CN102228449B - Gastrodin chronopharmaceutical medicine delivery preparation - Google Patents

Gastrodin chronopharmaceutical medicine delivery preparation Download PDF

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CN102228449B
CN102228449B CN 201110175929 CN201110175929A CN102228449B CN 102228449 B CN102228449 B CN 102228449B CN 201110175929 CN201110175929 CN 201110175929 CN 201110175929 A CN201110175929 A CN 201110175929A CN 102228449 B CN102228449 B CN 102228449B
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gastrodin
chronopharmaceuticalmedicine
medicine delivery
delivery preparation
controlled release
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CN102228449A (en
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蔡铮
刘中秋
杨兆祥
黄娟
普俊学
龚耘
罗辉
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Kun Yao Group Plc
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Kunming Pharmaceutical Corp
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Abstract

The invention discloses a gastrodin chronopharmaceutical medicine delivery preparation. The preparation consists of a coating and a tablet core containing gastrodin, an inner layer of the coating is an isolated layer, and an outer layer of the coating is a controlled release layer, wherein the isolated layer is made of hydroxypropyl methylcellulose, and the weight of the isolated layer accounts for 10 to 20 percent of the weight of the tablet core; and the controlled release layer is made of film coating agent and plasticizer, the weight ratio of the film coating agent to the plasticizer is 1:(0.1-0.3), and the weight of the controlled release layer accounts for 5 to 15 percent of the weight of the tablet core. The gastrodin is easily soluble in water, so the preset time lag is achieved by increasing the weight of the isolated layer and the controlled release layer of the coating, so that the aim that the gastrodin is released after being taken for 4 to 6h is fulfilled. The preparation is applicable to insomniacs who suffer from insufficient sleep caused by early morning awakening, is easy to prepare, and can be industrially produced conveniently.

Description

A kind of Gastrodin chronopharmaceuticalmedicine medicine delivery preparation
Technical field
The present invention relates to field of pharmaceutical preparations, particularly a kind of Gastrodin chronopharmaceuticalmedicine medicine delivery preparation.
Background technology
Along with society people rhythm of life is accelerated, stress increases, and insomnia has become one of ubiquitous misery, and it may be modal clinical symptoms except pain.Not having enough sleep for a long time to cause the patient to feel tired daytime, and aprosexia affects physical and mental health and quality of life, severe patient even depression occurs.World Health Organization (WHO) was once investigated in 14 countries, and about 27% people has sleeping problems, and Japanese insomnia's sickness rate is 20%, and the U.S. is about 34%, and the sickness rate of China is also up to about 30%, and was year by year ascendant trend.There is approximately 20% insomniac can seek Drug therapy, so the also corresponding steady-state growth situation that is of hypnotic market.China's sedative hypnotic market sales revenue was about 65.82 hundred million yuan in 2008, increased by 17% on a year-on-year basis, still kept the rapid growth of dibit number.Estimate that according to the expert global Insomnia therapy medication market was expected to nearly one times of dilatation in 2017, up to 6,900,000,000 dollars.
Insomnia's clinical manifestation mainly contains three kinds: one, and difficulty falling asleep also claims " starting point insomnia ", is more common in youngster; Its two, the shallow dreaminess of sleeping can not be kept and sleep soundly, and is called " sleep continue difficulty insomnia ", how to be caused by overtired; Its three, early awakening, namely night sleeping very not difficult, but wake up early in morning, sleepy but can't fall asleep again still after waking up is called " terminal point insomnia ", and is in the majority with the old people.Hypnotic generally all is to take before sleep, in the body enough dose performance curative effects is arranged when to need in the sleep procedure guaranteeing, the selected medicine of dissimilar insomnias is also different.The difficulty falling asleep type, (0.5~3h) medicine is such as quinalbarbitone, clonazepam etc. often to select the half-life weak point; The shallow dream of sleeping is many types of, and can selecting the half-life, slightly long (6~8h) medicine is such as estazolam, zopiclone etc.; For the early awakening type, (12~15h) medicine is such as nitrodiazepam etc. then to need to select long half time.The life-time service hypnotic is prone to untoward reaction, produces the medicine of drug resistance or addiction, particularly long half time, has larger drug safety hidden danger.Therefore, at present still lack desirable medicine for the treatment of Early morning awakening disease clinically.
Gastrodine is the main active of rare Chinese medicine Rhizoma Gastrodiae, and chemistry 4-hydroxy benzenes-β by name-D-pyranglucoside has the pharmacological actions such as calmness, hypnosis, vertigo, is widely used in clinically having a headache, the treatment of the diseases such as insomnia, neurasthenia.For the disease that needs the Long-term taking medicine treatment, the safety of medicine is most important undoubtedly.Compare with similar drugs, the advantage of gastrodine is that toxicity is low, eliminates soon, and untoward reaction is little.Therefore, gastrodine is subject to the favor of extensive patients, is number four in the market share of sedative hypnotic at home, accounts for 10%, and the sales volume average growth rate per annum surpasses 50%.
Because the biological half-life of gastrodine is lacked (t 1/2=2.1h), be usually used at present the treatment of difficulty falling asleep type insomnia.If can use the medicine controlled releasing technology will eliminate soon, safe gastrodine is applied to the treatment of Early morning awakening disease, has undoubtedly preferably using value and market prospect.
Summary of the invention
The technical problem to be solved in the present invention is short for gastrodine biological half-life in the prior art, can't realize the regularly problem of administration, and a kind of Gastrodin chronopharmaceuticalmedicine medicine delivery preparation is provided.
In order to overcome the above problems, technical scheme provided by the present invention is:
Preparation of the present invention is comprised of coating and the label that contains gastrodine, the coating internal layer is sealing coat, skin is controlled release layer, wherein insolated layer materials is hypromellose, its weightening finish is 10%~20% of label weight, the controlled release layer material comprises the agent of film clothing and plasticizer, and its weight ratio is 1: 0.1~0.3, and its weightening finish is 5%~15% of label weight.
Preparation of the present invention does not discharge medicine immediately in the usefulness that is taken at bed time after the administration, after about 4-6 hour, close on the awake period in morning, and autompulse discharges contained gastrodine, the performance syngignoscism.
The present invention adopts the medicine controlled releasing technology, realizes the pulsatile administration of gastrodine.At first prepare the pastille label than easy disintegrating, then outside label, successively wrap sealing coat and controlled release layer clothing film, to regulate lag time.Because gastrodine is soluble in water, committed step of the present invention is to reach predetermined time lag by increasing the weight of sealing coat and controlled release layer coating, thereby realizes the regularly purpose of administration of gastrodine.
Sealing coat coating material used in the present invention is hypromellose.
Controlled release layer coating material used in the present invention comprises the agent of film clothing, porogen and plasticizer.Wherein the agent of film clothing is ethyl cellulose or cellulose acetate; Porogen is Polyethylene Glycol, hydroxypropyl cellulose or polyvidone; Plasticizer is triethyl citrate, diethyl phthalate or dibutyl sebacate, and the weight ratio of the agent of film clothing, porogen and plasticizer is 1: 0~0.25: 0.1~0.3.
Label of the present invention is comprised of gastrodine, disintegrating agent, filler, adhesive or lubricant.Wherein disintegrating agent is carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium or polyvinylpolypyrrolidone.Filler is one or more in microcrystalline Cellulose, lactose, starch or the pregelatinized Starch; Adhesive is one or more in polyvidone, starch slurry or the hypromellose; Lubricant be magnesium stearate, micropowder silica gel or talcous one or more.
The weight ratio of gastrodine, disintegrating agent and other pharmaceutic adjuvants is in the label of the present invention: 1: 0.1~0.5: 1~4.
Gastrodin chronopharmaceuticalmedicine medicine delivery preparation of the present invention can adopt conventional method for preparing tablet thereof to make.
As preferably, get gastrodine, filler and disintegrating agent fine powder (crossing 80 mesh sieves) mixing, add adhesive soft material processed, 14 or 16 mesh sieves are granulated, in 60 ℃ of dryings, 12 or 14 mesh sieve granulate add lubricant, mixing, tabletting (also can adopt direct powder compression), coating (wrap first sealing coat, wrap controlled release layer again) can obtain.
Major advantage of the present invention is as follows:
1) the present invention controls the release time lag of gastrodine by increasing the weight of sealing coat and controlled release layer coating, reaches the purpose of division of day and night administration;
2) Gastrodin chronopharmaceuticalmedicine medicine delivery preparation provided by the invention, biological half-life is short, and safe gastrodine is applied to the treatment of Early morning awakening disease, has enlarged the application of gastrodine in insomnia's treatment field.
Description of drawings
Fig. 1 is the release curve of Gastrodin chronopharmaceuticalmedicine medicine delivery preparation three batch samples.
The specific embodiment
The invention discloses a kind of Gastrodin chronopharmaceuticalmedicine medicine delivery preparation and application, those skilled in the art can use for reference this paper content, suitably improve technological parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are deemed to be included in the present invention.Method of the present invention and application are described by preferred embodiment, the related personnel obviously can change or suitably change and combination methods and applications as herein described within not breaking away from content of the present invention, spirit and scope, realizes and use the technology of the present invention.
Principle of the present invention is: general adult's the ortho sleep time is 7~8h, the early awakening patient generally can shift to an earlier date 2h, the administration of gastrodine oral administration absorbs rapidly, and peak reaching time of blood concentration is 0.8h, so the slowbreak time of Gastrodin chronopharmaceuticalmedicine medicine delivery preparation can be designed to 4~6h.Gastrodin chronopharmaceuticalmedicine medicine delivery preparation of the present invention, oral enter gastrointestinal tract after, moisture content in the Digestive system can see through semipermeable membrane and enter label, but owing to there is not the release duct, there is no at the beginning drug release, through after a while (4~6h), when the moisture content that infiltrates label is increased to a certain degree, cause that disintegrating agent expands, coating membrane is cracked, the tablet disintegrate becomes granule, and gastrodine discharges rapidly.The Gastrodin chronopharmaceuticalmedicine medicine delivery preparation drug release time of this design is not subjected to the impact of the factors such as Digestive system pH value, gastrointestinal peristalsis and food.
In order to make those skilled in the art understand better technical scheme of the present invention, the present invention is described in further detail below in conjunction with specific embodiment.
Embodiment 1: the Gastrodin chronopharmaceuticalmedicine medicine delivery preparation prescription
Figure BDA0000071565160000041
Figure BDA0000071565160000051
Method for making: get gastrodine, lactose, microcrystalline Cellulose, carboxymethylstach sodium fine powder (crossing 80 mesh sieves) mixing, add 10% polyvidone alcoholic solution soft material processed, 16 mesh sieves are granulated, in 60 ℃ of dryings, 14 mesh sieve granulate, add magnesium stearate, mixing, tabletting, coating (wraps first sealing coat, wrap again controlled release layer), and get final product, every contains gastrodine 50mg.
Embodiment 2: the Gastrodin chronopharmaceuticalmedicine medicine delivery preparation prescription
Figure BDA0000071565160000052
Method for making: get gastrodine, lactose granule, microcrystalline Cellulose, hydroxypropyl cellulose, polyvidone, polyvinylpolypyrrolidone, magnesium stearate and micropowder silica gel, mixing, direct compression, coating (wraps first sealing coat, wrap again controlled release layer), and get final product, every contains gastrodine 100mg.
Embodiment 3: the Gastrodin chronopharmaceuticalmedicine medicine delivery preparation prescription
Figure BDA0000071565160000061
Method for making: get gastrodine, starch, microcrystalline Cellulose, low substituted hydroxy-propyl Zhang Weisu fine powder (crossing 80 mesh sieves) mixing, add 5% starch slurry soft material processed, 14 mesh sieves are granulated, in 60 ℃ of dryings, 12 mesh sieve granulate, add Pulvis Talci, mixing, tabletting, coating (wraps first sealing coat, wrap again controlled release layer), and get final product, every contains gastrodine 75mg.
Embodiment 4: the Gastrodin chronopharmaceuticalmedicine medicine delivery preparation prescription
Figure BDA0000071565160000062
Figure BDA0000071565160000071
Method for making: get gastrodine, lactose, microcrystalline Cellulose, carboxymethylstach sodium fine powder (crossing 80 mesh sieves) mixing, add 10% polyvidone alcoholic solution soft material processed, 16 mesh sieves are granulated, in 60 ℃ of dryings, 14 mesh sieve granulate, add magnesium stearate, mixing, tabletting, coating (wraps first sealing coat, wrap again controlled release layer), and get final product, every contains gastrodine 50mg.
Embodiment 5: the mensuration of Gastrodin chronopharmaceuticalmedicine medicine delivery preparation release
Get three batch samples that embodiment 1 makes, according to dissolution method (two appendix XC of Chinese Pharmacopoeia version in 2010 first method), take 900ml water as dissolution medium, rotating speed is that per minute 100 turns, in accordance with the law operation, respectively at 2,4,4.5,5,5.5,6, the 8h 5ml that takes a sample, replenish simultaneously isothermal equal-volume blank medium, sample is through 0.45 μ m filtering with microporous membrane, get the subsequent filtrate ultraviolet spectrophotometry, measure the concentration of gastrodine at 221nm wavelength place, and calculate the cumulative release percentage rate of each time point.The release curve is seen Fig. 1, and disintegrate occurs about 5h Gastrodin chronopharmaceuticalmedicine medicine delivery preparation, presents the feature of pulsed release.
With similar factors (f 2) investigate repeatability between three batch samples for index.f 2Computing formula suc as formula shown in the I, wherein, R tAnd T tRepresent respectively reference and be subjected to test preparation at the cumulative release degree of time t; N is number of test points.f 2Be worth greatlyr, illustrate that the similarity of two curves is higher, f 2Be that 100, two release profiles overlap fully.It is generally acknowledged f 2Value represented the release profiles there was no significant difference of two kinds of preparations greater than 50 o'clock.The result shows the f between first and second batch, first and the 3rd batch, second batch and the 3rd batch sample 2Value is respectively between 76.1,80.2 and 68.0, three batch samples does not have notable difference, shows that this prescription and technique have good stability.
f 2 = 50 log { [ 1 + 1 n Σ t = 1 n ( R t - T t ) 2 ] - 0.5 × 100 }
Formula I
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.

Claims (8)

1. Gastrodin chronopharmaceuticalmedicine medicine delivery preparation, it is characterized in that, said preparation is comprised of coating and the label that contains gastrodine, the coating internal layer is sealing coat, skin is controlled release layer, wherein insolated layer materials is hypromellose, its weightening finish is 10%~20% of label weight, the controlled release layer material comprises the agent of film clothing and plasticizer, the agent of described film clothing is ethyl cellulose or cellulose acetate, plasticizer is triethyl citrate, diethyl phthalate or dibutyl sebacate, and the agent of film clothing and plasticizer weight ratio are 1:0.1~0.3, and its weightening finish is 5%~15% of label weight.
2. described Gastrodin chronopharmaceuticalmedicine medicine delivery preparation according to claim 1 is characterized in that the controlled release layer material also comprises porogen.
3. described Gastrodin chronopharmaceuticalmedicine medicine delivery preparation according to claim 2 is characterized in that described porogen is Polyethylene Glycol, hydroxypropyl cellulose or polyvidone.
4. according to claim 2 or 3 described Gastrodin chronopharmaceuticalmedicine medicine delivery preparations, it is characterized in that the weight ratio of the agent of film clothing, porogen and plasticizer is 1:0~0.25:0.1~0.3.
5. described Gastrodin chronopharmaceuticalmedicine medicine delivery preparation according to claim 1 is characterized in that described label also comprises disintegrating agent, filler, adhesive or lubricant.
6. described Gastrodin chronopharmaceuticalmedicine medicine delivery preparation according to claim 5 is characterized in that described disintegrating agent is carboxymethylstach sodium, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium or polyvinylpolypyrrolidone.
7. described Gastrodin chronopharmaceuticalmedicine medicine delivery preparation according to claim 5 is characterized in that described filler is one or more in microcrystalline Cellulose, lactose, starch or the pregelatinized Starch; Adhesive is one or more in polyvidone, starch slurry or the hypromellose; Lubricant be magnesium stearate, micropowder silica gel or talcous one or more.
8. described Gastrodin chronopharmaceuticalmedicine medicine delivery preparation according to claim 5 is characterized in that the weight ratio of gastrodine, disintegrating agent and other pharmaceutic adjuvants is in the label: 1:0.1~0.5:1~4.
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CN105395907B (en) * 2015-12-08 2019-11-12 北京协和制药二厂 A kind of tablet of the active component containing Rhizoma Gastrodiae and preparation method thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1823802A (en) * 2005-12-31 2006-08-30 魏锐 Gastrodin slow release preparation
CN1857283A (en) * 2006-03-28 2006-11-08 沈阳药科大学 Control released gastrodin preparation
CN1861056A (en) * 2006-06-05 2006-11-15 沈阳药科大学 Slow-releasing prepn. contg. gastrodin

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1823802A (en) * 2005-12-31 2006-08-30 魏锐 Gastrodin slow release preparation
CN1857283A (en) * 2006-03-28 2006-11-08 沈阳药科大学 Control released gastrodin preparation
CN1861056A (en) * 2006-06-05 2006-11-15 沈阳药科大学 Slow-releasing prepn. contg. gastrodin

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