CN1488342A - Compressed-shaping formulation for hypnosis - Google Patents
Compressed-shaping formulation for hypnosis Download PDFInfo
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- CN1488342A CN1488342A CNA031565484A CN03156548A CN1488342A CN 1488342 A CN1488342 A CN 1488342A CN A031565484 A CNA031565484 A CN A031565484A CN 03156548 A CN03156548 A CN 03156548A CN 1488342 A CN1488342 A CN 1488342A
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- compressed
- shaping formulation
- hypnosis
- diphenhydramine
- shaping
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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Abstract
A compression molded hypnotic preparation is provided, which preparation has hypnotic/sedative actions, does not discolor, is stable, masks its bitter taste, and quickly and surely produces its effects. To provide a preparation which, while containing diphenhydramine or its acid salt as a medicinal component having hypnotic/sedative actions, does not discolor, is stable, masks its bitter taste, and quickly and surely produces its effects. The compression molded hypnotic preparation contains the diphenhydramine or its acid salt as the medicinal component having hypnotic/sedative actions, a lowly swellable polymer, and a highly swellable polymer, wherein the lowly swellable polymer is selected from crystalline cellulose, ethylcellulose and aminoalkyl methacrylate copolymer RS.
Description
Technical field
The present invention relates to compressed-shaping formulation for hypnosis, specifically, relate to the stable invariant color that contains diphenhydramine or its acid-addition salts, covered bitterness when taking and rapid-action compressed-shaping formulation for hypnosis, wherein diphenhydramine or its acid-addition salts are as the active ingredient with hypnosis sedation.
Background technology
In the past, diphenhydramine or its acid-addition salts be because of having antihistamine effect and central action, and be used as rhinitis, dermatosis, coldrex and relieving cough and expelling phlegm the effective elements of the medicine, but there is the shortcoming that produces sleepy side effect in it.
For example, well-known, diphhydramine hydrochloride and diphenhydramine citrate have and the gentle equal syngignoscism of hypnosis preparation.And, because it disappears rapidly, do not produce toleration again in blood, in American-European countries, as the OTC (over-the-counter) hypnotic use of the general pharmaceuticals that are equivalent to Japan, the dose of taking is by the dosage use of the each 50mg of adult.
But, produce when being stranded meaning in the blood plasma concentration of diphhydramine hydrochloride more than 50ng/ml by the sedation of diphhydramine hydrochloride, its concentration height in blood plasma when producing antihistamine effect of this concentration ratio.In addition, oral hydrochloride diphenhydramine 50mg, the meansigma methods of its concentration changes with time in blood plasma shows, takes concentration (Carruthers etc., Clin.Pharmacol, the Ther. that just can reach after 2-4 hour above 50ng/ml; 23 (4); 375-382; 1978).Therefore, when using,,, just can not give full play to the drug effect of somnifacient if the disintegrate of preparation and stripping are slack-off according to the condition of taking as oral hypnotic.
On the other hand, diphenhydramine or its acid-addition salts have the strong impulse bitterness, produce sense of discomfort when taking.But existing method is to utilize the slow down dissolution rate of diphenhydramine of the thin film contain oils and fats and insoluble polymer substance and substrate to come taste masking, though this method does not influence its drug effect as antihistaminic of performance, exists the problem that can not in time bring into play drug effect fully as hypnotic drug.In addition, the method for the taste masking of mixing sweetener or correctives exists bitterness not covered fully, still remains in the shortcoming on the tongue.
In addition, the preparation that contains diphenhydramine or its acid-addition salts causes variable color because of preparation additives such as the blended tax punishment agent of institute sometimes, or moisture absorption or preparation is sticked together each other under humid condition.And, also have because diphenhydramine or its acid-addition salts self are seen phototropic, even content does not reduce, the shortcoming of forfeiture commodity value is arranged also.
Summary of the invention
Therefore, requiring provides diphenhydramine or its acid-addition salts that contains as the active ingredient of hypnosis sedation, stablizes invariant color simultaneously, does not have bitterness and the rapid definite preparation of onset when taking.
Present inventors have carried out conscientiously research for the problems referred to above, find by diphenhydramine or its acid-addition salts multiple macromolecule different with swellability are made up the back compression forming, can obtain not influencing under the deliquescent situation, can prevent the diphenhydramine variable color, suppress bitterness, can bring into play the compressed-shaping formulation for hypnosis of the excellence of effects such as hypnosis really.Thereby finished the present invention.
That is, the invention provides compressed-shaping formulation for hypnosis, it is characterized by, contain diphenhydramine or its acid-addition salts, low swelling macromolecule and high swelling property macromolecule as the active ingredient of hypnosis sedation.
In addition, the present invention also provides a kind of purposes of diphenhydramine or its addition salts, and this purposes is to make the compressed-shaping formulation for hypnosis that improves sleep.
Concrete form of implementation
Compressed-shaping formulation for hypnosis of the present invention (below be called " preparation of the present invention ") is prepared as follows: combination diphenhydramine or its acid-addition salts, low swellability macromolecule and high swelling property macromolecule, be made into compression forming powder body, compression forming.
In the preparation of the present invention, as the diphenhydramine that hypnosis sedation active ingredient uses, can be the primitive form of its alkali, also can be the form of its acid-addition salts.But the primitive form of its alkali is a liquid, need make its granulating, for example makes its granulating with powders such as light silicon dioxides.Therefore, during actual fabrication preparation of the present invention, be preferably its acid-addition salts.Acid-addition salts as diphenhydramine can be enumerated: diphhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine citrate, tannic acid diphenhydramine, lauryl sulphate acid diphenhydramine and sulphuric acid diphenhydramine.Wherein, preferred acid-addition salts is diphhydramine hydrochloride and diphenhydramine citrate, and particularly preferred acid-addition salts is a diphhydramine hydrochloride.
The mean diameter of the former powder of these diphenhydramine or its acid-addition salts can be used the former powder of any size without limits, but preferably at 30 μ m or more than the 30 μ m, below the 500 μ m, preferred especially 50～300 μ m.Mean diameter is adjusted as required, can adjust by the method for routines such as former powder is pulverized or sieved, and this method has no particular limits.For example, pulverizing can utilize beater grinder, pulverizers such as pulverizer, roll-type pulverizing, draw point (impact) grinder, ball mill, vibrator, type vibrating crusher, jet pulverizer carry out fast, screening can be used the continous way vibrating screen classifier, and air-flowing type screening machine etc. carries out.
The content ratio of the diphenhydramine of preparation of the present invention or its acid-addition salts (below be called " diphenhydramine etc. ") is because different cannot treat different things as the same such as dosage form and dose, the preferably scope about 5～30 quality %.In addition, the addition of diphenhydramine that contains in 1 preparation of the present invention etc. without limits, 1 dosage of diphenhydramine etc. is 50mg, so 1 preparation can contain 1 dosage can dividing exactly 50mg in 12.5mg～50mg scope.
In addition, the low swellability macromolecule that uses in the preparation of the present invention is water insoluble and swellability is little, mixes with diphenhydramine etc., and it is reactive essential low, as invariant color after the compression forming.The high molecular object lesson of described low swellability can be enumerated: crystalline cellulose, ethyl cellulose, aminoalkyl (methyl) acrylate copolymer RS etc., can use wherein a kind of, and also can mix wherein two or more of use.Wherein, best concrete example is a crystalline cellulose.With respect to diphenhydramine of 1 mass parts etc., preferably use these low swelling macromolecule 1 mass parts or more than 1 mass parts, with respect to diphenhydramine of 1 mass parts etc., more preferably use these low swelling macromolecule 2 mass parts or more than 2 mass parts.Should low high molecular addition of swellability, though different because of the gross mass of the content of diphenhydramine etc. and preparation, with respect to the gross mass of preparation of the present invention, its addition should be in the scope of 3～90 quality %, preferably in the scope of 5～80 quality %.
The high swelling property macromolecule that preparation of the present invention uses is water insoluble, and swellability is big, mixes with diphenhydramine etc., and it is reactive essential low, as invariant color after the compression forming.The high molecular object lesson of described high swelling property can be enumerated: intersect sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, intersection polyvinylpyrrolidone etc., can use wherein a kind of, also can mix wherein two or more of use.Can enumerate the intersection sodium carboxymethyl cellulose as most preferred example, the high molecular addition of these high swellings, though different because of the gross mass of the content of diphenhydramine etc. and preparation, but gross mass with respect to preparation of the present invention, its addition should be in the scope of 0.1～5 quality %, preferably in the scope of 0.5～3 quality %.
Need among the present invention these low swellability macromolecules and high swelling property macromolecule are used in combination, the proportioning of combination for the high swelling property macromolecule be low high molecular 0.01 quality of swellability doubly or 0.01 quality doubly more than, be preferably 0.2 quality doubly or 0.2 quality doubly more than.
Preparation of the present invention removes and contains above-mentioned diphenhydramine etc., outside low swellability macromolecule and the high swelling property macromolecule, can also add known medical additive as required, for example: excipient, bonding agent, disintegrating agent, lubricant, stabilizing agent, surfactant, cosolvent, Reducing agent, buffer agent, adsorbent, fluidizer, antistatic agent, coating materials, plasticizer, anti-adsorbent, opacifier, optical brightener, antioxidant, sweeting agent, correctives, refrigerantization agent, coloring agent, fumet, spice, aromatic etc., be mixed with compression forming powder body, use the conventional method compression forming then, thereby finish manufacturing.
The medical additive that uses as preparation of the present invention preferably uses and mixes a kind of not causing after the compression forming in metachromatic water soluble polymer, light silicon dioxide, saccharide, sugar alcohol, starch, Pulvis Talci, the magnesium stearate or multiple with diphenhydramine etc.
Wherein, can not enumerate hydroxypropyl methylcellulose, hydroxypropyl cellulose, Polyethylene Glycol etc. with not causing metachromatic water soluble polymer after diphenhydramine etc. mixes compression forming.In addition, as starch, can enumerate alphalysed starch, corn starch, potato starch, wheaten starch, rice starch etc.As saccharide, sugar alcohol, can enumerate lactose, mannitol, xylitol, dextrin, sorbitol etc.The addition of these water soluble polymers, starch, saccharide, sugar alcohol is decided with the manufacture method of powder body according to the size and the compression forming of compressed-shaping formulation, though its consumption is different, the gross mass of compressed-shaping formulation is approximately used 0～80 quality % relatively.
In addition, the light silicon dioxide in the above-mentioned pharmaceutical additive can increase compression forming with the flowability of powder body, has the moisture absorption that prevents compressed-shaping formulation and the effect of adhesion simultaneously.The light silicon dioxide that the preferred mean diameter of this light silicon dioxide is less, preferably using mean diameter is the light silicon dioxide of 4～5nm.Its addition preferably uses 1～10 quality % of compressed-shaping formulation gross mass.
And, preferably add Pulvis Talci and magnesium stearate or any one material wherein of 0.1～5 quality % of compressed-shaping formulation gross mass.
The powder body of compression forming can directly use the mixed-powder of mentioned component, also can use the powder of part or all of granulation.When granulating, adopts this powder body conventional method of granulating, for example can utilize the spray granulation method of using the solution contain water or organic solvent or dispersion liquid, stir granulation, the granulation that flows, rotate wet granulation methods such as granulation, rotational flow granulation, use the dry granulation methods such as weight granulation of powder adhesive.
The compressed moulding process of above-mentioned mixed-powder or granulation powder forms preparation of the present invention.Concrete compressing and forming process can be enumerated the method for tablet machine such as rotary tablet machine or single punch tablet machine, perhaps use the method for oil pressure forcing press etc., the preferred method of using tablet machine, because the production efficiency height when using rotary tablet machine, so especially preferably use rotary tablet machine.In addition, the pressure of compression forming is decided according to the kind or the weight of size, shape and the pharmaceutical additive of compressed-shaping formulation, for example, when the manufacturing diameter is the compressed-shaping formulation of 9mm, preferred 300kg/cm
2Or 300kg/cm
2Above pressure, more preferably 500～1500kg/cm
2Pressure.
The dosage form of the preparation of the present invention that so obtains is a tablet, and its shape can be disk, special-shaped sheet etc., has no particular limits.In addition, in this tablet line of cut can be arranged.
In addition, preparation of the present invention can be made instant type coated preparation or sugar-coated preparation by pan coating method, fluidized bed coating method, the combined method etc. of rotating coating method, dry coating or these methods.At this moment, also the membrane agent of water solublity or gastric solubility can be dissolved or be dispersed in water or the organic solvent, carry out spray coating or directly be coated with these membrane agents, dried coating is carried out in heating, pressurization.In addition, also can add plasticizer, anti-adsorbent, opacifier, filler etc. in the membrane agent.
Best form of implementation of the present invention more than has been described, contain 12.5～50mg diphhydramine hydrochloride in each preparation, relative 1 part of diphhydramine hydrochloride, mixing as the low high molecular crystalline cellulose of swellability is more than 2 parts or 2 parts, and the intersection sodium carboxymethyl cellulose of 0.1～5 quality % of mixing preparation gross mass of the present invention is as the high swelling property macromolecule, the light silicon dioxide of 1～10 quality % of preparation gross mass of the present invention, the hydroxypropyl cellulose of 1～5 quality % of preparation gross mass of the present invention as water soluble polymer, the lactose that mixes 20～80 quality % of preparation gross mass of the present invention, the Pulvis Talci and the magnesium stearate of mixing 0.1～5 quality % of preparation gross mass of the present invention, obtain the compression forming powder body, use tablet machine with 500～1500kg/cm
2Pressure this powder body is pressed into the compressed-shaping formulation that each quality of the pharmaceutical preparations is 100～750mg.
The preparation of the present invention that so obtains contains diphenhydramine etc., low swellability macromolecule and high swelling property macromolecule, and the bitterness when taking has been covered in its stable invariant color, and effect onsets such as hypnosis are rapid.Said preparation has sedation to insomnia, anxiety, excitement, restless with anxiety etc., and can alleviate these symptoms with nose heave, tired sleepy sense, eliminate uneasy sense etc.
Enumerate embodiment below and further specify the present invention, but the present invention is not limited to these embodiment.
Embodiment 1
Compressed-shaping formulation (1):
Mix 100g diphhydramine hydrochloride (mean diameter is 220 μ m), 100g crystalline cellulose, 728g lactose, 20g intersection sodium carboxymethyl cellulose, 48g light silicon dioxide, add the alcoholic solution of 240g 10% hydroxypropyl cellulose, stir, granulate and drying, cross 20 mesh sieves then.In this granule of 1009.4g, mix 9.8g magnesium stearate and 9.8g Pulvis Talci, obtain the compression forming granule, use rotary tablet machine with 900kg/cm
2Pressure, with this compression forming granule compression forming, obtain the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Embodiment 2
Compressed-shaping formulation (2):
The consumption that changes 200g, lactose except the consumption of crystalline cellulose into changes into the 628g, and other are identical with embodiment 1, obtain the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Embodiment 3
Compressed-shaping formulation (3):
The consumption that changes 400g, lactose except the consumption of crystalline cellulose into changes into the 428g, and other are identical with embodiment 1, obtain the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Embodiment 4
Compressed-shaping formulation (4):
The consumption that changes 600g, lactose except the consumption of crystalline cellulose into changes into the 228g, and other are identical with embodiment 1, obtain the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Embodiment 5
Compressed-shaping formulation (5):
The consumption that changes 800g, lactose except the consumption of crystalline cellulose into changes into the 28g, and other are identical with embodiment 1, obtain the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Embodiment 6
Compressed-shaping formulation (6):
Mix 125g diphhydramine hydrochloride (mean diameter is 220 μ m), 380g crystalline cellulose, 385g lactose, 20g intersection sodium carboxymethyl cellulose, 50g light silicon dioxide, add the alcoholic solution of 200g 10% hydroxypropyl cellulose, stir, granulate and drying, cross 20 mesh sieves then.In this granule of 960.4g, mix 9.8g magnesium stearate and 9.8g Pulvis Talci, obtain the compression forming granule, use rotary tablet machine with about 900kg/cm
2Pressure, with this compression forming granule compression forming, obtain the compressed-shaping formulation of every tablet quality 100mg, diameter 5.5mm, thick 4.2mm.
Embodiment 7
Compressed-shaping formulation (7):
Mix 37.5g diphhydramine hydrochloride (mean diameter is 220 μ m), 375g crystalline cellulose, 652.5g lactose, 24g intersection sodium carboxymethyl cellulose, 60g light silicon dioxide, add the alcoholic solution of 270g10% hydroxypropyl cellulose, stir, granulate and drying, cross 20 mesh sieves then.In this granule of 1152.5g, mix 11.8g magnesium stearate and 11.8g Pulvis Talci, obtain the compression forming granule, use rotary tablet machine with about 900kg/cm
2Pressure, with this compression forming granule compression forming, obtain the compressed-shaping formulation of every tablet quality 400mg, diameter 10mm, thick 4.3mm.
Embodiment 8
Compressed-shaping formulation (8):
Mix 500g diphhydramine hydrochloride (mean diameter is 220 μ m), 500g crystalline cellulose, 77g lactose, 20g intersection sodium carboxymethyl cellulose, 55g light silicon dioxide, add the alcoholic solution of 240g 10% hydroxypropyl cellulose, stir, granulate and drying, cross 20 mesh sieves then.In this granule of 1152.5g, mix 11.8g magnesium stearate and 11.8g Pulvis Talci, obtain the compression forming granule, use rotary tablet machine with about 900kg/cm
2Pressure, with this compression forming granule compression forming, obtain the compressed-shaping formulation of every tablet quality 120mg, diameter 6mm, thick 4mm.
Embodiment 9
Compressed-shaping formulation (9):
Mix 150g diphhydramine hydrochloride (mean diameter is 220 μ m), 465g crystalline cellulose, 450g lactose, 24g intersection sodium carboxymethyl cellulose, 60g light silicon dioxide, add the alcoholic solution of 270g 10% hydroxypropyl cellulose, stir, granulate and drying, cross 20 mesh sieves then.In this granule of 1152.5g, mix 11.8g magnesium stearate and 11.8g Pulvis Talci, obtain the compression forming granule, use rotary tablet machine with about 900kg/cm
2Pressure, with this compression forming granule compression forming, obtain the compressed-shaping formulation of every tablet quality 400mg, diameter 10mm, thick 4.3mm.
Comparative example 1
Compare compressed-shaping formulation (1):
Except the consumption without crystalline cellulose, lactose changes into the 828g, other are identical with embodiment 1, obtain the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Comparative example 2
Compare compressed-shaping formulation (2):
The consumption that changes 40g, lactose except the crystalline cellulose consumption into changes into the 788g, and other are identical with embodiment 1, obtains the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Comparative example 3
Compare compressed-shaping formulation (3):
The consumption that changes 60g, lactose except the consumption of crystalline cellulose into changes into the 768g, and other are identical with embodiment 1, obtain the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Comparative example 4
Compare compressed-shaping formulation (4):
Change into the 648g except intersecting the consumption that the consumption of sodium carboxymethyl cellulose, crystalline cellulose changes 200g, lactose into, other are identical with embodiment 1, obtain the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Embodiment 10
Compressed-shaping formulation (10):
Mix 100g diphhydramine hydrochloride (mean diameter is 220 μ m), 440g crystalline cellulose, 410g lactose, 10g and intersects sodium carboxymethyl cellulose, mistake 20 mesh sieves then.In this granule of 940.8g, mix 19.6g light silicon dioxide, 9.8g magnesium stearate and 9.8g Pulvis Talci, obtain the compression forming granule, use rotary tablet machine with about 900kg/cm
2Pressure, with this compression forming granule compression forming, obtain the compressed-shaping formulation of every tablet quality 250mg, diameter 9mm, thick 4.1mm.
Embodiment 11
Compressed-shaping formulation (11):
Mix 200g diphhydramine hydrochloride (mean diameter is 220 μ m), 400g crystalline cellulose, 200g lactose, 192g corn starch, add the alcoholic solution of 160g 5% hydroxypropyl cellulose, stir, granulate and drying, cross 20 mesh sieves then.In this granule of 980g, mix 882g crystalline cellulose, 19.6g intersection sodium carboxymethyl cellulose, 39.2g light silicon dioxide, 19.6g magnesium stearate and 19.6g Pulvis Talci, obtain the compression forming granule, use rotary tablet machine with about 900kg/cm
2Pressure, this compression forming is obtained the compressed-shaping formulation of every tablet quality 250mg, diameter 9mm, thick 4.0mm with the granule compression forming.
Embodiment 12
Compressed-shaping formulation (12):
Mix 200g diphhydramine hydrochloride (mean diameter is 220 μ m), 640g crystalline cellulose, 1016g lactose, 40g intersection sodium carboxymethyl cellulose, 96g light silicon dioxide, add the alcoholic solution of 480g 10% hydroxypropyl cellulose, stir, granulate and drying, cross 20 mesh sieves then.In this granule of 1999.2g, mix 19.6g magnesium stearate and 19.6g Pulvis Talci, obtain the compression forming granule, use rotary tablet machine with about 900kg/cm
2Pressure, with this compression forming granule compression forming, obtain the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Embodiment 13
Compressed-shaping formulation (13):
Get the compressed-shaping formulation that 6000 embodiment 12 obtain, carry out spray coating with containing the talcous 10% aqueous coatings liquid of 150g hydroxypropyl methylcellulose, 10g Polyethylene Glycol, 22g titanium dioxide and 18g, with respect to plain sheet, the coating amount of drying regime is the 5mg/ sheet.
Comparative example 5
Compare compressed-shaping formulation (5):
Except lactose changed castor sugar into, other were identical with embodiment 1, obtained the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Comparative example 6
Compare compressed-shaping formulation (6):
Except lactose changed glucose into, other were identical with embodiment 1, obtained the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Comparative example 7
Compare compressed-shaping formulation (7):
Except hydroxypropyl cellulose changed polyvinylpyrrolidone into, other were identical with embodiment 1, obtained the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Comparative example 8
Compare compressed-shaping formulation (8):
Except the intersection sodium carboxymethyl cellulose changes into the sodium carboxymethyl cellulose, other are identical with embodiment 1, obtain the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Test example 1
Taste test:
The compressed-shaping formulation that the foregoing description and comparative example obtain is sucked 1 respectively, does not chew, and includes for 10 seconds at mouth, swallows then.10 normal adults with following evaluation criterion, are carried out the bitterness evaluation to taste at this moment.10 people's average result is as shown in table 1.Show that with respect to diphhydramine hydrochloride the compressed-shaping formulation that blended low swellability macromolecule obtains does not have intensive bitterness when taking when 1 mass parts or 1 mass parts are above.
Sense of taste evaluation criterion mark
There is not bitterness: 0 minute
Bitter slightly: 1 minute
Bitter: 2 minutes
Table 1
| The sense of taste (on average) | The sense of taste (on average) | The sense of taste (on average) | |||
| Embodiment 1 | ????0.6 | Embodiment 8 | ????0.5 | Comparative example 2 | ????1.6 |
| Embodiment 2 | ????0.3 | Embodiment 9 | ????0.3 | Comparative example 3 | ????1.3 |
| Embodiment 2 | ????0.3 | Embodiment 10 | ????0.2 | Comparative example 4 | ????0.2 |
| Embodiment 4 | ????0.1 | Embodiment 11 | ????0.1 | Comparative example 5 | ????0.5 |
| Embodiment 5 | ????0.1 | Embodiment 12 | ????0.2 | Comparative example 6 | ????0.6 |
| Embodiment 6 | ????0.4 | Embodiment 13 | ????0.1 | Comparative example 7 | ????0.5 |
| Embodiment 7 | ????0.1 | Comparative example 1 | ????1.8 | Comparative example 8 | ????0.7 |
Test example 2
Slaking test
With reference to the slaking test method of the 14th edition Pharmacopeia of Japan, the compressed-shaping formulation that the foregoing description and comparative example are obtained, is measured with 37 ℃ pure water under no wire rod spare with NT-2HS type slaking test instrument (Fushan Mountain industry (strain) system).The disintegration time scope of 6 compressed-shaping formulations is as shown in table 2.Mixed the disintegrate soon of high swelling property high molecular compressed-shaping formulation.
Table 2
| Disintegration time (minute) | Disintegration time (minute) | Disintegration time (minute) | |||
| Embodiment 1 | ??2.9～4.6 | Embodiment 8 | ??3.6～4.8 | Comparative example 2 | ??3.2～4.8 |
| Embodiment 2 | ??3.2～4.7 | Embodiment 9 | ??3.8～5.8 | Comparative example 3 | ??3.3～4.8 |
| Embodiment 2 | ??3.1～5.2 | Embodiment 10 | ??2.3～4.2 | Comparative example 4 | ??9.2～15.3 |
| Embodiment 4 | ??3.4～5.4 | Embodiment 11 | ??3.2～4.2 | Comparative example 5 | ??3.4～4.6 |
| Embodiment 5 | ??3.5～5.9 | Embodiment 12 | ??3.4～4.9 | Comparative example 6 | ??3.5～4.8 |
| Embodiment 6 | ??2.7～4.2 | Embodiment 13 | ??3.8～5.3 | Comparative example 7 | ??3.3～4.4 |
| Embodiment 7 | ??3.8～5.8 | Comparative example 1 | ??2.8～4.5 | Comparative example 8 | ??3.5～5.2 |
Test example 3
The storage stability test:
The compressed-shaping formulation that the foregoing description and comparative example are obtained is preserved 6 months (40 ℃, relative humidity be 75%) and 1 year (25 ℃), and the observation outward appearance is estimated based on following evaluation criterion over time, and its result is as shown in table 3.Preparation of the present invention has excellent storage stability.
The storage stability evaluation criterion is estimated
No change: zero
Flavescence a little: △
Flavescence: *
Table 3
| 6 months * | 1 year ** | 6 months * | 1 year ** | 6 months * | 1 year ** | |||
| Embodiment 1 | ????○ | ??○ | Embodiment 8 | ????○ | ???○ | Comparative example 2 | ??○ | ??○ |
| Embodiment 2 | ????○ | ??○ | Embodiment 9 | ????○ | ???○ | Comparative example 3 | ??○ | ??○ |
| Embodiment 2 | ????○ | ??○ | Embodiment 10 | ????○ | ???○ | Comparative example 4 | ??○ | ??○ |
| Embodiment 4 | ????○ | ??○ | Embodiment 11 | ????○ | ???○ | Comparative example 5 | ??△ | ??△ |
| Embodiment 5 | ????○ | ??○ | Embodiment 12 | ????○ | ???○ | Comparative example 6 | ??× | ??× |
| Embodiment 6 | ????○ | ??○ | Embodiment 13 | ????○ | ???○ | Comparative example 7 | ??× | ??× |
| Embodiment 7 | ????○ | ??○ | Comparative example 1 | ????○ | ???○ | Comparative example 8 | ??△ | ??△ |
*40℃、CRH75％
**25℃
Embodiment 14
Compressed-shaping formulation (14):
Use 200g diphhydramine hydrochloride (mean diameter is 220 μ m), 640g crystalline cellulose, 1016g lactose, 40g intersection sodium carboxymethyl cellulose, 96g light silicon dioxide, 48g hydroxypropyl cellulose, 20g magnesium stearate and 20g Pulvis Talci, obtain the tabletting granule, according to a conventional method, use rotary tablet machine with about 900kg/cm
2Pressure, this tabletting is carried out tabletting with granule, obtain the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Embodiment 15
Compressed-shaping formulation (15):
Except replacing with 200g diphhydramine hydrochloride (mean diameter is 403 μ m) the 200g diphhydramine hydrochloride (mean diameter is 220 μ m) of embodiment 14, other are identical with embodiment 14, obtain the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Comparative example 9
Compare compressed-shaping formulation (9):
Use 640g crystalline cellulose, 1216g lactose, 40g intersection sodium carboxymethyl cellulose, 96g light silicon dioxide, 48g hydroxypropyl cellulose, 20g magnesium stearate and 20g Pulvis Talci, obtain the tabletting granule, according to a conventional method, use rotary tablet machine with about 900kg/cm
2Pressure, this tabletting is carried out tabletting with granule, obtain the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Test example 4
The hypnosis test:
With 8 the adults of slight insomnia tendency being arranged is object, and the precontract of sleeping was taken the compressed-shaping formulation that 2 embodiment 14,15 and comparative example 9 obtain in 30 minutes, took 7 days, and the research medicament is to sleeping and dormant influence.The result of sleeping test is as shown in table 4, and the result of sleep state test is as shown in table 5.Compressed-shaping formulation of the present invention compares the effect excellence than compressed-shaping formulation aspect sleeping and sleep state.
Table 4
| Sleeping | Good | Good slightly | Do not have and improve | Poor slightly | Difference |
| Embodiment 14 | ????3 | ????3 | ????1 | ????1 | ????0 |
| Embodiment 15 | ????2 | ????4 | ????1 | ????1 | ????0 |
| Comparative example 9 | ????0 | ????0 | ????7 | ????1 | ????0 |
Table 5
| Sleep state | Good | Good slightly | Do not have and improve | Poor slightly | Difference |
| Embodiment 14 | ????2 | ????4 | ????2 | ????0 | ????0 |
| Embodiment 15 | ????1 | ????5 | ????2 | ????0 | ????0 |
| Comparative example 9 | ????0 | ????1 | ????6 | ????1 | ????0 |
Embodiment 16
Compressed-shaping formulation (16):
Except replacing with 200g diphhydramine hydrochloride (mean diameter is 54.3 μ m) the 200g diphhydramine hydrochloride (mean diameter is 220 μ m) of embodiment 14, other are identical with embodiment 14, obtain the compressed-shaping formulation of every tablet quality 260mg, diameter 9mm, thick 4.2mm.
Test example 4
Taste test:
The compressed-shaping formulation that the foregoing description 14～16 obtains is sucked 1 respectively, does not chew, and includes for 10 seconds at mouth, swallows then.10 normal adults with following evaluation criterion, are carried out the bitterness evaluation to taste at this moment.10 people's average result is as shown in table 6.Compressed-shaping formulation of the present invention is not felt bitterness.
Table 6
| The sense of taste (on average) | |
| Embodiment 14 | ????0.3 |
| Embodiment 15 | ????0.2 |
| Embodiment 16 | ????0.6 |
Contain the compressed-shaping formulation for hypnosis of the present invention that diphenhydramine etc. has hypnosis sedation active ingredient, by mixing low swellability macromolecule and high swelling property macromolecule, become invariant color, covered the bitterness when taking, the compressed-shaping formulation for hypnosis of taking convenience.And, thisly made up low swellability macromolecule and the easy disintegrate of the high molecular compressed-shaping formulation of high swelling property self, can in blood, discharge enough diphenhydramine as hypnosis sedation active ingredient etc.
Therefore, diphenhydramine etc. can be used as hypnosis sedation medicament and uses.And, the present invention can provide compressed-shaping formulation for hypnosis, and described compressed-shaping formulation for hypnosis plays sedation to insomnia, anxiety, excited, impatience etc., and can alleviate that these symptoms follow nose heave and tired sleepy also eliminated uneasy sense etc., onset rapidly, and determined curative effect.
Claims (7)
1. compressed-shaping formulation for hypnosis is characterized by and contains as the diphenhydramine with hypnosis sedation active ingredient or its acid-addition salts, low swellability macromolecule and high swelling property macromolecule.
2. compressed-shaping formulation for hypnosis as claimed in claim 1,0.01 quality that it is characterized by the high molecular addition of high swelling property and be the low high molecular addition of swellability doubly or 0.01 quality doubly more than.
3. compressed-shaping formulation for hypnosis as claimed in claim 1 or 2, it is characterized by low swellability macromolecule is a kind or the multiple material of selecting from crystalline cellulose, ethyl cellulose, aminoalkyl (methyl) acrylate copolymer RS.
4. compressed-shaping formulation for hypnosis as claimed in claim 1 or 2, it is characterized by the high swelling property macromolecule is a kind or the multiple material of selecting from intersection sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, intersection polyvinylpyrrolidone.
5. compressed-shaping formulation for hypnosis as claimed in claim 1 is characterized by a kind or multiple material also containing in water soluble polymer, light silicon dioxide, saccharide, sugar alcohol, starch, Pulvis Talci and the magnesium stearate.
6. as any described compressed-shaping formulation for hypnosis in the claim 1～5,1 dosage that it is characterized by diphenhydramine or its acid-addition salts is 50mg.
7. the purposes of diphenhydramine or its acid-addition salts is characterized by the compressed-shaping formulation for hypnosis that is used to make the improvement sleep.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2002263041A JP5148801B2 (en) | 2002-09-09 | 2002-09-09 | Hypnotic solid formulation |
| JP263041/2002 | 2002-09-09 | ||
| JP272093/2002 | 2002-09-18 | ||
| JP2002272093A JP2004107258A (en) | 2002-09-18 | 2002-09-18 | Compression molded hypnotic preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1488342A true CN1488342A (en) | 2004-04-14 |
| CN100356911C CN100356911C (en) | 2007-12-26 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB031565484A Expired - Fee Related CN100356911C (en) | 2002-09-09 | 2003-09-08 | Compressed-shaping formulation for hypnosis |
Country Status (4)
| Country | Link |
|---|---|
| KR (1) | KR20040023503A (en) |
| CN (1) | CN100356911C (en) |
| HK (1) | HK1060853A1 (en) |
| TW (1) | TW200404004A (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0971523A (en) * | 1995-09-07 | 1997-03-18 | Riyuukakusan:Kk | Tablet quickly disintegrating in oral cavity |
| DE19901692C2 (en) * | 1999-01-18 | 2002-06-20 | Gruenenthal Gmbh | Process for the production of pellets containing up to 90% by weight of an active pharmaceutical ingredient |
-
2003
- 2003-07-21 TW TW092119864A patent/TW200404004A/en not_active IP Right Cessation
- 2003-08-14 KR KR1020030056551A patent/KR20040023503A/en not_active Application Discontinuation
- 2003-09-08 CN CNB031565484A patent/CN100356911C/en not_active Expired - Fee Related
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Also Published As
| Publication number | Publication date |
|---|---|
| TWI306763B (en) | 2009-03-01 |
| TW200404004A (en) | 2004-03-16 |
| HK1060853A1 (en) | 2004-08-27 |
| CN100356911C (en) | 2007-12-26 |
| KR20040023503A (en) | 2004-03-18 |
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