose polymerizable in the present invention. The materials (HEC's) are available from AQUALON under different trade grades under the trade name "Natrosol®" and from Amerchol under the trade name Cellosize®. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1284043

V. Description of the invention (5 Low-viscosity polymer, for example, the cable L8 and the cable J@, the viscosity of the 2〇/❶ aqueous solution at 25 ° C is 1 〇亳 Baska and 20 MPa. The medium viscosity polymer is, for example, the same as G® and Nassau®, and its 2% aqueous solution = 25 ° C has a viscosity of 2 〇〇 MPa and 15 〇〇 MPa. For example, for the cable M8 and the cable HH@, the viscosity of the 2% aqueous solution at 25 C is 4 〇〇〇 MPa and 9 MPa, respectively. In a particular embodiment, the formulation comprises a mixture of high or medium viscosity hydroxypropyl methylcellulose (HPMC) and high or medium viscosity hydroxyethyl cellulose (HEC). High or medium viscosity HPMC with high or medium viscosity hEC The ratio is 1/〇·85 to 1/1.2, preferably new", more preferably 1/〇" to ^ 〇5 and most preferably 1/1. The formulation may optionally contain a low viscosity HPMC. The ratio of '鬲 or medium viscosity HPMC to low viscosity HPMC is 1/0.01 to 1/0.2 and preferably 1/0.01 to 1/〇", and more preferably 1/〇〇2 to 1/〇〇5. Surprisingly found that a formulation having the aforementioned composition is available In the preparation of a tablet, the release rate of the tablet is independent of the ionic strength of the normal range of the gastrointestinal digestive juice. The normal range is from 〇17 to 〇35 mol/L. In addition to being unaffected by the ionic strength, the formulation is formulated. The release control principle is also unaffected by the pH range of ρΗ=1·3 to ΡΗ=7·4. This means that the release rate of the active substance is not affected by the pH, in which case the release of the active substance is not limited by the solubility of the active substance. In other words, the difference in release enthalpy (expressed as a percentage) at a certain point in time is less than 2% of the indicated pH requirement in the entire pH range of 1.3 to 7.4 (refer to the Dissolution Specification section (1〇8〇-昤page), FIP solid oral product dissolution ~ test guide (final version, 19 9.5 years), drug information journal 19 9.6, 30, 1071-84 pages. -8- This paper scale applies to Chinese national standards ( CNS) A4 size (210X 297 mm) 1284043 A7 B7 V. Description of the invention (As a result of having the most desirable properties as a sustained release formulation, the formulation according to the invention can be used to treat a range of diseases requiring sustained release properties. Provisioning for sustained release deployment The active substance is an active substance for the treatment of central nervous system disorders including schizophrenia, episodic paroxysmal anxiety (EPA) disorders such as forced thinking and obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD). , phobia and panic disorder, severe depression, bipolar disorder, Parkinson's disease, generalized anxiety disorder, loneliness, delusions, multiple sclerosis, Alzheimer's disease/dementia and other neurodegenerative diseases, severe mental Hysteresis and difficulty in movement, such as Huntington's disease or Gilles dela Tourett's, anorexia, bulimia, stroke, addiction/dependency/thirst, sleep disorders, epilepsy, migraine; loss of attention/ Hyperactivity syndrome (ADHD); cardiovascular disease including heart failure, angina pectoris, arrhythmia, myocardial infarction, cardiac hypertrophy, hypotension, hypertension such as essential hypertension, renal hypertension or pulmonary hypertension, thrombosis, arteries Hardening 'cerebral vasospasm' subarachnoid hemorrhage, cerebral ischemia, cerebral infarction, peripheral vascular disease, Ray's disease, kidney disease such as kidney failure; blood Metabolic abnormalities; obesity; vomiting; gastrointestinal disorders including stimulating bowel syndrome (IBs), inflammatory bowel disease (IBD), gastroesophageal reflux disease (GERD), motility disorders, and delayed pregnancy such as postoperative or diabetic Gastric insufficiency and diabetic ulcers such as gastric ulcer; diarrhea; other diseases including pine disease; gynecological disorders, inflammation; infections such as bacterial, bacillary, protozoal and viral infections caused by special hiv〇 or HIV-2 Infection; pain; cancer sales; chemotherapy-induced injury; tumor entry, immune disorders; urinary retention; asthma; allergies; arthritis; benign prostate hypertrophy, · endotoxic shock; septicemia; -9 -

1284043

V. Description of the invention (7. The preferred formulation of the active substance is a biological substance such as FluvGxamine or Fusinoza (7) which can be used for the treatment of central nervous system disorders. Whether tedisamil or propanolol; or an active substance for the treatment of gynecological conditions, such as dydr〇gester〇ne, estradiol or total Yoke estrogen. The present invention is particularly useful for the active substance iron disamate, preferably sesquiterptoconate (N,N,-dicyclopropylmethyl_9,9_tetramethylene-3, a formulation of 7-diazabicyclo[3·31]oxime 5 chloro-antibutadiate. The compound is described in ΕΡα55〇383 and Us 5,324,732. The invention also relates to a method for preparing the aforementioned formulation Characterized by (1) a core comprising: a mixture comprising one or more active substances and a mixture of at least two hydrophilic high or medium viscosity cellulose ethers, obtained by compression to be substantially unaffected by ionic strength and substantially long term substantially Zero release of active substance; and (2) selection of the core The composition of the components HPMC, HEC, active substances, pigment chelates and slip agents are mixed in a suitable mixer. The powder mixture is mixed with stearyl decanoyl disodium in a suitable mixer. The active substance can be pre-granulated. The form of the agent is added to the powder mixture for compression. In addition, the powder mixture for tableting can be produced via a mixing procedure, followed by a (wet or dry) granulation process. A set of component mixtures using commercial equipment such as Courtoy® R0) Compressed into ingots, using a flow formulation such as colloidal cerium oxide and a lubricant such as talc, stearyl succinate or magnesium stearate. When finished, -10 - this paper size is applicable to China Standard (CNS) A4 size (210X 297 mm) 1284043 A7 B7 V. Description of invention (8) The hydrophilic cellulose content of the formulation is 15°/❶ to 99.5%, and the active substance content is from 0.1% to 80%. The range of flow regulators or lubricants is fixed to improve the flowability of the blister and to prevent the powder from sticking to the wall or punch of the stamper. The amount of the slip agent is 0.05% to 5% and preferably about 0.2%. About 5% to 5% Preferably, it is about 0.4%. Due to commercial factors, the powder mixture can be colored with 〇1% to 10% of the pigment conjugate. Typical pigment conjugates are commercially available, for example, under the trade name Opadry®. COLORCON®, Inc. All publications cited herein, including but not limited to, patents and patent applications, are hereby incorporated by reference in their entirety as if individually individually individually The examples are only intended to illustrate further details of the invention, and such examples are not intended to limit the scope of the invention. Example 1 - Preparation of a formulation which is not affected by ionic strength Example la. Summary preparation procedure First, colloidal cerium oxide was sieved. The sieve preferably has a mesh of 0.40 mm to 〇595 mm. In a suitable mixer, the active material is mixed with hydrophilic cellulose, colloidal cerium oxide, pigment chelates, and if desired, mixed mannitol. The mixer is preferably a South Male Mixer' granulator in the off position. Sodium stearyl-p-butyrate is sieved. The sieve preferably has a mesh of 0.40 mm to 595 mm. The powder mixture is compressed into a bond having a predetermined dimension. The compression device is preferably a rotating machine such as Korsch and Kutoy equipment. The tablet may optionally be coated with a water-soluble cellulose or a cellulose derivative, an ethyl cellulose or an aqueous suspension based on acrylic acid acrylate or an organic solvent, as needed. The coating process is preferably carried out on a perforated drum device or a device based on a fluidized bed technique. -11 -

1284043 A7 B7 V. INSTRUCTIONS (9) Table 1. Composition of uncoated ingots (core ingots) in milligrams/ingots. Contents of Fushi language sand: 2 mg/Acetaminophen : 2.2 mg / bond Fufoshamin maleate labeling content · · 100 mg / bond iron disaramide dihydrochloride labeled content: 100 mg / bond iron disamid sesquiterpene diphosphate Labeled content · · 150 mg / bond Fusinosa hydrochloride 2.18 nananana Assimifen na 2.19 nanana Fufoshamin maleate nana 100.00 nana Tidisham dihydrochloride nanoana- 124.4 na Iron disamid sesquicon naanana 240.0 HPMC K4M 69.63 69.63 17.00 125.2 81.0 HPMC E5 7.50 7.50 12.50 20.0 14.0 HEC HX250PH 69.63 69.63 17.00 125.2 81.0 Mannitol SD200 nana 100.00 nana Colloidal cerium oxide 0.30 0.30 0.50 1.60 4.0 Pigment composition PB23015 0.15 0.15 na 0.40 na Sodium stearyl reverse succinate 0.60 0.60 3.00 3.20 5.0 Total weight (mg) 150.00 150.00 250.00 400.00 425.00 na: Not applicable -12- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1284043 A7 B7 V. Description of invention (1〇) Table 2. Properties of several compositions Key properties: Fushi language sand labeling content: 2 mg / drum assimivirin labeling content: 2.2 mg / ingot fosfosin maleate labeling content · · 100 mg / ingot iron disaramide two salt Acid salt labeling content: 100 mg / ingot iron disamid sesquicon acid salt labeled content · 150 mg / spinner dimension (mm) 5.5 X 11.0 mm special shape 7.0 mm round 8.0 mm round · 8.0 X 15.0 mm oval 8.0 X 15.0 mm oval lozenge weight (mg) 150 150 _ 275 400 425 crushing strength (Newton) 83 75 144 71 90 Fragility (%) Not determined Not determined Not determined 0.4 0.05 Release Side Drawing Table 4 Table 4 Table 4 Table 4 Table 4 Example lb. Release Properties of Several Formulations The active substance is released from the hydrophilic master tablet in USP unit 2 for blade rotation at 50 rpm, and the tablet is dissolved in USP. The buffer medium pH 6.8 is 〇.〇5 molar concentration (Μ), 0·17 Μ and 0·34 Μ is made of disodium hydrogen phosphate 2 hydrate and citric acid monohydrate (labeled as codes F, G, and 分别, respectively). Or the tablet is placed in the semi-replacement of the dissolution medium 1 in the first part of the test (90 minutes) prepared from a 0.1% aqueous solution of hydrogenated hydrogen, and the second part of the test is adjusted to 0.2 using trisodium phosphate 12 hydrate in the second part of the test. M pH 6.8. In order to increase the ionic strength of the aqueous solution during the test, sodium chloride was added to the solution. 1 liter of the second part of the dissolved medium containing sodium vaporized gas is gram (dissolving medium A), 10 grams (dissolving medium - 13 - the paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1284043 A7 B7 V. INSTRUCTIONS (11) B), 15 g (dissolving medium C), 30 g (dissolving medium D1 and D2) and 50 g (dissolving medium E1 and E2). In the dissolution media B, C, D1 and E1, sodium chloride was only added to the second part of the test. In the dissolution media D2 and E2, 75% sodium hydride was added to the first part of the test and 25% to the second part. The release of the active substance was sampled at intervals of one hour for the first two hours, followed by a 16 hour period of sampling measurements every two hours during the test period. Samples were analyzed online using HPLC systems or UV spectroscopy. The release of the different active compounds from the formulation is shown in Tables 4a-4c. From the release profiles listed in Tables 4a-4c, it was concluded that the release of the active substance from the formulation according to the present invention is substantially independent of pH and ionic strength, with a difference in release enthalpy of less than 20%. Further conclusions were found that when the ionic strength was at a low pH (pH 1.2) and a higher ρΗ(ρΗ6·8), there was no difference in the release. Table 3. Dissolution medium overview Dissolution method Dissolving medium A Β C D1 D2 Ε1 Ε2 1) ρ Η 1.2 1.5 hours 750 ml 0.1 Μ hydrochloric acid added gasified steel (g) 22.5 37.5 2) pH 6.8 14.5 hours 250 ml 0.2 citric acid Trisodium 12 hydrate added sodium gasification (g) 0 10 15 30 7.5 50 12.5 Final dissolved medium ionic strength (mole / liter) 0.14 0.31 0.40 0.65 0.65 1.00 1.00 Dissolution method, a dissolution medium - FG Η pH 6.8 squaric acid Sodium hydrogenate 2 hydrate + citric acid 1 hydrate 0.05M 0.17M 0.34 离子 ionic strength (mole / liter) 0.11 0.38 0.77 . -14- This paper scale applies to China National Standard (CNS) Α 4 specifications (210 X 297 PCT) 1284043 A7 B7 V. INSTRUCTIONS (12) Table 4a. Release of several uncoated ingots as a function of time. Active substance release (%) Forchnosha labeling content: 2 mg/injection of acitamino Fen labeling content: 2.2 mg/infloxacin cis-butane bismuthate Labeling content: 100 mg/bond Dissolving medium AB D1 El FG Η ABC 0 hours 0 0 0 0 0 0 0 0 0 1 hour 20 18 20 18 21 15 25 22 22 22 2 hours 32 28 31 30 34" 29 38 3 6 36 35 6 hours 59 52 53 50 70 63' 70 67 66 64 16 hours 91 84 83 79 107 105 103 99 99 99 Table 4b. Release of several uncoated ingots as a function of time as a function of active substance release (% Iron dimethoate dihydrochloride labeled content: 100 mg / bond iron disamid sesquiterpene diphosphate salt content: 150 mg / bond dissolution medium ABCA D1 D2 El E2 0 hours 0 0 0 2 0 0 2 0 1 hour 32 32 33 20 18 20 20 21 2 hours 50 51 52 32 . 24 32 32. 33 6 hours 84 85 84 47 45 49 47 52 16 hours 92 94 93 79 75 76 75 81 -15- Paper scale Applicable to Chinese National Standard (CNS) A4 Specification (210 X 297 mm) 1284043 A7 B7 V. Description of Invention (13) Table 4c. Iron disamid sesquicarbonate uncoated in a single dissolution medium

Binding

Release of the active substance as a function of time (%) Tidimiramidol sesquiterpene dicarboxylate labeling content: 150 mg / indium dissolution medium 750 ml 0.1 Μ hydrochloric acid (pH 1.2) 750 ml 0.1 Μ hydrochloric acid + 250 ML 0.2 Trisodium sulphate 12 hydrate (pH 6.8) 0 hours 0 0 1 hour 20 13 2 hours 33 22 6 hours 64 48 16 hours 97 89 -16- This paper scale applies to China National Standard (CNS) A4 specifications ( 210 X 297 mm) This φ% application period is 90. 9. 19. Case No. 090123012 Category φκ%9 (The above are filled by this Council)

I2M041. A4 C4 Chinese Manual Replacement Page (December 95) Patent Specification I. Invention and continuous release of pharmaceutical products formulated by Aun Stone in Chinese without ionic strength English ION-STRENGTH INDEPENDENT SUSTAINED RELEASE PHARMACEUTICAL FORMULATION 1 Henry RM RM Gleason name HENRICUS RM GORISSEN 2. Hendrick W. Flylin HENDERIK W. FRIJLINK Nationality Helan -, inventor _ cake people live, residence in the Netherlands, the city of Visp, CJ Holland Road, No. 36 Name Dutch company Solvay Pharmaceutical Co., Ltd. (name) SOLVAY PHARMACEUTICALS BV Nationality Netherlands III, Applicant %SP) Representative name of M. Vijung M. VERHAGE -1 - CJ·Hendenland Road, Visp, Netherlands Packing paper size scales _ home scale (CNS) A4 specifications (21GX297 public 褒)

Claims (1)

Patent Application No. A Patent Application Replacement (April 1996) Patent Application Fan Park - a pharmaceutical hydrophilic gel-forming parent material preparation containing one or more active substances, and when exposed to The gastrointestinal digestive juice may prolong the release of the one or more active species, characterized in that the hydrophilic gel-forming parent material comprises at least two hydrophilic high viscosity or medium viscosity cellulose acid mixtures as carriers. And the release is substantially unaffected by ionic strength, wherein the formulation comprises high or medium viscosity hydroxypropyl methylcellulose (HPMC) and high or medium viscosity hydroxyethyl cellulose (HEC) in a ratio of HPMC/HEO1 /0.85-1/1.2, and optionally a low-viscosity HPMC' with a high or medium viscosity HPMC/low viscosity HPMC=l/〇.〇ll/〇.2 〇2· as claimed in the 丨A formulation according to the invention, characterized in that the formulation is coated. 3. The formulation according to claim 1 or 2, wherein the one or more active substances are selected from the group consisting of active substances for treating disorders of the central nervous system, including schizophrenia, onset Type of paroxysmal anxiety (EPA) conditions such as forced thinking and obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), phobia and panic disorder, severe depression, bipolar disorder, Parkinson's disease, generalized anxiety Obstacles 'lonely, delusional, multiple sclerosis, Alzheimer's disease/dementia and other neurodegenerative diseases, severe mental retardation and difficulty in movement, such as Huntington's disease or Gilles dela Tourett's, Anorexia, bulimia, stroke, addiction/dependency/thirst, sleep disorders, epilepsy, migraine; attention deficit/hyperactivity syndrome (ADHD); cardiovascular disease including heart failure, angina pectoris, arrhythmia, myocardial infarction, heart Hypertrophy, low 73840-960410.doc _ 】. This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1284043 Inter-blood pressure, such as essential hypertension, renal hypertension or high pulmonary hypertension, thromboarteriosclerosis, cerebral vasospasm, subarachnoid hemorrhage, cerebral infarction, peripheral vascular disease, Ray's disease, kidney disease, for example, 4 , lipid metabolism, f; obesity; vomiting; gastrointestinal disorders, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), gastroesophageal reflux disease (GERD) 'if dysfunction and gastric emptying Delayed conditions such as postoperative or diarrhea, diarrhea and diabetic ulcers such as gastric ulcer; diarrhea, other diseases including pine disease; gynecological disorders, inflammation; infections such as bacterial, fungal, protozoal and viral Sexual infections or infections caused by HIV_2; pain; cancer; chemotherapy for sudden injury; tumor invasion; immune disorders; urinary retention; asthma; allergies; arthritis; benign prostate hypertrophy, endotoxic shock; Diabetes complications. 4. The formulation according to claim 3, characterized in that the active substance is an active substance for treating a central nervous system disorder. 5. A formulation according to claim 4, characterized in that the active substance is a fluv〇xamine or flesin〇xan pharmaceutically acceptable salt. 6. The formulation according to item 5 of the patent application, characterized in that the active substance is an active substance for treating a cardiovascular condition. 7. A formulation according to claim 6 of the patent application, characterized in that the active substance is tedisamii or pp〇nran (pr〇pran〇1〇1) or a pharmaceutically acceptable salt thereof. 8. The formulation according to claim 7 of the patent application, characterized in that the active substance is iron disamitage sesquiterpuccinate (N,N,-dicyclopropylmethyl·9 73840-960410. Doc , 2. This paper scale applies to Chinese National Standard (CNS) Α 4 specifications (210χ 297 mm) 1284043 as B8 C8 Tetramethyl-3,7-diazabicyclo[3·31]pyrene 15 nitrogen antibutane salt). 9. The formulation according to item 3 of the patent application, characterized in that the active substance is an active substance for hormone replacement therapy. 10. The formulation according to claim 6 of the patent application, characterized in that the active substance is dydr0gesterone, estradiol or conjugated estrogen. 11. A method of preparing a formulation according to the scope of claim 2, characterized in that (1) a core comprising a mixture comprising one or more active substances and at least two hydrophilic high or medium viscosity cellulose ethers The mixture is compressed to obtain substantially no ionic strength and long-term substantially zero 羃 release of the active material; and (2) the core is selectively coated. 73840-960410.doc This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)