CN103933003A - Fentanyl controlled release tablet, and preparation method thereof - Google Patents
Fentanyl controlled release tablet, and preparation method thereof Download PDFInfo
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- CN103933003A CN103933003A CN201410064350.4A CN201410064350A CN103933003A CN 103933003 A CN103933003 A CN 103933003A CN 201410064350 A CN201410064350 A CN 201410064350A CN 103933003 A CN103933003 A CN 103933003A
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- fentanyl
- controlled release
- release tablet
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Abstract
The invention belongs to the technical field of medicine, and discloses a fentanyl controlled release tablet used for relieving moderate and severe pain, and a preparation method thereof. The fentanyl controlled release tablet is a controlled release tablet, and is capable of releasing medicine slowly at a constant speed or close to a constant speed in water or other specified mediums.
Description
Invention field
The present invention relates to chemical pharmacy field, be specifically related to a kind of fentanyl controlled release tablet and preparation method thereof.
Background of invention
A pain of Japan in 2004 adjusts Check to show, chronic pain patient is suffered from by Japan nearly 1,700 ten thousand, satisfied although 88% pain patients represents doctor, only has 23% patient to please oneself to the alleviation degree of pain.In Japan, also generally do not reach " pain is medicable " common recognition, in doctor, also lack the common recognition of " must treat pain ".The Huang Yuguang of China teaches the tune Check result of carrying out before 4 years similarly.Not only in Asia, all there is identical problem in the whole world in fact, and pain does not obtain fine control.
In recent years, one of progress of pain therapy aspect was that oneself is known WHO three step by numerous doctors.WHO recommends, if effectively pain relieving of on-steroidal AID (NSAIDs) can add with a kind of weak opioid drug, also can apply the compound formulation of NSAIDs and weak opioid drug.But no matter be to strengthen NSAIDs dosage, or low dose of NSAIDs prolonged application, all can there is coagulation disorders or gastrointestinal side effect in patient.Therefore, there is the patient of contraindication for application NSAIDs, can directly use the opioid drug in the second ladder, from low dose, can reach same analgesic effect, and there is no the side effect of NSAIDs.
Fentanyl and citric acid fentanyl are synthetic opiates narcotic-based painkillers, and the analgesic activity effect that has proved it in animal experiment is approximately 200 times of morphine.At present, for commercially available the obtaining of storage type durative action preparation of containing fentanyl of percutaneous absorption type type, the pain causing for alleviating cancer, described preparation can actually keep fentanyl blood concentration M to 72 hour at effect level.
But, the shortcoming that these that absorb for percutaneous store type durative action preparation is, after using, drug absorption is quite slow, and only after initial application, after 12 to M hours, blood concentration reaches effect level, therefore, they can not produce analgesic effect at once, and reason is because they are for storing type preparation, they have fluid leaks problem, and they are very strong to using damage zest owing to containing ethanol.
Up to the present, attempted manufacturing the matrix type patch preparations absorbing for percutaneous, as the means that overcome the above problems.For example, the preparation commercialization that uses the percutaneous of acrylic adhesives to absorb.But the general drug release of acrylic adhesives is poor, cause following problem, only have the content by increasing main medicine just can reach required drug release level (patent documentation 1).Main medicament contg increase causes other problem, for example the remaining fentanyl problem in preparation in the problem of main drug crystallization between the storage life and after using.
On the other hand, although also openly wherein use the patch that contain fentanyl of styrene isoprene styrene block copolymer (SIS) (being abbreviated as " SIS ") as main matrix (based on the preparation of SIS) in patent documentation 2 and 3 later.
[patent document 1] Japanese patent publication (Tokuhyo) A2004-524336
[patent document 2] WO2003/070228
[patent document 3] Japanese patent publication A2008-273865.
Chinese Pharmacopoeia (version in 2005) has recorded fentanyl patch, transdermal patch and paster.The present invention by repetition test, obtains fentanyl controlled release tablet of the present invention, safety aspect, and patient feels sick, vomiting, constipation, dizzy and calm incidence rate are all lower, does not exceed 4%.Therefore applicant thinks, effectively alleviating pain of short-term or prolonged application fentanyl controlled release tablet 5mg/ days, in the lenitive while, patients ' life quality also can be improved significantly, oral fentanyl controlled release tablet can effectively be treated chronic pain, patient tolerability is better.
Fentanyl controlled release tablet provided by the invention, significantly reduction of patient pain, processing technology is simple, and the quality of the pharmaceutical preparations is reliable and stable.
Summary of the invention
The invention provides a kind of new fentanyl controlled release tablet, significantly reduction of patient pain, processing technology is simple, and the quality of the pharmaceutical preparations is reliable and stable.
On the one hand, the invention provides a kind of fentanyl controlled release tablet, wherein, this controlled release tablet is the tablet of making taking fentanyl as principal agent, and every contains fentanyl 0.05mg～5mg.
Some embodiments therein, fentanyl controlled release tablet of the present invention, wherein, this controlled release tablet constant speed or approach the release medicine of constant speed lentamente in water or in the release medium of regulation.
Some embodiments therein, fentanyl controlled release tablet of the present invention, wherein, the preparation of tablet is not limited to adopt direct compression or the rear tabletting of granulating, and this controlled release tablet is made up of following component:
The prescription of coating solution
Some embodiments therein, fentanyl controlled release tablet of the present invention, wherein, described filler is one or more in dextrin, starch, microcrystalline Cellulose or lactose; Plasticizer is one or more in polyethylene, phthalic acid dibutyl ester; Binding agent is 70%pvp ethanol; Solubilizing agent is cellulose acetate; Emulsifying agent is polysorbate-80.
Some embodiments therein, fentanyl controlled release tablet of the present invention, wherein, described filler: plasticizer: binding agent: solubilizing agent: emulsifying agent is l:0.02～0.5:0.3～5:0.01～1.5:0.01～0.5.
In other embodiments, fentanyl controlled release tablet of the present invention, wherein, one of prescription of this controlled release tablet is:
The prescription of coating solution
On the other hand, the invention provides the preparation method of fentanyl controlled release tablet of the present invention, it comprises the following steps: get fentanyl, and dextrin, polyethylene mixes, and granulates with 70%pvp ethanol, is dried granulate, tabletting.Get cellulose acetate, polysorbate-80, phthalic acid dibutyl ester is appropriate, dissolves and joins to obtain coating solution with 90% ethanol-acetone mixed solvent 1000ml.Coating to every coating tablets layer is heavily 8.5～9mg.Product inspection, coating.
Excipient of the present invention comprises, but be not limited to, ion-exchanger, aluminum, aluminium stearate, lecithin, serum albumin, as human albumin, buffer substance is as phosphate, glycine, sorbic acid, potassium sorbate, the partial glycerol ester admixture of saturated vegetable fatty acid, water, salt or electrolyte, as protamine sulfate, sodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloid silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymer, lanoline, sugar, as lactose, dextrose plus saccharose, starch is as corn starch and potato starch, the derivant of cellulose and it is as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, natural gum powder, Fructus Hordei Germinatus, gelatin, Pulvis Talci, adjuvant is as cocoa butter and suppository wax, oily as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum Sesami, olive oil, Semen Maydis oil and Oleum Glycines, glycols compound, as propylene glycol and Polyethylene Glycol, esters is as ethyl oleate and ethyl laurate, agar, buffer agent is as magnesium hydroxide and aluminium hydroxide, alginic acid, pyrogen-free water, Deng oozing salt, Lin Ge (family name) solution, ethanol, phosphate buffer solution, and other nontoxic proper lubrication agent are as sodium laurylsulfate and magnesium stearate, coloring agent, releasing agent, coating dress material, sweeting agent, flavoring agent and spice, antiseptic and antioxidant.
Pharmaceutical composition of the present invention can also optionally contain one or more diluent.The example of diluent comprises mannitol, sorbitol, biphosphate calcium dihydrate, microcrystalline Cellulose and efflorescence cellulose.Preferred diluent is microcrystalline Cellulose.Microcrystalline Cellulose can be obtained from several suppliers, comprises Avicel PH101, Avicel PH102, Avicel PH103, Avicel PH105 and Avicel PH200 that FMC Corporation manufactures.
Pharmaceutical composition of the present invention can also optionally contain disintegrating agent.Disintegrating agent can be the one in several modified starches, modified cellulose polymer or polycarboxylic acids, such as crosslinked Carboxymethyl cellulose sodium, Explotab, polacrilin potassium and calcium carboxymethylcellulose (CMCCalcium).In one embodiment, disintegrating agent is croscarmellose sodium.Croscarmellose sodium NF type A obtains with trade name " Ac-di-sol " on market.
Pharmaceutical composition of the present invention can also optionally contain one or more surfactants or wetting agent.Surfactant can be anion, cation or neutral surface active agent.Anion surfactant comprises sodium lauryl sulfate, dodecyl sodium sulfate, oleyl sodium sulfate and the sodium laurate mixing with stearate and Talcum.Cationic surfactant comprises benzalkonium chloride and alkyl trimethyl ammonium bromide.Neutral surface active agent comprises glycerol list olein, polyoxyethylene sorbitan fatty acid ester, polyvinyl alcohol and anhydro sorbitol fat.The embodiment of wetting agent comprises poloxamer, polyoxyethylene alkyl ether, castor oil derivatives and polyoxyethylene 8 stearate fat.
The present invention can also optionally join antioxidant in preparation, thereby gives its chemical stability.Antioxidant is selected from the extract of a-tocopherol, Y-tocopherol, S-tocopherol, tocopherol enrichment natural origin, sodium or calcium salt, the Vitamin C acyl cetylate of L-AA and it, amass wealth by heavy taxation propyl propionate, amass wealth by heavy taxation misery ester, amass wealth by heavy taxation sour dodecyl ester, Yoshinox BHT (BHT) and butylated hydroxyanisol (BHA).In one embodiment, antioxidant is BHT or BHA.
The preferred dosage form of drug composition of the present invention is the tablet of preparing by compression method.Described tablet can carry out film with the mixture such as hydroxypropyl cellulose and hydroxypropyl emthylcellulose, contains titanium dioxide and/or other coloring agent, such as ferrum oxide, dyestuff and Se Dian in this mixture; The mixture of polyvinyl alcohol (PVA) and Polyethylene Glycol (PEG), contains titanium dioxide and/or other coloring agent, such as ferrum oxide, dyestuff and Se Dian; Or any other suitable instant-free coating agent.Coating provides taste masked and other stability to final tablet.What commercially available film provided for Colorcon is preparation mixture of powders
The present invention can also add sweeting agent and/or fumet.
Detailed description of the invention
Further explain the present invention below in conjunction with embodiment, but embodiment does not limit in any form to the present invention.
A kind of fentanyl controlled release tablet of the present invention is made up of following component:
The prescription of coating solution
A kind of fentanyl controlled release tablet of the present invention is achieved through the following technical solutions:
Get fentanyl, dextrin, polyethylene mixes, with 70./。Pvp ethanol is granulated, dry, granulate, tabletting.Get cellulose acetate, polysorbate-80, phthalic acid dibutyl ester is appropriate, dissolves and joins to obtain coating solution with 90% ethanol-acetone mixed solvent 1000ml.Coating to every coating tablets layer is heavily 1.0～5mg.Product inspection, coating.
A kind of fentanyl controlled release tablet that the present invention obtains has that method is simple, good stability, feature that quality is high.
Embodiment 1: 1000 of specifications
Prescription:
The prescription of coating solution
Method for making:
Get fentanyl, dextrin, polyethylene mixes, and granulates with 70%pvp ethanol, is dried granulate, tabletting.Get cellulose acetate, polysorbate-80, phthalic acid dibutyl ester is appropriate, dissolves and joins to obtain coating solution with 90% ethanol-acetone mixed solvent 1000ml.Coating to every coating tablets layer is heavily 1.0～5mg.Product inspection, coating.Embodiment 2:
1000 of specifications
Prescription:
The prescription of coating solution
Method for making:
Get fentanyl, dextrin, polyethylene mixes, and granulates with 70%pvp ethanol, is dried granulate, tabletting.Get cellulose acetate, polysorbate-80, phthalic acid dibutyl ester is appropriate, dissolves and joins to obtain coating solution with 90% ethanol-acetone mixed solvent 1000ml.Coating to every coating tablets layer is heavily 1～5mg.Product inspection, coating.
Embodiment 3:
1000 of specifications
Prescription:
The prescription of coating solution
Method for making:
Get fentanyl, dextrin, polyethylene mixes, and granulates with 70%pvp ethanol, is dried granulate, tabletting.Get cellulose acetate, polysorbate-80, phthalic acid dibutyl ester is appropriate, dissolves and joins to obtain coating solution with 90% ethanol-acetone mixed solvent 1000ml.Coating to every coating tablets layer is heavily 1～5mg.Product inspection, coating.
Fentanyl controlled release tablet good stability of the present invention, quality is high, evident in efficacy, untoward reaction is little, the fentanyl controlled release tablet that application said method makes constant speed or approach the release medicine of constant speed lentamente in water or in the release medium of regulation.
Biological activity test
Clinical practice
1. cancer pain field
Remifentanil controlled release tablet of the present invention is assessed for the efficacy and saferry of chronic cancer pain and non-cancer pain adult patient, has evaluated respectively the alleviation situation of medication 3～4 weeks and 6 months later pain.30 routine patients' curative effect evaluation is shown, compared with before application fentanyl controlled release tablet, medication first stage (l week), second stage (3～4 weeks) and after 6 months, the overall pain intensity of patient, cancerous pain, neuropathic pain and musculoskeletal pain intensity are all the decline of carrying out property.General curative effect and toleration to muscle skeleton pain patients are analyzed, within 6 months, Follow-up results shows, most patient's curative effects and toleration is evaluated as or very good, compared with before treatment, medication first stage and second stage, patient's general health, locomotor activity and sleep quality all have clear improvement.
2. non-cancer pain field
In non-Pain Treatment field, fentanyl controlled release tablet is mainly used in the pain that pain, peri-operation period and postoperative pain that surgery anesthesia, rheumatic/osteoarthritis pain, backache, postherpetic neuralgia, diabetic neuropathy cause and other reasons cause.Fentanyl accounts for 9.8% for the recipe quantity of cancer pain, accounts for 87.9% for the recipe quantity of non-cancer pain.
The present invention is at assessment fentanyl controlled release tablet Zhi Liao Zhong during through the curative effect of pathological pain, and employing need to be accepted the case load (NNT) of additional procedures as index of assessment of curative effect, and this index value is lower, shows that analgesic effect is better.Result demonstration, the therapeutic equivalence of fentanyl controlled release tablet and gabapentin is even better than gabapentin.
Calmness and analgesic activity that the present invention also anaesthetizes before operation for fentanyl controlled release tablet are simultaneously studied:
Case 1: female, 28 years old, just before giving birth cesarean, took this product in first 30 minutes in operation, and in operation process, patient is substantially painless, and operation is smoothly;
Case 2: man, 36 years old, kidney transfer operation, took this product in first 30 minutes in operation, and in operation process, patient is substantially painless, and operation is smoothly;
This product has following characteristics:
Fentanyl controlled release tablet is opiates oral analgesic, has safe, efficient and every 12 hours and takes the feature of 1 time.Fentanyl controlled release tablet has two-phase absorption mode: medicine discharges to impel medicine to absorb in early days (medicine plays a role in 1 hour) rapidly, while there is afterwards the absorption of a section longer to ensure the effective blood drug concentration in 12 hours.This fentanyl dosage form has reduced the number of times that patient takes medicine, needn't be because of the disrupted sleep of frequently taking medicine, and make patient there is good compliance to medicine, thereby be conducive to the control of pain.
Claims (7)
1. a fentanyl controlled release tablet, wherein, this controlled release tablet is the tablet of making taking fentanyl as principal agent, every contains fentanyl 0.05mg～5mg.
2. according to the described fentanyl controlled release tablet of claim 1, wherein, this controlled release tablet constant speed or approach the release medicine of constant speed lentamente in water or in the release medium of regulation.
3. according to the described fentanyl controlled release tablet of claim 1, wherein, the preparation of tablet is not limited to adopt direct compression or the rear tabletting of granulating, and this controlled release tablet is made up of following component:
The prescription of coating solution
4. according to the described fentanyl controlled release tablet of claim 3, wherein, described filler is one or more in dextrin, starch, microcrystalline Cellulose or lactose; Plasticizer is one or more in polyethylene, phthalic acid dibutyl ester; Binding agent is 70%pvp ethanol; Solubilizing agent is cellulose acetate; Emulsifying agent is polysorbate-80.
5. according to the described fentanyl controlled release tablet of claim 3, wherein, described filler: plasticizer: binding agent: solubilizing agent: emulsifying agent is l:0.02～0.5:0.3～5:0.01～1.5:0.01～0.5.
6. fentanyl controlled release tablet according to claim 3, wherein, one of prescription of this controlled release tablet is:
The prescription of coating solution
7. a preparation method for the fentanyl controlled release tablet described in claim 1-6 any one, it comprises the following steps: get fentanyl, dextrin, polyethylene mixes, and granulates with 70%pvp ethanol, is dried granulate, tabletting.Get cellulose acetate, polysorbate-80, phthalic acid dibutyl ester is appropriate, dissolves and joins to obtain coating solution with 90% ethanol-acetone mixed solvent 1000ml.Coating to every coating tablets layer is heavily 8.5～9mg.Product inspection, coating.
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| CN201410064350.4A CN103933003A (en) | 2014-02-25 | 2014-02-25 | Fentanyl controlled release tablet, and preparation method thereof |
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| CN201410064350.4A CN103933003A (en) | 2014-02-25 | 2014-02-25 | Fentanyl controlled release tablet, and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104000795A (en) * | 2014-06-03 | 2014-08-27 | 青岛市市立医院 | Diammonium glycyrrhizinate controlled release tablets and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101467977A (en) * | 2007-12-29 | 2009-07-01 | 北京琥珀光华医药科技开发有限公司 | Oxycodone controlled release tablets |
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- 2014-02-25 CN CN201410064350.4A patent/CN103933003A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101467977A (en) * | 2007-12-29 | 2009-07-01 | 北京琥珀光华医药科技开发有限公司 | Oxycodone controlled release tablets |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104000795A (en) * | 2014-06-03 | 2014-08-27 | 青岛市市立医院 | Diammonium glycyrrhizinate controlled release tablets and preparation method thereof |
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Application publication date: 20140723 |