CN103054830B - Soft capsule for treating nerve diseases - Google Patents
Soft capsule for treating nerve diseases Download PDFInfo
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- CN103054830B CN103054830B CN201310000690.6A CN201310000690A CN103054830B CN 103054830 B CN103054830 B CN 103054830B CN 201310000690 A CN201310000690 A CN 201310000690A CN 103054830 B CN103054830 B CN 103054830B
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- soft capsule
- idebenone
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- medicinal liquid
- glycerol
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Abstract
The invention relates to a soft capsule for treating nerve diseases. The soft capsule comprises a liquid medicine and a soft capsule casing for sealing the liquid medicine, wherein the liquid medicine contains active ingredients. The medicine composition of the soft capsule is the only medicine which achieves double improvements on brain metabolism and psychiatric symptoms and has no direct competitor at present; and the soft capsule is a brain metabolism improver and cranial nerve cell protective agent, can prevent mitochondrial diseases, inhibit platelet aggregation and improve microcirculation effectively, has an effective antioxidation function, and is also a preferred medicine for treating FRDA (Friedreich ataxia). The successful development of the soft capsule can provide enormous economic and social benefits for the pharmacy industry.
Description
Technical field
The present invention relates to a kind of soft capsule that is used for the treatment of sacred disease.
Background technology
After neuronal damage, neurodegenerative disease and syndrome (Alzheimer, multiple sclerosis, Friedreich ataxia (Friedrich ' s ataxia), brain and spinal cord injury and neurotrauma, apoplexy, parkinson disease, alcoholism and narcolepsy (narcolepsy), post-operative recovery syndrome and anesthesia, recover syndrome) and many other diseases need effectively treatment and prevention.
Postoperative apoplexy and cognitive defect (POSCD) syndrome is common, particularly carry out on a large scale surgical operation as the old people of operation on heart or hip replacement surgery in.In North America, surpass every year the such surgical operation of 2,500,000 example, and the sickness rate of POSCD surpasses 30%.Existence to interventional therapy in the urgent need to, and also do not have enough treatment to select for this distressful postoperative disease.In the U.S., only with regard to operation on heart, just surpass every year 2000000 routine surgical operations.The rear recovery of anesthesia of Lente anesthetic medicine conventionally causes in the state of patient in significant disorientation and cognitive impairment and continues very over a long time.Even if there is newer fugitive anesthetics, act on after also not alleviating the anesthesia of geratic surgery patient with operation.
The sickness rate of hands severe postoperative adverse events (comprising cognitive defect and apoplexy) is up to operating 30-35% on a large scale, and this has caused extensively and serious quality of life problem of the hospital stay extending and affected patient and health care supplier thereof.By apoplexy after anesthesia from approximately 2.5% be reduced to 1.5% or by cognitive defect operation substantially from the ability of current approximately 30% reduction can produce significant cost savings and quality of life problem of management improvement.There are now a large amount of evidences to show that many gerontal patients are performing the operation by being subject to cognitive decline.In the perspective randomized test of the general anesthesia contrast epidural anesthesia (thering is sedation) carrying out at the total knee replacement for age >70 year patient, when evaluating by psychometry, the patient of 4-6% cognitive performance of six months after anesthesia and surgical operation is poorer than preoperative baseline.Another large-scale perspective contrast international research confirms that 9.9% patient has cognitive defect in latter three months in operation, and only have an appointment in the matched group of age-matched, 3% has similar damage.At the age, surpass in the patient of 75 years old, 14% patient has lasting cognitive defect after general anesthesia and surgical operation.
In many cases, the neural degeneration relevant with anoxia cause because blood circulation reduces, and with the excessive of free radical and the inhibition to mitochondria activity.
Antioxidant is considered to reduce the possible protective agent due to the brain injury that general anesthesia causes on a large scale.Various materials---antioxidant and free radical scavenger---have obtained test in cell culture, in vitro brain section and the interior animal model of body in vitro.In these experiments, idebenone has shown significant antioxidant activity and can protect significantly the not oxidated property damage of brain cell.The oral form of idebenone is used for the treatment of the myocardial atrophy in Friedreich ataxia as hepatoprotective; and in limited degree, be used for the treatment of Alzheimer [United States Patent (USP) 5; 916; 925 " Pharmaceutical composition for treatment of dementia " and United States Patent (USP)s 6; 133; the people such as 322Rustin P., " Quinone derivatves for treating or preventing diseases associated with ironoverload "].
In the small-sized human research who carries out the patient who nine is suffered to cerebrovascular disease, give the idebenone of 90mg every day, and monitor cerebral electrograph and clinical symptoms.Result shows that the supplementary administration of idebenone has produced improvement to these patients' EEG (electroencephalogram) and clinical symptoms.
The cortical neuron that idebenone protection is cultivated makes it the degeneration of not necrosing property.It even still can save cortical neuron when within 30 minutes after NMDA pulse, using again, this has shown described interfering effects of drug toxic reaction chain triggering due to overstimulation excitatory amino acid receptor.
To suffering from, the patient of Friedreich ataxia is oral gives the sign that idebenone (every day 5mg/kg continue 8 weeks) has reduced oxidative dna damage significantly.Idebenone has prevented lipid peroxidation and the myocardial damage of ferrum induction in three patients that give 5mg/kg and continue 4-9 month every day, thereby causes the reduction that in these patients, left ventricle expands.
In cell culture experiment, idebenone has been removed various Kinds of Free Radicals.Idebenone also carries out redox couple with Myoglobin or the hemoglobin of high valence state kind, thereby has prevented the lipid peroxidation that promoted by these kinds.Similarly, shown that idebenone has suppressed the foundation of microsomal Lipid Peroxidation by ADP-iron complexes or organic hydroperoxide induction.Oneself shows the destruction that idebenone has so prevented Cytochrome P450, and the destruction of described Cytochrome P450 can be followed lipid peroxidation in addition.
Be reported in the experimental model producing by cerebral embolism formation, cerebral ischemia or damage in Basal Forebrain of Rats, it is disorderly that idebenone has improved learning and memory, and described basal forebrain is the origin area that projects the acetylcholine neuron system in cerebral cortex, Hippocampus and corpus amygdaloideum.In clinical trial, it is effective that idebenone is considered to for reducing mental deficiency (as decline and the disorientation of memory maintenance).
The method of the disease association that can treat with idebenone is still expected to be useful in this area.
Summary of the invention
The object of this invention is to provide a kind of method for the disease association that can treat with idebenone.
In one aspect, the invention provides a kind of pharmaceutical composition, it is soft capsule, and it comprises medicinal liquid and by the soft capsule shell of this medicinal liquid sealing, comprises the idebenone as active ingredient in described medicinal liquid.
According to soft capsule of the present invention, in wherein said medicinal liquid, the concentration of idebenone is 1-40% (w/w), 1-20% (w/w), preferably 2-15% (w/w), preferably 3-10% (w/w).
According to soft capsule of the present invention, in wherein said medicinal liquid, comprise the idebenone of 1-40% (preferably 1-20%, preferably 2-15%, preferably 3-10%), and the acceptable adjuvant of optional pharmacy.In one embodiment, the acceptable adjuvant of described pharmacy is soft capsule content adjuvant.In one embodiment, the acceptable adjuvant of described pharmacy is selected from: vegetable oil (soybean oil for example, Oleum Brassicae campestris, Semen Maydis oil), polyoxyethylene olein, fatty glyceride (tristerin for example, tripalmitin, medium chain acid glyceride etc.), mineral oil (for example liquid Paraffin), polyoxyethylene hydrogenated Oleum Ricini, Oleum Ricini, Cera Flava, hard paraffin, hydrogenated vegetable oil, vegetable oil, spans (for example span 20 ~ 85), Tweens (for example polysorbas20 ~ 85), lecithin, vitamin E, water, Polyethylene Glycol (the Polyethylene Glycol that for example molecular weight is 200～20000, the Polyethylene Glycol that for example molecular weight is 200～2000, the Polyethylene Glycol that for example molecular weight is 200 ~ 600), glycerol, propylene glycol, polyvinylpyrrolidone, poloxamer etc. or its combination.
According to soft capsule of the present invention, wherein said soft capsule shell comprises gelatin and plasticizer.In one embodiment, described plasticizer is selected from: glycerol, sorbitol, mannitol, anhydro sorbitol acid anhydride, Polyethylene Glycol (Polyethylene Glycol that for example molecular weight is 200 ~ 1000, the Polyethylene Glycol that for example molecular weight is 200 ~ 600) or its combination.In one embodiment, the weight ratio of described gelatin and plasticizer is 1:(0.3 ~ 0.8), preferred 1:(0.35 ~ 0.75), preferred 1:(0.4 ~ 0.7) and, preferred 1:(0.42～0.58).
According to soft capsule of the present invention, wherein said soft capsule shell also comprises and is selected from following adjuvant: antiseptic (for example ethyl hydroxybenzoate, methyl hydroxybenzoate), coloring agent (for example ferrum oxide, titanium oxide).
According to soft capsule of the present invention, wherein said soft capsule shell is by comprising that following material makes: gelatin, plasticizer, He Shui, and optional be selected from following adjuvant: antiseptic (for example ethyl hydroxybenzoate, methyl hydroxybenzoate), coloring agent (for example ferrum oxide, titanium oxide).In one embodiment, described plasticizer is selected from: glycerol, sorbitol, mannitol, anhydro sorbitol acid anhydride, Polyethylene Glycol (Polyethylene Glycol that for example molecular weight is 200 ~ 1000, the Polyethylene Glycol that for example molecular weight is 200 ~ 600) or its combination.In one embodiment, the weight ratio that described gelatin and plasticizer use is 1:(0.3 ~ 0.8), preferred 1:(0.35 ~ 0.75), preferred 1:(0.4 ~ 0.7) and, preferred 1:(0.42～0.58).In one embodiment, the weight ratio that described gelatin and water are used is 1:(0.6 ~ 1.5), preferred 1:(0.75 ~ 1.25), preferred 1:(0.8 ~ 1.2).
According to soft capsule of the present invention, the weight ratio of wherein said antiseptic and described gelatin is (0 ~ 5): 100, preferably (0～2.5): 100, preferably (0～2): 100, preferably (0 ~ 1): 100, preferably (0 ~ 0.5): 100.
According to soft capsule of the present invention, wherein when calculating the weight of described gelatin, be that the gelatin that is dried is as the criterion and calculates.
According to soft capsule of the present invention, wherein said plasticizer is glycerol.
According to soft capsule of the present invention, wherein said soft capsule shell comprises gelatin and glycerol.In one embodiment, the weight ratio of described gelatin and glycerol is 1:(0.3 ~ 0.8), preferred 1:(0.35 ~ 0.75), preferred 1:(0.4 ~ 0.7) and, preferred 1:(0.42～0.58).Although the above-mentioned weight ratio of gelatin and glycerol can easily be determined by the operation of weighing-preparing burden when feeding intake in this soft capsule shell, but after forming preparation, at gelatin, G & W, be made into glue, after parcel medicinal liquid drying, soft capsule shell water is dried and removes and be substantially devoid of water and only contain glycerol and gelatin and optional a little other adjuvant for example antiseptic and coloring agent.The in the situation that of this soft capsule medicament finished product, form the two amount of the gelatin of soft capsule shell and glycerol and also can determine by other method, such as determining by chemical analysis, red, orange, green, blue, yellow (ROGBY) etc.Particularly, due to antiseptic with coloring agent equal size is considerably less is conventionally less than 5%, more generally be less than 2%, more generally be less than 1%, more generally be less than 0.5%, therefore more generally do not need to add this type of adjuvant, in the soft capsule shell of determining soft capsule finished product during the two weight ratio of gelatin and glycerol, can think simply in soft capsule shell and only contain this two kinds of materials.The content of soft capsule of the present invention can be extruded like this, retain empty soft capsule shell (clean and make content without remnants with for example ethanol if desired), by chemical method or chromatographic process, measure the composition of soft capsule shell and particularly measure the amount of glycerol in this soft capsule shell.A kind ofly for the typical chemical method of measuring glycerol, for example can with reference to the content assaying method of two 68 pages " glycerol " kinds of Chinese Pharmacopoeia version in 2005, use chemical titration measure.A kind ofly for the typical color spectral method of measuring glycerol, for example can with reference to the content assaying method of two 68 pages " glycerin and fructose injection " kinds of Chinese Pharmacopoeia version in 2005, use high performance liquid chromatography measure.
According to soft capsule of the present invention, the amount that comprises active component idebenone in its every is 15mg ~ 150mg, for example 20mg ~ 100mg, for example 30mg ~ 90mg, for example 30mg, 45mg, 60mg, 75mg, 90mg.
Another aspect of the present invention provides the method for preparing soft capsule of the present invention, and it comprises the following steps:
(1) medicinal liquid preparation: idebenone and the optional acceptable adjuvant of pharmacy are mixed with to medicinal liquid;
(2) preparation of soft capsule shell material: gelatin, plasticizer, water, optional antiseptic, optional coloring agent are mixed, dissolved, make soft capsule shell feed liquid;
(3) prepare soft capsule: use dropping preparation method or pressing, by medicinal liquid sealed envelope globulate or oval or other soft capsule shape, then dry to remove the moisture in soft capsule shell by soft capsule shell feed liquid, obtain.
Again further, the present invention provides the purposes of medicinal composition soft capsule agent of the present invention in preparing medicine in another aspect again.
According to purposes of the present invention, wherein said medicine is used for following either side or many-sided disease or disease: cerebrovascular; Improve brain metabolism, improve mental symptom; Activate brain mitochondria respiratory activity, improve cerebral ischemia brain energy metabolism, improve glucose utilization rate in brain, ATP in brain produced increase, suppress brain mitochondria to generate lipid peroxide, suppress the film obstacle due to brain mitochondria lipid peroxidation; The caused Brain function damages such as chronic cerebral angiopathy and cerebral trauma; Improve subjective symptom, language, anxiety, depression, hypomnesis, the lower degradation mental act obstacle of intelligence; Promote intelligence; Compose the brain mitochondria function of living, improve brain energy metabolism, improve brain function; Improve that cerebral infarction sequela, apoplexy sequela, cerebral arteriosclerosis cause feel down in spirits, realize is low, affective disorder, aphasis etc.; Improve brain metabolism, protection cranial nerve cell; Mitochondriopathy; Anticoagulant, improve microcirculation; Antioxidation; Treatment or prevention FRDA (ataxia); Treatment or prevention neurological disorder; And the improvement disease relevant to neuronal damage.
In the present invention, described neurological disorder is caused by neurotrauma.More preferably, described neurological disorder is apoplexy.More preferably, described neurological disorder is encephalomyelitis.Preferably, neurological disorder is relevant to mitochondria dysfunction.Preferably, described neurological disorder is relevant to anaerobic condition.Preferably, neurological disorder is alcohol withdrawal syndrome or fetal alcohol syndrome.Preferably, the neuronal damage that neurological disorder infects to by antibacterial or viral infection causes is relevant.
Well-known, formula I compound itself has above-mentioned therapeutic use, so pharmaceutical composition of the present invention has such use equally.
Described in first aspect present invention in compound arbitrary embodiment can with other scheme combination in any, also can with pharmaceutical composition described in second aspect in appoint arbitrary embodiment combination in any; Similarly, described in second aspect present invention in pharmaceutical composition arbitrary embodiment can with other scheme combination in any, also can with compound described in first aspect in appoint arbitrary embodiment combination in any; As long as these combinations are not conflicting.
As the active component idebenone of soft capsule of the present invention, its chemistry 6-(10-hydroxyl decyl)-2 by name, 3-dimethoxy-5-methyl isophthalic acid, 4-benzoquinone, has with chemical structural formula shown in following formula I:
In the present invention, the active constituents of medicine formula I compound of mentioning, its chemistry idebenone by name, molecular formula C
19h
30o
5molecular weight 338.44, it is a kind of effective cerebrovascular medication, this medicine is that brain metabolism, mental symptom are improved medicine, can activate brain mitochondria respiratory activity, improves the brain energy metabolism of cerebral ischemia, improve glucose utilization rate in brain, making in brain ATP produce increases, and suppresses brain mitochondria and generates lipid peroxide, suppresses the film obstacle due to brain mitochondria lipid peroxidation.This product toxicity is low, LD50 mice, rat >10000mg/kg, and rat 20mgkg/d oral half a year, Canis familiaris L. 100mgkgd has no overt toxicity reaction for oral 1 year, without teratogenesis, carcinogenic, mutagenic action.According to document announcement, 6 routine apoplexy sequela patient oral meal this product 30mg, Tmax is 3.31 hours, and Cmax is 290 μ gml, and eliminating the half-life is 7.69 hours, does not detect original shape medicine in urine, is metabolite, excretion rate 7.32% in urine in 24 hours.This medicine indication is clinically: the caused Brain function damages such as chronic cerebral angiopathy and cerebral trauma, can improve subjective symptom, language, anxiety, depression, hypomnesis, the lower degradation mental act obstacle of intelligence.The each 30mg of oral adult (1), every day 3 times, one after each meal.Its formulation products is generally tablet and every amount is generally 30mg.The compounds of this invention is orange-yellow to orange crystallization, crystalline powder or block, odorless; Very easily be dissolved in chloroform, methanol or dehydrated alcohol, be soluble in ethyl acetate, be insoluble in normal hexane, water-soluble hardly.mp52~55°C。For intelligence, promote medicine, can compose the brain mitochondria function of living, improve brain energy metabolism, improve brain function.Cerebral infarction sequela, apoplexy sequela, cerebral arteriosclerosis are caused feel down in spirits, realize is low, affective disorder, aphasis etc. are improved effect.
In the present invention, soft capsule comprises two parts: medicinal liquid (also can be described as in the present invention the similar statements such as " content " or content of the present invention) and softgel shell (also can be described as in the present invention the similar statements such as soft capsule shell).
Formula I compound of the present invention is current unique medicine with brain metabolism and the dual improvement of mental symptom, at present temporarily without direct competitive opponent; And its be cerebral metabolism, nerve cell protection agent, mitochondriopathy effectively, anticoagulant, improve microcirculation, effectively antioxidation, FRDA (ataxia) choice drug.
In addition, formula I compound of the present invention or pharmaceutical composition also can be used for treating neurological disorder, and for improving the disease relevant to neuronal damage.
Preferably, described neurological disorder is caused by neurotrauma.More preferably, described neurological disorder is apoplexy.More preferably, described neurological disorder is encephalomyelitis.
Preferably, described neurological disorder is relevant to mitochondria dysfunction.Preferably, described neurological disorder is relevant to anaerobic condition.Preferably, described neurological disorder is alcohol withdrawal syndrome or fetal alcohol syndrome.Preferably, the neuronal damage that described neurological disorder infects to by antibacterial or viral infection causes is relevant.
The specific embodiment
Following embodiment is intended to illustrate some preferred embodiment of the present invention, and limitation of the present invention does not disclose by the content of these embodiment.
In various tests below, active component in empty in soft capsule is carried out to assay or related substance inspection constantly, all adopt high-performance liquid chromatogram determination, specifically according to two appendix VD high performance liquid chromatography standards of Chinese Pharmacopoeia version in 2010, carry out, mensuration mode is as follows:
(1) chromatographic condition and system suitability: the chromatographic column (4.6 * 250mm that is filler with octadecylsilane chemically bonded silica, 5 μ m), the methanol-water (72:28) of take is mobile phase, flow velocity 1.0ml/min, ultraviolet detection wavelength is 278nm, column temperature is 30 ° of C, and number of theoretical plate calculates and is not less than 2000 by idebenone peak;
(2) preparation of test solution: get soft capsule content of the present invention appropriate, accurately weighed, add mobile phase and dissolve and quantitatively dilute and make the solution that approximately contains 0.2mg formula I compound or concentration suitable with it in every 1ml, as need testing solution; Precision measures 1ml, puts in 100ml measuring bottle, by mobile phase, is diluted to scale, shakes up, in contrast solution; Separately get the adjuvant in soft capsule content, accurately weighed, add mobile phase and dissolve and quantitatively dilute and make the concentration corresponding with 0.2mg/ml formula I compound concentration, as adjuvant solution;
(3) chromatograph test: get contrast solution 20 μ l injection liquid chromatographies, regulate detection sensitivity, make the peak height at main constituent peak be about 10% of full scale, precision measures need testing solution and each 20 μ l of contrast solution again, injection liquid chromatography, records chromatogram to 2.5 times of main constituent peak retention time respectively; Separately get adjuvant solution 20 μ l injection liquid chromatographies, injection liquid chromatography, records chromatogram to 2.5 times of main constituent peak retention time;
(4) chromatographic computation: (4i) record contrast solution chromatogram main peak area (this peak area can be expressed as A1 in the present invention) and retention time thereof; (4ii) record need testing solution chromatogram main peak area (this peak area can be expressed as A100 in the present invention) and retention time thereof; Record the chromatographic peak that in adjuvant solution chromatogram, adjuvant forms; (4iii) in need testing solution chromatogram, the chromatographic peak corresponding with adjuvant retention time disregarded (or disregard further or deduct the impurity peaks that relative retention time is less than 0.2), in need testing solution chromatogram, the chromatographic peak of 0.05 of any A1 of being less than times is ignored, record the impurity peak area of 0.05 times (this peak area can be expressed as Am in the present invention, and m represents that m peak area is greater than the impurity peaks of 0.05 times of A1) and retention time thereof that each peak area in need testing solution chromatogram is greater than A1.
The chromatographic purity of soft capsule content of the present invention can be calculated as follows:
or can be calculated as follows:
In the need testing solution chromatogram of the high-performance liquid chromatogram determination of soft capsule content of the present invention, with main peak retention time, be as the criterion, calculate the relative retention time of each impurity peaks, the relative retention time of a certain impurity peaks (RRt) can be calculated as follows:
In the need testing solution chromatogram of the high-performance liquid chromatogram determination of soft capsule content of the present invention, the chromatograph content of single impurity can be calculated as follows:
or can be calculated as follows:
In soft capsule content of the present invention, total chromatograph content of each impurity can be calculated as follows:
or can be calculated as follows:
embodiment 1: prepare soft capsule of the present invention
Liquid formula:
| Idebenone: | 6g |
| Soybean oil: appropriate, add to | 100g |
Soft capsule shell formula:
| Gelatin: | 100g |
| Glycerol: | 50g |
| Water: | 100g |
Preparation process:
(1) medicinal liquid preparation: at room temperature idebenone and adjuvant are mixed with to medicinal liquid;
(2) preparation of soft capsule shell material: gelatin, plasticizer, water are mixed, dissolved, make soft capsule shell feed liquid;
(3) prepare soft capsule: use dropping preparation method, every content weight is that (those skilled in the art can be easily in regulating the scope of controlling as content 200mg～2000mg/ grain, such as controlling as about 250mg, about 500mg, about 750mg, about 1000mg, about 1500mg etc. for 500mg.Or the amount that comprises active component idebenone in controlling every is 15mg ~ 150mg, 20mg ~ 100mg for example, 30mg ~ 90mg for example, for example 30mg, 45mg, 60mg, 75mg, 90mg), by soft capsule shell feed liquid by medicinal liquid sealed envelope globulate soft capsule, then under 35-37 ° of C, aeration-drying, to remove the moisture in soft capsule shell, obtains.
Note: above liquid formula and soft capsule shell are filled a prescription, and both are preparations separately, does not have between the two consumption to be related to, generally according to the thickness of producing concrete situation control soft capsule shell.
embodiment 2: prepare soft capsule of the present invention
Liquid formula:
| Idebenone: | 3g |
| Semen Maydis oil: appropriate, add to | 100g |
Soft capsule shell formula:
| Gelatin: | 100g |
| Glycerol: | 55g |
| Water: | 75g |
Preparation process: the method for reference example 1 is carried out.
embodiment 3: prepare soft capsule of the present invention
Liquid formula:
| Idebenone: | 10g |
| Oleum Brassicae campestris: appropriate, add to | 100g |
Soft capsule shell formula:
| Gelatin: | 100g |
| Glycerol: | 45g |
| Water: | 125 |
Preparation process: the method for reference example 1 is carried out.
embodiment 4: prepare soft capsule of the present invention
Liquid formula:
| Idebenone: | 15g |
| Polyoxyethylene hydrogenated Oleum Ricini: appropriate, add to | 100g |
Soft capsule shell formula:
| Gelatin: | 100g |
| Glycerol: | 42g |
| Water: | 90g |
Preparation process: the method for reference example 1 is carried out.
embodiment 5: prepare soft capsule of the present invention
Liquid formula:
| Idebenone: | 2g |
| Oleum Ricini/Cera Flava (1/1): appropriate, add to | 100g |
Soft capsule shell formula:
| Gelatin: | 100g |
| Glycerol: | 58g |
| Water: | 110g |
Preparation process: the method for reference example 1 is carried out.
realexecute
example 6: prepare soft capsule of the present invention
Liquid formula:
| Idebenone: | 1g |
| Polyoxyethylene olein: appropriate, add to | 100g |
Soft capsule shell formula:
| Gelatin: | 100g |
| Glycerol: | 53g |
| Water: | 120g |
Preparation process: the method for reference example 1 is carried out.
embodiment 7: prepare soft capsule of the present invention
Liquid formula:
| Idebenone: | 20g |
| PEG400/PVP/ propylene glycol (10:1:0.5): appropriate, add to | 100g |
Soft capsule shell formula:
| Gelatin: | 100g |
| Glycerol: | 48g |
| Ferrum oxide: | 0.1g |
| Water: | 85g |
Preparation process: the method for reference example 1 is carried out.
embodiment 8: prepare soft capsule of the present invention
Liquid formula:
| Idebenone: | 6g |
| Soybean oil/lecithin (10:0.5): appropriate, add to | 100g |
Soft capsule shell formula:
| Gelatin: | 100g |
| Glycerol: | 49g |
| Ethyl hydroxybenzoate: | 0.2g |
| Water: | 110g |
Preparation process: the method for reference example 1 is carried out.The soft capsule of making (drying has been removed the moisture in soft capsule shell) is cut off, remove content, soft capsule shell is removed remaining medicinal liquid by dehydrated alcohol Rapid Cleaning, dry up, measure the glycerol content (using respectively Chinese Pharmacopoeia two 68-69 page chemical titrations of version in 2005 and high performance liquid chromatography) in soft capsule shell, the content that two kinds of methods of result are measured glycerol in soft capsule shell is respectively 49.11% and 49.03%, substantially coincide with above-mentioned batching (although having a little ethyl hydroxybenzoate impact), and say and soft capsule shell, do not basically contain water from result, and two kinds of method measurement results are consistent.
embodiment 9: prepare soft capsule of the present invention
Liquid formula:
| Idebenone: | 6g |
| Hydrogenated vegetable oil/vitamin E (10:0.5): appropriate, add to | 100g |
Soft capsule shell formula:
| Gelatin: | 100g |
| Glycerol: | 52g |
| Titanium dioxide | 0.1g |
| Water: | 100g |
Preparation process: the method for reference example 1 is carried out.
embodiment 10: prepare soft capsule of the present invention
Liquid formula:
| Idebenone: | 40g |
| Hydrogenated vegetable oil/vitamin E (10:0.5): appropriate, add to | 100g |
Soft capsule shell formula:
| Gelatin: | 100g |
| Glycerol: | 52g |
| Titanium dioxide | 0.1g |
| Water: | 100g |
Preparation process: the method for reference example 1 is carried out.
test example 1: prepare soft capsule
Liquid formula: with embodiment 1.
Soft capsule shell formula: the dosing (numbering No. is respectively totally 20 of C101 to C120) of preparing 20 soft capsule materials shown in following table 1 with 100 grams of gelatin, 100 grams of water and not commensurability glycerol (30-75 gram), method according to embodiment 1, be respectively used to wrap up above medicinal liquid, make the soft capsule of the tolerant 500mg of every intragranular.
20 kinds of soft capsules that obtain are above placed in to (every bottled 50 of each formula of lid sealing for high-density polyethylene bottle, each formula with 2 bottles totally 100 test), placement in the Constant Temperature and Humidity Chambers of 36-37 ° of C relative humidity 75% is after 10 months, check the leakage number of different prescription gained soft capsules, leak number divided by 100 of each formulas, obtain slip (%) (slip can represent with R), the results are shown in Table 1.
test example 2: prepare soft capsule
Liquid formula: with embodiment 5.
Soft capsule shell formula: the dosing (numbering No. is respectively totally 20 of C201 to C220) of preparing 20 soft capsule materials shown in following table 1 with 100 grams of gelatin, 100 grams of water and not commensurability glycerol (30-75 gram), method according to embodiment 1, be respectively used to wrap up above medicinal liquid, make the soft capsule of the tolerant 500mg of every intragranular.
20 kinds of soft capsules that obtain are above placed in to (every bottled 50 of each formula of lid sealing for high-density polyethylene bottle, each formula with 2 bottles totally 100 test), placement in the Constant Temperature and Humidity Chambers of 36-37 ° of C relative humidity 75% is after 10 months, the slip that checks different prescription gained soft capsules, the results are shown in Table 1.
test example 3: prepare soft capsule
Liquid formula: with embodiment 7.
Soft capsule shell formula: the dosing (numbering No. is respectively totally 20 of C301 to C320) of preparing 20 soft capsule materials shown in following table 1 with 100 grams of gelatin, 100 grams of water and not commensurability glycerol (30-75 gram), method according to embodiment 1, be respectively used to wrap up above medicinal liquid, make the soft capsule of the tolerant 500mg of every intragranular.20 kinds of soft capsules that obtain are placed in to (every bottled 50 of each formula of lid sealing for high-density polyethylene bottle, each formula with 2 bottles totally 100 test), placement in the Constant Temperature and Humidity Chambers of 36-37 ° of C relative humidity 75% is after 10 months, the slip that checks different prescription gained soft capsules, the results are shown in Table 1.
Result shows, at gelatin: within the scope of the weight ratio of glycerol=100:40 ~ 60, particularly 100:42 ~ 58, slip is significantly lower than the soft capsule shell formula outside this ratio range.And unexpectedly show, for the content medicinal liquid (two kinds of oiliness, a kind of aqueous) of above three types, all show identical character.
Table 1:
| No. | C101 | C102 | C103 | C104 | C105 | C106 | C107 | C108 | C109 | C110 |
| Gelatin/g | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Water/g | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Glycerol/g | 30 | 33 | 35 | 38 | 40 | 42 | 44 | 46 | 48 | 50 |
| R/% | >30 | 24 | 19 | 16 | 13 | 2 | 1 | 1 | 0 | 1 |
| No. | C111 | C112 | C113 | C114 | C115 | C116 | C117 | C118 | C119 | C120 |
| Gelatin/g | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Water/g | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Glycerol/g | 52 | 54 | 56 | 58 | 60 | 63 | 65 | 67 | 70 | 75 |
| R/% | 0 | 0 | 1 | 2 | 10 | 14 | 17 | 24 | >30 | >30 |
| No. | C201 | C202 | C203 | C204 | C205 | C206 | C207 | C208 | C209 | C210 |
| Gelatin/g | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Water/g | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Glycerol/g | 30 | 33 | 35 | 38 | 40 | 42 | 44 | 46 | 48 | 50 |
| R/% | >30 | 25 | 18 | 15 | 11 | 3 | 0 | 1 | 0 | 1 |
| No. | C211 | C212 | C213 | C214 | C215 | C216 | C217 | C218 | C219 | C220 |
| Gelatin/g | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Water/g | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Glycerol/g | 52 | 54 | 56 | 58 | 60 | 63 | 65 | 67 | 70 | 75 |
| R/% | 0 | 0 | 1 | 2 | 11 | 15 | 18 | 27 | >30 | >30 |
| No. | C301 | C302 | C303 | C304 | C305 | C306 | C307 | C308 | C309 | C310 |
| Gelatin/g | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Water/g | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Glycerol/g | 30 | 33 | 35 | 38 | 40 | 42 | 44 | 46 | 48 | 50 |
| R/% | >30 | 26 | 20 | 16 | 11 | 2 | 0 | 0 | 0 | 1 |
| No. | C311 | C312 | C313 | C314 | C315 | C316 | C317 | C318 | C319 | C320 |
| Gelatin/g | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Water/g | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Glycerol/g | 52 | 54 | 56 | 58 | 60 | 63 | 65 | 67 | 70 | 75 |
| R/% | 0 | 1 | 0 | 2 | 9 | 15 | 19 | 27 | >30 | >30 |
test example 4: prepare soft capsule
Soft capsule shell formula: with the dosing (numbering No. is respectively totally 10 of C450 to C459) of 10 soft capsule materials shown in 100 grams of gelatin, 75 grams or 125 grams of water and not commensurability glycerol (42-58 gram) preparation following table 2, method according to embodiment 1, be respectively used to wrap up the medicinal liquid of embodiment 5, make the soft capsule of the tolerant 500mg of every intragranular.
Soft capsule shell formula: with the dosing (numbering No. is respectively totally 10 of C470 to C479) of 10 soft capsule materials shown in 100 grams of gelatin, 75 grams or 125 grams of water and not commensurability glycerol (42-58 gram) preparation following table 2, method according to embodiment 1, be respectively used to wrap up the medicinal liquid of embodiment 7, make the soft capsule of the tolerant 500mg of every intragranular.
Table 2:
| No. | C450 | C451 | C452 | C453 | C454 | C455 | C456 | C457 | C458 | C459 |
| Gelatin/g | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Water/g | 75 | 125 | 75 | 125 | 75 | 125 | 75 | 125 | 75 | 125 |
| Glycerol/g | 42 | 42 | 46 | 46 | 50 | 50 | 54 | 54 | 58 | 58 |
| No. | C470 | C471 | C472 | C473 | C474 | C475 | C476 | C477 | C478 | C479 |
| Gelatin/g | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 | 100 |
| Water/g | 75 | 125 | 75 | 125 | 75 | 125 | 75 | 125 | 75 | 125 |
| Glycerol/g | 42 | 42 | 46 | 46 | 50 | 50 | 54 | 54 | 58 | 58 |
20 kinds of soft capsules that obtain are above placed in to (every bottled 50 of each formula of lid sealing for high-density polyethylene bottle, each formula with 2 bottles totally 100 test), placement in the Constant Temperature and Humidity Chambers of 36-37 ° of C relative humidity 75%, after 10 months, checks the slip of different prescription gained soft capsules.Result demonstration, 20 kinds of soft capsule slips are all lower than 3%, and it is particularly most that lower than 2%, for example only C451 is 3%, and only C452 and C476 are 2%, and other sample is 1% or 0.Visible, at gelatin and glycerol in the situation that within the scope of the weight ratio of 100:42 ~ 58, gelatin all has identical performance in being 100:75 ~ 125 scope with water weight ratio.
test example 5: soft capsule character of the present invention is investigated
The soft capsule of the present invention that above embodiment 1-10 obtains is placed under room temperature and is placed 24 months, and result shows that these capsule slips are all (every Lot sample is investigated more than 200) below 1%.The soft capsule of the present invention that above embodiment 1-9 obtains is measured through HPLC method, and the impurity peaks chromatograph content at its RRt approximately 0.8 place is all between 0.07～0.33%; And these samples are placed after 24 months through room temperature, through HPLC method, to measure, the impurity peaks chromatograph content at its RRt approximately 0.8 place is all between 0.12～0.48%.The soft capsule of the present invention that above embodiment 1-9 obtains is measured through HPLC method, and total chromatograph content of its each impurity is all between 0.21～0.46%; And these samples are placed after 24 months through room temperature, through HPLC method, to measure, total chromatograph content of its each impurity is all between 0.32～0.71%.These results show that soft capsule of the present invention has good physical stability and chemical stability.
Claims (13)
1. a soft capsule, it comprises medicinal liquid and by the soft capsule shell of this medicinal liquid sealing, comprises the idebenone as active ingredient in described medicinal liquid; Wherein,
In described medicinal liquid, comprise the idebenone of 1-20%, and be selected from the acceptable adjuvant of following pharmacy: the PEG that soybean oil, Oleum Brassicae campestris, Semen Maydis oil, polyoxyethylene olein, polyoxyethylene hydrogenated Oleum Ricini, Oleum Ricini, Cera Flava, hydrogenated vegetable oil, lecithin, vitamin E, molecular weight are 200 ~ 600, propylene glycol, polyvinylpyrrolidone or its combination;
Described soft capsule shell comprises gelatin and as the glycerol of plasticizer, the weight ratio of described gelatin and glycerol is 1:(0.42 ~ 0.58).
2. according to the soft capsule of claim 1, in wherein said medicinal liquid, comprise the idebenone of 2-15%.
3. according to the soft capsule of claim 1, in wherein said medicinal liquid, comprise the idebenone of 3-10%.
4. according to the soft capsule of claim 1, wherein said soft capsule shell also comprises and is selected from following adjuvant: antiseptic, coloring agent.
5. according to the soft capsule of claim 4, described antiseptic is selected from ethyl hydroxybenzoate, methyl hydroxybenzoate.
6. according to the soft capsule of claim 4, described coloring agent is selected from ferrum oxide, titanium oxide.
7. according to the soft capsule of claim 1, wherein said soft capsule shell is by comprising that following material makes: gelatin, plasticizer, He Shui, and optional be selected from following adjuvant: antiseptic, coloring agent.
8. according to the soft capsule of claim 7, the weight ratio that described gelatin and water are used is 1:(0.8 ~ 1.2).
9. according to the soft capsule of claim 4, the weight ratio of described antiseptic and described gelatin is (0 ~ 0.5): 100.
10. according to the soft capsule of claim 4, wherein in soft capsule shell, the content of coloring agent is less than 0.5%.
11. according to the soft capsule of claim 1 to 10 any one, and the amount that comprises active component idebenone in its every is 15mg ~ 150mg.
12. according to the soft capsule of claim 1 to 10 any one, and the amount that comprises active component idebenone in its every is 20mg ~ 100mg.
13. according to the soft capsule of claim 1 to 10 any one, and the amount that comprises active component idebenone in its every is 30mg, 45mg, 60mg, 75mg or 90mg.
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| CN201310000690.6A CN103054830B (en) | 2013-01-01 | 2013-01-01 | Soft capsule for treating nerve diseases |
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| CN109364050B (en) * | 2018-10-19 | 2021-02-02 | 大连医科大学 | Application of idebenone in preparation of medicine for treating pulmonary hypertension |
| CN112043679B (en) * | 2020-08-28 | 2023-04-07 | 广州六顺生物科技股份有限公司 | Soft capsule preparation containing quinazoline compound and preparation method thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1164388A (en) * | 1996-02-01 | 1997-11-12 | 武田药品工业株式会社 | Pharmaceutical composition for treatment of dementia |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1164388A (en) * | 1996-02-01 | 1997-11-12 | 武田药品工业株式会社 | Pharmaceutical composition for treatment of dementia |
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