CN1698588A - Popofol oral anesthesia agent and preparation method thereof - Google Patents
Popofol oral anesthesia agent and preparation method thereof Download PDFInfo
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Abstract
Disclosed is a popofol oral anesthesia agent which comprises propofol solute 1-20% and balancing auxiliary material. The propofol medicament is prepared into different oral preparation for administering through gastrointestinal tract. The propofol is found to have effects of tranquilization, hypnotism and anesthetic to mouse.
Description
Technical field
The invention belongs to medical drugs series, relate to a kind of drug administration approach and related preparations, particularly relate to Popofol oral anesthesia agent and preparation method thereof.
Background technology
Propofol (propofol) is a kind of novel intravenous anesthetic, is mainly used in that general anesthesia is induced and anesthesia is kept.Also be widely used in the short and small operation of outpatient service in recent years, nonpain treatments such as the gastrointestinal mirror is looked into, artificial abortion, its advantage be quick, fugitive, revive rapidly and fully, continue behind the infusion characteristics such as no cumulative action.But the intravenously administrable use is inconvenient, safety range is little, injects too fast the generation and breathes and untoward reaction such as circulation inhibition and injection site pain, and use brings certain restriction to clinical safety.
Summary of the invention
The objective of the invention is to, provide propofol to pass through anesthetics of oral administration and preparation method thereof.
To achieve these goals, the technical scheme that the present invention takes is, contains propofol solute 1%～20% in the Popofol oral anesthesia agent, and surplus is adjuvant.And make fat emulsion formulation or Liposomal formulation or fat milk lyophilized powder enteric coated capsule preparation.
The present invention passes through gastrointestinal tract with the propofol medicine of 1%～20% content, find that propofol can produce calm, hypnosis and anesthetic action to mice, the propofol medicine is used to prepare oral anesthetics, for clinical more extensive, safety be convenient to use propofol new route of administration is provided.
The specific embodiment
The present invention is described in further detail for embodiment that provides below in conjunction with the inventor and zoopery.
One, Popofol oral anesthesia agent formulation preparation embodiment
The present invention verifies listed propofol oral formulations.Under technology of the present invention and condition, the arbitrary consumption of the consumption of propofol medicine in can playing calm, hypnosis and anesthetic action content range all guarantees to make stable final products.
Embodiment 1: the preparation of propofol fat emulsion formulation
Prescription 1:
| Title | Heavy content (%) | Inventory |
| Lecithin | ????1.25 | ????12.5g |
| Soybean oil | ????10 | ????100ml |
| Propofol | ????1.0 | ????10g |
| Water for injection | Surplus | |
| Add up to | ????100 | ????1000ml |
Prescription 2:
| Title | Heavy content (%) | Inventory |
| Lecithin | ????1.5 | ????15.g |
| Soybean oil | ????10 | ????100ml |
| Propofol | ????10.0 | ????100g |
| Water for injection | Surplus | |
| Add up to | ????100 | ????1000ml |
Prescription 3:
| Title | Heavy content (%) | Inventory |
| Lecithin | ????2.0 | ????20g |
| Soybean oil | ????20 | ????200ml |
| Propofol | ????20.0 | ????200g |
| Water for injection | Surplus | |
| Add up to | ????100 | ????1000ml |
Method for making: lecithin, propofol and the soybean oil of recipe quantity is miscible, under electromagnetic agitation helps, be heated to 45 ℃ while stirring, lecithin is dissolved fully.Under the state of cutter high-speed stirred (3000 rev/mins), lecithin-propofol-soybean oil mixed solution is joined in the 800ml water for injection slowly, under the condition of nitrogen protection, continue to stir 30 minutes, promptly get propofol medicine colostric fluid.Propofol medicine colostric fluid obtains the propofol fat emulsion formulation of particle diameter 280-350nm through homogenizer or mulser homogenizing 7-10 time repeatedly, and makes additional liquid with proper amount of water for injection, makes that the volume of final emulsion is 1000ml.Divide and be filled in specific cillin bottle or the peace unstrained spirits bottle.
Example has herein only been listed the preparation method of the propofol fat emulsion formulation of 1%, 10%, 20% content, is applicable to the preparation of the arbitrary concentration content of from 1% to 20% propofol but the empirical tests result proves this preparation technology.
Embodiment 2: the preparation of propofol fat milk lyophilized powder enteric coated capsule preparation
Prescription 1:
| Title | Heavy content (%) | Inventory |
| Lecithin | ??6.5 | ????13g |
| Soybean oil | ??45 | ????90g |
| Propofol | ??5.0 | ????10g |
| Mannitol | ??16.5 | ????33g |
| Lactose | ??20 | ????40g |
| Micropowder silica gel | ??6 | ????12g |
| Magnesium stearate | ??1 | ????2g |
| Water for injection | ????800ml | |
| Add up to | ??100 | ????200g |
Prescription 2:
| Title | Heavy content (%) | Inventory |
| Lecithin | ??5 | ????10g |
| Soybean oil | ??30 | ????60g |
| Propofol | ??10.0 | ????20g |
| Mannitol | ??20 | ????40g |
| Lactose | ??25 | ????50g |
| Micropowder silica gel | ??8 | ????16g |
| Magnesium stearate | ??2 | ????4g |
| Water for injection | ????800ml | |
| Add up to | ??100 | ????200g |
Prescription 3:
| Title | Heavy content (%) | Inventory |
| Lecithin | ??5 | ????10g |
| Soybean oil | ??45 | ????90g |
| Propofol | ??20.0 | ????40g |
| Mannitol | ??15 | ????30g |
| Lactose | ??10 | ????20g |
| Micropowder silica gel | ??6 | ????12g |
| Magnesium stearate | ??1 | ????2g |
| Water for injection | ????800ml | |
| Add up to | ??100 | ????200g |
Method for making: recipe quantity lecithin, propofol and soybean oil is miscible, under electromagnetic agitation helps, be heated to 45 ℃ while stirring, lecithin is dissolved fully.Under the state of cutter high-speed stirred (3000 rev/mins), lecithin-propofol-soybean oil mixed solution is joined in the 800ml water for injection slowly, under the condition of nitrogen protection, continue to stir 30 minutes, promptly get propofol medicine colostric fluid.Propofol medicine colostric fluid obtains the propofol fat milk solution of particle diameter 280-350nm through homogenizer or mulser homogenizing 7-10 time repeatedly.Mannitol and lactose joined to stir in the propofol fat milk make dissolving, moisture is removed in lyophilization then, and content is collected, and adds micropowder silica gel and magnesium stearate, stir evenly, and the enteric coated capsule of packing into No. 0, promptly.Example has herein only been listed the preparation method of the propofol fat milk lyophilized powder enteric coated capsule preparation of 5% content, is applicable to the preparation of the arbitrary concentration content of from 1% to 20% propofol but applicant's checking result proves this preparation technology.
Embodiment 3: the preparation of propofol Liposomal formulation
Prescription:
| Title | Heavy content (%) | Inventory (g) |
| Lecithin | ????70 | ????70 |
| Cholesterol | ????20 | ????20 |
| Propofol | ????10 | ????10 |
| Water for injection | In right amount |
| Add up to | ????100 | ????100g |
Method for making: recipe quantity lecithin, cholesterol, propofol are dissolved in the 20ml ethanol, on magnetic stirrer, are heated to 45 ℃ while stirring, make it to dissolve fully, cool; Under the state of cutter high-speed stirred (3000 rev/mins), mixed solution is joined in the 150ml water for injection lentamente then, under the condition of nitrogen protection, continue to stir 30 minutes, promptly get the multiphasic liposomes drug solution.This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml.Ultrafiltrate is pushed repeatedly through the film of squeezer with 5 layers of 200nm, obtain the single-phase liposome medicament solution of big single chamber of particle diameter 250 ± 40nm.Add proper amount of water for injection, the ultrafiltration sterilization, aseptic subpackaged.
Embodiment 4: the preparation of propofol fat milk lyophilized powder enteric coated capsule
Prescription:
| Title | Heavy content (%) | Inventory (g) |
| Lecithin | ????40 | ????40 |
| Cholesterol | ????10 | ????10 |
| Propofol | ????10 | ????10 |
| Mannitol | ????10 | ????10 |
| Lactose | ????25 | ????25 |
| Micropowder silica gel | ????4 | ????4 |
| Magnesium stearate | ????1 | ????1 |
| Add up to | ????100 | ????100g |
Method for making: recipe quantity lecithin, cholesterol, propofol are dissolved in the 20ml ethanol, on magnetic stirrer, are heated to 45 ℃ while stirring, make it to dissolve fully, cool; Under the state of cutter high-speed stirred (3000 rev/mins), mixed solution is joined in the 150ml water for injection lentamente then, under the condition of nitrogen protection, continue to stir 30 minutes, promptly get the multiphasic liposomes drug solution.This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml.Ultrafiltrate is pushed repeatedly through the film of squeezer with 5 layers of 200nm, obtain the single-phase liposome medicament solution of big single chamber of particle diameter 250 ± 40nm.The mannitol of recipe quantity and lactose joined to stir in the liposome medicament solution make dissolving, moisture is removed in lyophilization then, and content is collected, and adds the micropowder silica gel and the magnesium stearate of recipe quantity, stir evenly, and the enteric coated capsule of packing into No. 0, promptly.
Embodiment 5: the preparation of propofol dispersant
Prescription:
| Title | Content (%) | Inventory (g) |
| Emulsifying agent | ????5 | ????10 |
| Cholic acid | ????4 | ????8 |
| Oleic acid | ????5 | ????10 |
| Propofol | ????5 | ????10 |
| Vitamin E | ????1 | ????2 |
| Lactose | ????5 | ????10 |
| Water for injection | In right amount | |
| Add up to | ????100 | ????200 |
Method for making: recipe quantity emulsifying agent, oleic acid, vitamin E and cholic acid are dissolved in the propofol, are heated to 45 ℃ while stirring, make it to dissolve fully; Under the state of high-speed stirred (3000 rev/mins) mixed solution is joined in the 150ml water for injection lentamente, continuation was stirred 30 minutes under the condition of nitrogen protection, lactose was joined to stir in the drug solution make dissolving, and packing promptly then.
The syrupy preparation of embodiment 6 propofols
Prescription:
| Title | Content (%) | Inventory (g) |
| Emulsifying agent | ????5 | ????10 |
| Propofol | ????5 | ????10 |
| Vitamin E | ????1 | ????2 |
| Polysaccharide | ????15 | ????30 |
| Lactose | ????5 | ????10 |
| Thickening agent | ????3 | ????6 |
| Water for injection | In right amount | |
| Add up to | ????100 | ????200 |
Method for making: recipe quantity emulsifying agent and vitamin E are dissolved in the propofol, are heated to 45 ℃ while stirring, make it to dissolve fully; Under the state of high-speed stirred (3000 rev/mins) mixed solution being joined 150ml lentamente contains in the water for injection of polysaccharide and lactose; under the condition of nitrogen protection, continue to stir 30 minutes; add thickening agent and regulate the viscosity of drug solution, packing promptly then.
Two, the propofol oral administration obtains the zoopery of calm, hypnosis and anaesthetic effect
2.1 the calmness of oral propofol preparation, anesthetic action, and the safety of administration
2.1.1. materials and methods
Animal and grouping: Kunming kind white mice (The Fourth Military Medical University zoopery center provides), body is strong, and body weight (20 ± 2g) (18～22g), be regardless of by male and female.Be divided into matched group, ED at random
50Group (including 5 subgroups) and LD
50Group (including 5 subgroups), each 10 of every subgroup and matched groups, male and female half and half.ED
50Group is divided into 5 dosage groups by geometric progression, is reassembled as basal dose with the 150mg/kg body and increases progressively 1.2 times successively, is respectively 180,216,259 and 311mg/kg group; LD
50Group is divided into 5 dosage groups by geometric progression, is that basal dose increases progressively 1.15 times successively with the 624mg/kg body weight, is respectively 717,825,949 and 1091mg/kg group.Before the experiment each group mice is positioned over peace and quiet, dim light and temperature and is in 22～25 ℃ the environment more than the 24h, water is prohibited in the 8h fasting before irritating stomach, to guarantee the empty stomach of mice.
Medication: propofol oral formulations (seeing the embodiment first of this patent), the traditional gastric infusion method of oral employing, with the fixing white mice of left hand, abdominal part up, cervical region is stretching, the right hand inserts the oral cavity with mouse stomach device bead angle, is close to palate from lingual surface and enters esophagus, pours into the propofol of normal saline or various dose.
Observation index: after the oral propofol, the behavioral activity of observing mice changes; Observe every group by anesthetized mice and dead mice number of elements.The righting reflex loss that anesthetic action produces with mice is a sign.Make the dosage of the required oral propofol of 50% animal generation anesthetic action, i.e. ED
50The dosage that makes 50% animal dead required oral propofol preparation occur is LD
50Calculate the therapeutic index (TI=LD of oral administration
50/ ED
50).ED
50Group, LD
50The mice of group survival and control group mice are all put back to and are fed and observe diet and behavior situation in the cage.
Statistical analysis: enumeration data X
2The simplification exact propability statistics of check, (x ± s) expression relatively adopts paired t-test to measurement data in the group, relatively adopt one factor analysis of variance between group with mean ± standard deviation.Adopt the SPSS10.0 statistical software to analyze, P＜0.05 is variant significance.
2.1.2 experimental result
Ordinary circumstance: ED
50Group, LD
50Inject speed difference when the sex of group and control group mice, average weight, taboo water are eaten the time and irritated stomach and do not have significance (P＞0.05).
ED
50When (n=50) measuring, after the oral propofol, increase with dosage, the sleeping rate of mice increases, and anaesthetizing onset time is (17.45 ± 0.38) min, and be (77.96 ± 0.87) min action time.All animals all keep autonomous respiration, no laboratory animal death.
LD
50During mensuration (n=50), have 24 dead mouses.18 mices apnea at once after stopping administration wherein, heart beating stop and dead.Righting reflex disappears immediately after 6 mice administrations, tiny tic of whole body or spasm occur, and gatism is breathed and weakened gradually, slows down, and is dead in 1h.
Using modified karber's method
[1]Calculate ED
50, LD
50Be respectively 208.33 and 835.80mg/kg.Propofol oral administration TI is 4.01.
ED
50Group, LD
50Group survival mice and control group mice fed for 1 week, and activity is all normal, and weight increase is all arranged.
2.1.3 conclusion
Propofol has been widely used in clinical each section's surgery anesthesia and various restless sedation treatment
[1], but clinically can only intravenously administrable.In clinical practice, behind the vein fast injection propofol, hemodynamic acute variation and respiration inhibition often appear, and its degree is dose dependent
[2]It is inconvenient that this brings misery and outpatient service to use to clinical practice especially children's, limited its application to a certain extent, if change route of administration, adopt oral administration to be expected to overcome the shortcoming of intravenously administrable, may more be applicable to the needs of the short and small operations of various outpatient services such as burn is changed dressings, got involved, beauty treatment, painless abortion, gastroscope, intestinal mirror.
The peroral dosage form of research and development intravenous pharmacy is one of important content of present medicament research and development.Present oral premedicant is in American-European countries's widespread usage
[3], the basal anesthesia of Taking oral midazolam and ketamine before the art also has report at home
[4,5]Li Zhen etc.
[6]Discover that by experiment oral etomidate has inhibitory action to the rat noxious stimulation, think that oral etomidate has analgesic activity, but its dosage and also indeterminate in the effect of human body.Han Sheng etc.
[7]Think that Taking oral midazolam, ketamine mixed liquor are the ideal anesthesia premedicates of children's.
The present clinical measurement anesthetics best index of tiring should be to make 50% animal or human not produce the concentration of the moving reaction of body to noxious stimulation, so the applicant causes the ED of mice righting reflex loss with medicine
50As the index of weighing the anesthetics potency.This laboratory observation can make the mice righting reflex loss after the oral propofol preparation administration, and that points out that oral propofol preparation can dose dependent produces calm, anesthetic action to mice.
LD
50Be the important indicator of judging the medicine acute toxicity, its stability and accuracy are all better
[8]Therapeutic index (TI) is a classical index of judging the pharmacodynamics safety.TI is big more, and drug safety is high more.The TI of the oral propofol preparation that this research is measured is 4.01.And Zhou Jianxin etc.
[9]The TI of the intravenous injection propofol of measuring is 3.10, shows that the safety of oral propofol preparation is better than intravenous injection, proves that adopting the approach of oral administration is safe and feasible.
List of references
[1]James?P，Zacny，Dennis?W，et?al.Propofol?at?conscious?sedationdoses?produces?mild?analgesia?to?cold?pressor-induced?pain?inhealthy?volunteers.J?Clin?Anesth，1996，8：469-474.
[2] Xu Longhe, Zhang Hong, Zhu Jianguo. the propofol of para-sleep dosage is to the influence of the mice threshold of pain. Chinese anesthesiology magazine, 1998,18:753-755.
[3]Chen?J，Luo?C，Li?HL，et?al.Primary?hyperalgesia?to?mechanicaland?heat?stimuli?following?subcutaneous?bee?venom?injection?intothe?plantar??surface?of?hindpaw?in?the?conscious?rat：Acomparative?study?with?the?formalin?test[J].Pain，1996；66：271-277.
[4] Xu Shuyun, Bian Rulian, Chen Xiu chief editor. pharmacological experimental methodology. the 2nd edition, Beijing: People's Health Publisher, 1994:968-969.
[5] Chen Jun. the spinal cord pain sensation is transmitted [A]. sees: Jiang Chengchuan, Zhao Zhiqi, Jiang Hao. the basis of pain and clinical [M]. Shanghai: publishing house of Fudan University/publishing house of Shanghai Medical Univ, 2001:30-81.
[6]Tjolsen?A，Berge?OG，Hunskaar?S，et?al.The?formalin?test：anevaluation?of?the?method.Pain，1992，51：5-17.
[7]Abbott?FV，Frankl?in?KBJ，Westbrook?RF.The?formal?in?test：scoringproperties?of?the?first?and?second?phases?of?the?pain?responsein?rats.Pain，1995，60：91-102.
[8]Erenmemisoglu?A，Madenoglu?H，Tekol?Y.Anti-nociceptive?effectof?propofol?on?somatic?and?visceral?pain?in?subhypnotic?dose.Curr?Ther?Res，1993，53：677-681.
[9] Wang Liyun, kingdom is good, Sun Yanwu, etc. the inhibitory action that the persistent ache that the intrathecal injection propofol is led to subcutaneous rat injection Apis poison reacts. Chinese anesthesiology magazine, 2003,23:118-119.
[10]Davies?PA，Kirkness?EF，Hales?TG.Modulation?by?generalanaesthetizes?of?rat?GABAA?receptors?comprised?of?alphal?beta3subunits?expressed?in?human?embryonic?kidney?293?cells.Br?JPharmacol，1997，120(5)：899-909.
[11]Nadeson?R，Good?chi?ld?CS.Antinociceptive?properties?ofpropofol：involement?of?spinal?cord?gamma-aminobutryic?acid(A)receptors.J?Pharmacol?Exp?Ther.1997，282(3)：1181-6.
2.2, the analgesic activity of oral propofol preparation
2.2.1 material and method
Experimental animal: Kunming kind white mice, provide by The Fourth Military Medical University zoopery center, body weight (20 ± 2g) (18～22g), be regardless of by male and female.Before the experiment each group mice is positioned over peace and quiet, dim light and temperature and is in 22～25 ℃ the environment more than the 24h, 8h fasting before irritating stomach, prohibit water, to guarantee the empty stomach of mice.Strictly observe the regulation of " about the outline of using clear-headed animal to carry out pain research " [Zimmermann 1983] of IASP (LASP) formulation.
Medicine and reagent: the propofol oral formulations is seen the embodiment part of this patent.Formalin and glacial acetic acid (analytical pure) are available from Suzhou Jin Cheng chemical reagent work.
Medication: the propofol oral formulations adopts traditional gastric infusion method, and with the fixing white mice of left hand, abdominal part up, cervical region is stretching, the right hand inserts the oral cavity with mouse stomach device bead angle, is close to palate from lingual surface and enters esophagus, pours into the propofol of normal saline or various dose.
Gate-Papacostas' tests: (18～22g) 50 of Kunming mouses, be divided into matched group and experimental group at random, experimental group again according to dosage difference be divided into 4 groups of P1 (100mg/kg), P2 (150mg/kg), P3 (200mg/kg) and P4 (250mg/kg) group, every treated animal number is 10.Experimental group 20min before formalin injection gives propofol 0.2ml/10g body weight, and matched group 20min before formalin injection gives and normal saline 0.2ml/10g body weight.
The foundation of formalin animal pain model: subcutaneous at the bottom of the parapodum of the formalin 20ul injection mice with 5%, can bring out the spontaneous foot reflex behavior of contracting that animal shows a long time journey two-phase, first is 0-10min mutually, and second from the later sustainable 2h that reaches of 15min
[4]
Mice acetic acid twisting test: Kunming mouse 18～22g, the male and female dual-purpose, with 0.6% acetic acid 0.1ml/10g mouse peritoneal is injected earlier, and write down to cause in the 15min of pain back and turn round the body number of times, turn round the body number of times as pain threshold with this, and select qualified mice with this, turn round the body number of times in all 15min more than 60 times or be less than 10 persons and give it up.Begin test after one week.50 of mices, be divided into matched group (normal saline group) and experimental group (propofol oral formulations group) at random, experimental group is divided into 4 groups of P1 (100mg/kg), P2 (150mg/kg), P3 (200mg/kg) and P4 (250mg/kg) group by propofol dosage difference again, and every treated animal number is 10.Irritating the stomach volume is the 0.2ml/10g body weight.Administration 20min pneumoretroperitoneum is injected 0.6% acetic acid 0.1ml/10g, and the writhing response number in the every 15min of opening entry till 45min, and calculates the suppression ratio of propofol to writhing response.Suppression ratio (%)=(administration group writhing response number-matched group writhing response number)/matched group writhing response number * 100%.The standard of mouse writhing reaction (writhing response) is that the abdominal part indent appears in mice, and trunk and hind leg are upheld, behavior reactions such as hips up.
Statistical procedures: (x ± s) expression relatively adopts paired t-test to measurement data in the group, relatively adopt one factor analysis of variance between group with mean ± standard deviation.Adopt the SPSS10.0 statistical software to analyze, P＜0.05 is variant significance.
2.2.2 result
2.2.2.1 respectively organize mice sex, body weight etc. there are no significant difference (P＞0.05)
2.2.2.2 the effect of the spontaneous foot reflex that contracts that the propofol oral formulations is led to formalin
In formalin model, the lasting spontaneous foot reflex that contracts that the propofol oral formulations is led to the formalin subcutaneous injection has the obvious suppression effect, when low dose group P1 (100mg/kg), the foot reflex that contracts to first, second phase does not have inhibitory action (P＞0.05), further increase (150mg/kg, 200mg/kg, 250mg/kg) behind the dosage, the propofol oral formulations all plays obvious suppression effect (P＜0.05) with second mutually the spontaneous foot reflex behavior of contracting mutually to first of formalin-induced.Its maximal percentage inhibition reaches (66.9 ± 7.16) %.
2.2.2.3 the propofol oral formulations is to the effect of the acetic acid twisting reaction of mice
In the acetic acid twisting test of mice, propofol oral formulations low dose group P1 (100mg/kg) compares with matched group, the body number of times of turning round of mice does not have obvious minimizing (P＞0.05), further behind the increase dosage (150mg/kg, 200mg/kg, 250mg/kg), the writhing response number of times of mice obviously reduces (P＜0.05).Suppression ratio is respectively 150mg/kg group (39.1 ± 6.89) %, 200mg/kg group (59.9 ± 7.15) %, 250mg/kg group (71.3 ± 5.96) %.
2.2.3 conclusion
The rational pain of clinical disease usually shows as persistence or intermittent spontaneous pain, simultaneously also can be with the quick phenomenon of pain, even unusual pain sensation phenomenon also can appear
[1]The formalin experiment is the good model of clinical acute and chronic inflammation pain, is widely used in the experiment of research Theory of Pain Mechanism and evaluation analgesic at present
[2,3], subcutaneous injection formalin can bring out one and reach the lasting spontaneous pain phenomenon of 2h, the quick phenomenon of pain do not occur but follow.The test of mice acetic acid twisting is to stimulate by acetic acid to cause that the mouse peritoneum inflammation produces pain, shows as writhing response.The nocuity reaction of acetic acid mediation may be because the abdominal cavity pH value reduces and directly stimulates nocuity nerve fiber and the synthetic combined effect of inflammatory mediator cause, and is the method for a kind of sensitivity, easy, good reproducibility.The applicant has adopted gate-Papacostas' tests and the test of mice acetic acid twisting simultaneously, thereby more comprehensive to the analgesic activity research of propofol.
The pharmacology thinks that propofol does not have analgesic activity, but more and more evidences shows propofol and has analgesic activity, the propofol of mouse peritoneal injection para-sleep dosage, survey body pain with the burn method, the acetic acid twisting method is surveyed visceral pain, propofol prolongs Mus and bounces back incubation period, reduces the mouse writhing number of times, and relevant with dosage
[4]Wang Liyun etc.
[5]Research thinks that propofol has analgesic activity at spinal cord, and is dose dependent, and propofol both can be used for the pain prevention and also can be used for pain therapy, and its therapeutical effect is better than preventive effect.
Experimental result shows, the propofol oral formulations can obviously suppress the pain reaction that formalin and acetic acid bring out.Illustrate oral way to can be used as a kind of new route of administration of propofol and bring into play analgesic activity.For clinical practice propofol analgesia provides foundation, also provide reference frame for better choice route of administration and administration time.Because oral administration convenience, no wound, systemic adverse reactions are little, expection will have more wide application prospect.
Generally believe that at present propofol is to pass through GABA
AReceptor is finished its analgesic activity
[6], using GABA
ABehind the receptor antagonist pocket choline, the inhibitory action of propofol is by complete antagonism.In addition, Nadeson and Goodchild
[7]The curvature (natridole) of receiving the antagonist of discovery intrathecal injection opium δ receptor also can reverse the analgesic activity of propofol, but think the not direct and opium δ receptors bind of propofol, but cause the release of endogenous opiatepeptide, thereby strengthened the activity of opium δ receptor, played analgesic activity.These all may be that propofol produces analgesic mechanism.Whether the mechanism that oral propofol produces analgesic activity is identical with the mechanism of lumbar injection and intrathecal injection, still not fully aware of, and its mechanism of action awaits further to further investigate.
List of references
[1] Chen Jun. the spinal cord pain sensation is transmitted [A]. sees: Jiang Chengchuan, Zhao Zhiqi, Jiang Hao. the basis of pain and clinical [M]. Shanghai: publishing house of Fudan University/publishing house of Shanghai Medical Univ, 2001:30-81.
[2]Tjolsen?A，Berge?OG，Hunskaar?S，et?al.The?formalin?test：an?evaluation?of?the?method.Pain，1992，51：5-17。
[3]Abbott?FV，Franklin?KBJ，Westbrook?RF.The?formal?in?test：scoring?properties?of?the?first?and?second?phases?of?the?pain?responsein?rats.Pain，1995，60：91-102。
[4]Erenmemisoglu?A，Madenoglu?H，Tekol?Y.Anti-nociceptiveeffect?of?propofol?on?somatic?and?visceral?pain?in?subhypnotic?dose.Curr?Ther?Res，1993，53：677-681。
[5] Wang Liyun, kingdom is good, Sun Yanwu, etc., " the intrathecal injection propofol injects the inhibitory action of the persistent ache reaction that the Apis poison leads to subcutaneous rat ", Chinese anesthesiology magazine, 2003,23:118-119.
[6]Davies?PA，Kirkness?EF，Hales?TG.Modulation?by?generalanaesthetizes?of?rat?GABAA?receptors?comprised?of?alphal?beta3subunits?expressed?in?human?embryonic?kidney?293?cells.Br?JPharmacol，1997，120(5)：899-909。
[7]Nadeson?R，Good?child?CS.Antinociceptive?properties?ofpropofol：involement?of?spinal?cord?gamma-aminobutryic?acid(A)receptors.J?Pharmacol?Exp?Ther.1997，282(3)：1181-6。
Claims (7)
1. Popofol oral anesthesia agent is characterized in that, contains propofol solute 1%～20% in this oral anesthetics, and surplus is adjuvant.
2. Popofol oral anesthesia agent is prepared into the method for fat emulsion formulation, it is characterized in that, follows these steps to preparation:
At first that lecithin, the soybean oil of 1%～20% propofol medicine and recipe quantity is miscible, on magnetic stirrer, be heated to 45 ℃ while stirring, lecithin is dissolved fully;
Cutter with 3000 rev/mins stirring under, above-mentioned lecithin, propofol, soybean oil mixed solution are joined in the 800ml water for injection slowly, under the condition of nitrogen protection, continue to stir 30 minutes, promptly get propofol medicine colostric fluid;
Propofol medicine colostric fluid is through homogenizer or mulser homogenizing 7-10 time repeatedly, obtain the propofol fat emulsion formulation of particle diameter 280-350nm, and with the additional liquid of proper amount of water for injection work, make that the volume of final emulsion is 1000ml, divide to be filled in cillin bottle or the peace unstrained spirits bottle promptly to get the Popofol oral anesthesia agent fat emulsion formulation.
3. Popofol oral anesthesia agent is prepared into the method for fat milk lyophilized powder enteric coated capsule preparation, it is characterized in that, follows these steps to preparation:
With 1%～20% propofol medicine and recipe quantity is that the soybean oil of 5～6.5% lecithin and 30～45% is miscible, is heated to 45 ℃ on magnetic stirrer while stirring, and lecithin is dissolved fully;
Cutter with 3000 rev/mins stirring under, lecithin, propofol, soybean oil mixed solution are joined in the 800ml water for injection slowly, under the condition of nitrogen protection, continue to stir 30 minutes, promptly get propofol medicine colostric fluid;
Propofol medicine colostric fluid obtains the propofol fat milk solution of particle diameter 280-350nm through homogenizer or mulser homogenizing 7-10 time repeatedly;
Mannitol with 15～20% and 10～25% lactose join to stir in the propofol fat milk and make dissolving, lyophilization then, remove moisture, content is collected, the magnesium stearate that adds 5～8% micropowder silica gels and 1～2%, stir evenly, the enteric coated capsule of packing into No. 0 promptly gets propofol fat milk lyophilized powder enteric coated capsule preparation.
4. Popofol oral anesthesia agent is prepared into the method for Liposomal formulation, it is characterized in that, follows these steps to preparation:
At first lecithin, 15～25% cholesterol with 1%～20% propofol medicine and 50～70% are dissolved in the 20ml ethanol, are heated to 45 ℃ on magnetic stirrer while stirring, make it to dissolve fully, cool;
Under the state that the rotating speed of 3000 rev/mins of cutters stirs, mixed solution is joined in the 150ml water for injection lentamente then, under the condition of nitrogen protection, continue to stir 30 minutes, promptly get the multiphasic liposomes drug solution;
This liposome medicament solution is removed organic solvent with the ultrafilter ultrafiltration repeatedly, and make to replenish liquid with 0.9% sodium chloride solution, the volume of final ultrafiltrate is 100ml;
Ultrafiltrate is pushed repeatedly through the film of squeezer with 5 layers of 200nm, obtain the single-phase liposome medicament solution of big single chamber of particle diameter 250 ± 40nm;
Add proper amount of water for injection, the ultrafiltration sterilization, promptly aseptic subpackaged.
5. Popofol oral anesthesia agent is prepared into the method for propofol dispersant, it is characterized in that, follows these steps to preparation:
With at first emulsifying agent, oleic acid, vitamin E and the cholic acid of recipe quantity being dissolved in 1%～20% the propofol, be heated to 45 ℃ while stirring, make it to dissolve fully;
Under 3000 rev/mins high-speed stirred state, mixed solution is joined in the 150ml water for injection lentamente, under the condition of nitrogen protection, continue to stir 30 minutes;
Lactose joined in the drug solution to stir make dissolving, packing promptly then.
6. Popofol oral anesthesia agent is prepared into the syrupy method of propofol, it is characterized in that, follows these steps to preparation:
Recipe quantity emulsifying agent and vitamin E be dissolved in 1%～20% the propofol, be heated to 45 ℃ while stirring, make it to dissolve fully;
Under the state of 3000 rev/mins high-speed stirred mixed solution being joined 150ml lentamente contains in the water for injection of polysaccharide and lactose; under the condition of nitrogen protection, continue to stir 30 minutes; add thickening agent and regulate the viscosity of drug solution, packing promptly then.
7. the propofol medicine is used to prepare the application of oral anesthetics.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110893186A (en) * | 2018-09-12 | 2020-03-20 | 宜昌人福药业有限责任公司 | Pharmaceutical composition and preparation method and application thereof |
| US11439653B1 (en) | 2021-03-30 | 2022-09-13 | Epalex Corporation | Fospropofol formulations |
| US11478490B1 (en) | 2021-03-30 | 2022-10-25 | Epalex Corporation | Fospropofol formulations |
| US11547714B2 (en) | 2020-02-05 | 2023-01-10 | Epalex Corporation | Fospropofol salts, methods and compositions |
| US11628178B2 (en) | 2019-03-26 | 2023-04-18 | Epalex Corporation | Fospropofol methods and compositions |
-
2005
- 2005-05-30 CN CNB200510042739XA patent/CN100475200C/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110893186A (en) * | 2018-09-12 | 2020-03-20 | 宜昌人福药业有限责任公司 | Pharmaceutical composition and preparation method and application thereof |
| US11628178B2 (en) | 2019-03-26 | 2023-04-18 | Epalex Corporation | Fospropofol methods and compositions |
| US11547714B2 (en) | 2020-02-05 | 2023-01-10 | Epalex Corporation | Fospropofol salts, methods and compositions |
| US11439653B1 (en) | 2021-03-30 | 2022-09-13 | Epalex Corporation | Fospropofol formulations |
| US11478490B1 (en) | 2021-03-30 | 2022-10-25 | Epalex Corporation | Fospropofol formulations |
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| Publication number | Publication date |
|---|---|
| CN100475200C (en) | 2009-04-08 |
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