CN1264504C - Composition and preparation method of soft capsule shell colloid emulsion - Google Patents

Abstract

The present invention discloses a composition and a preparation method of soft capsule shell colloid emulsion. The colloid emulsion comprises the following components and weight percentage: 30 to 60% of gelatin, 5 to 25% of glycerol, 0.1 to 10% of surface active agent, 0 to 1% of bacteriostatic agent, 0.1 to 10% of grease and the rest of water. The preparation method of the colloid emulsion of the present invention comprises the following steps: 1) the surface active agent, the grease and the water are prepared into emulsion; 2) the gelatin, the glycerol and the bacteriostatic agent are added into the water and are heated and mixed, and after the emulsion is added, mixed and degasified, the colloid emulsion is obtained. The soft capsule shell colloid emulsion is tested by adopting the specification of the Chinese pharmacopoeia (a second version of the year 2000) and is placed for six months at the temperature of 40 DEG C and two years at the room temperature, and the disintegration time of the soft capsule shell colloid emulsion conforms to the requirements of the Chinese pharmacopoeia (a second version of the year 2000). Because of quick disintegration, the soft capsule can be quickly absorbed in bodies; the peaking time of the medicine is shortened; the treating effects of the medicine are quickly displayed, or the biological availability of the medicine is increased in bodies.

Description

The composition of soft capsule shell colloidal emulsion and preparation method

Technical field

The present invention relates to the composition and the preparation method of medicine and health food soft capsule shell rubber solution.

Technical background

Soft capsule is a kind of tablet that continues, the novel form that grows up behind the injection, it can and be encapsulated in the gelatin softgel shell quantitative pressure injection such as lipophilic substance, hydroaropic substance, suspension, pastel, form big or small, different sealing soft capsule, compare with other dosage form, soft capsule has the bioavailability height, and content is accurate, good evenness, appearance looks elegant and carrying and characteristics such as easy to use.

Though soft capsule preparation is rapidly developed, but the rubber solution of soft capsule is continued to use the conventional formulation of traditional gelatin, water, glycerol mostly, the soft capsule made from this class rubber solution often in storage period disintegration time obviously prolong, even disintegration is defective, badly influences soft capsule in intravital infiltration rate of machine and bioavailability.The aging keeping life that causes of soft capsule rubber prolongs or the defective development that is always restricting soft capsule interior disintegration, therefore, further studying the aged reason of rubber is the task of top priority of basic research and industrialness applied research with preventing aging or studying new rubber prescription.

Gelatin solution its molecule more than 40 ℃ the time is the random coil conformation, when temperature is reduced to freezing point (about 35 ℃) when following, some segment of gelatin molecule is cross-linked to form helicoidal structure by hydrogen bond, along with increasing of crosslinking points, whole system forms the three-dimensional netted body of poly-peptide molecule and solidifies, owing to be subjected to the influence of temperature and oxidation, along with the prolongation gelatin of time can wear out.Japan scholar tomb field waits the people to use the influence of the storage temperature of differential scanning calorimetry (DSC) and calorimetric analysis method (TG) research soft capsule to disintegration time thoroughly.The calorimetric analysis Faxian shows has the collagen bundle to exist in the soft capsule cyst membrane, the soft capsule long term store is in the time of 40 ℃, collagen micelle in the network structure of gelatin produces degeneration, causus change takes place in the structure of gelatin, form random disorderly structure, in case form this kind structure, soft capsule becomes and is difficult to dissolving, and disintegration time obviously prolongs.Through the soft capsule of storing under 40 ℃ of conditions 4 months is contrasted with the same sample of storing under 6 ℃ of conditions, the former needs the disintegrate of 100 minutes ability, the latter only 25 minutes with regard to disintegrate.The soft capsule that will contain MCT Oil (MCT) is stored under the different temperature conditions, measure of the influence of its storage temperature with differential scanning calorimetry to disintegration time, sample 15 ℃, 25 ℃, 32 ℃, 37 ℃ storages, its disintegration time prolongs with the increase of storage temperature, but when storing for 40 ℃ or 50 ℃, the two disintegration time increases rapidly.

In order to solve the problem of soft capsule difference disintegration, more domestic soft capsule manufacturing enterprises have carried out some researchs to this.People such as Chen Youhong study the rubber solution of MAITONG JIAONANG according to people's such as Hom result of the test, they add citric acid in rubber solution, consumption is 6% of a gelatin amount, can the slow down aging speed of soft gelatin capsule of the MAITONG JIAONANG made from this rubber solution, store in saturated vapor or under the ambient temperature and moisture, low temperature that disintegration rate changes little after 5 months, but in orthogonal test, other prescription is under the accelerated test condition, when preserving for 2～April, just occur that obviously prolong disintegration or rubber dissolution phenomena not fully.Wu Mingfu also studies the softgel shell prescription of MAITONG JIAONANG, the PEG400 that in rubber solution, adds gelatin amount 5%, make MAITONG JIAONANG and former MAITONG JIAONANG with this prescription and placed 4 months through 45 ℃, the former disintegration (1.5 hours) is faster than the latter (2 hours).Above research does not fundamentally solve soft capsule before the deadline, especially when room temperature storage is more than 1.5 years, meets the requirement of Chinese Pharmacopoeia disintegration.

At present, very good soft capsule rubber prescription is not arranged as yet at home, therefore researching and developing a kind of soft capsule rubber prescription new, that disintegration is good is a very urgent task.

Summary of the invention

The technical issues that need to address of the present invention are to disclose a kind of composition and preparation method for preparing the soft capsule shell colloidal emulsion, to overcome the above-mentioned defective that prior art exists, satisfy the needs of relevant field development.

Technical conceive of the present invention is such: inventor's imagination, the Emulsion of adding o/w type is made colloidal emulsion in traditional rubber solution, prolongs or the underproof defective of disintegrate disintegration in storage period thereby can overcome existing soft capsule.The Emulsion that in conventional rubber solution, adds the o/w type, because particle diameter can be evenly distributed in the network structure of gelatin at the breast grain of 1～5 μ m, the peptide chain of gelatin cut apart surround, prevent from effectively to produce further crosslinked and cohesion between the peptide chain, thereby prevent the aging of gelatin; Secondly, contain surfactant in the rubber solution and can play and reduce capillary effect, can be very fast when soft capsule runs into water by moistening and produce exapnsion; In addition, have the antioxidative effect, can be used as the oxidation that antioxidant prevents gelatin as the nonionic surfactant of soy phospholipids itself.

According to above-mentioned technical conceive, the inventor proposes following technical scheme:

Soft capsule rubber solution of the present invention is a kind of colloidal emulsion, for a kind of in the colloidal emulsion for preparing fat-soluble content and hydrophilic content soft capsule shell aspect medicine and the health food, the breast grain that contains the o/w type in this colloidal solution, the size of its breast grain is between 0.1～20 micron, on average below 5 microns.

The component and the weight percent content of this colloidal emulsion comprise:

Gelatin 30～60%

Glycerol 5～25%

Surfactant 0.1～10%

Antibacterial 0～1%

Oils and fats 0.1～10%

Water surplus.

Said surfactant comprises nonionic surfactant, naturally occurring emulsifying agent and anionic surfactant.The condensation substance class that nonionic surfactant is polyglyceryl fatty acid ester class, sucrose higher fatty acids esters, the sorbitol higher fatty acids esters that anhydrates, polyoxyethylene anhydrate Span, polyoxyethylene higher fatty acids ester condensates class, polyoxyethylene high fatty alcohol condensation substance class, polyoxyethylene castor oil condensation substance class, polyoxyethylene hydrogenated Oleum Ricini condensation substance class, polyoxyethylene polyoxypropylene block polymer (Pluronic) class etc.; Naturally occurring emulsifying agent is phospholipid (comprising soybean phospholipid, lecithin), hydrogenated phospholipid class, arabic gum, tragakanta, sodium alginate etc.; Anionic surfactant is one or more in alkali metal soap kind, polyvalent metal soap kind, sodium lauryl sulphate, the sodium stearyl sulfate.Said antibacterial comprises one or more in P-hydroxybenzoic acid alkane esters, quaternary ammonium compound class, benzoic acid and salt, boric acid and salt thereof, sorbic acid and salt thereof, chlorobutanol, the benzyl alcohol etc.The purpose that adds antibacterial is rotten in order to prevent colloidal emulsion, and disintegration rate is not had substantial influence.

Said oils and fats comprises Vegetable oil lipoprotein, animal oil and mineral oil.

Above-mentioned colloidal emulsion can adopt method well known in the art to be prepared into soft capsule shell, with fat-soluble content of content or hydrophilic content.

Fat-soluble content of the present invention means fat-soluble medicine and health food; Hydrophilic content of the present invention means hydrophilic medicament and health food.

The preparation method of colloidal emulsion of the present invention comprises the steps:

(1) surfactant, oils and fats and hydromining are prepared into Emulsion with conventional paddling process, colloid milling, high pressure homogenization method and supercritical ultrasonics technology etc.

(2) gelatin, glycerol, the antibacterial with recipe quantity joins in an amount of water, heating, stir into uniform glue after, add above-mentioned Emulsion, continue to stir and to make evenly, the degassing, colloidal emulsion.

The soft capsule made from colloidal emulsion of the present invention has the fast advantage of disintegrate, adopt the regulation of Chinese Pharmacopoeia (version was two ones in 2000) to test, placed 6 months and room temperature was placed 2 years for 40 ℃, meet Chinese Pharmacopoeia (version be'sed two ones in 2000) requirement its disintegration, the soft capsule made from this colloidal emulsion is applicable to oral, and rectum and intravaginal are used.

The soft capsule made from this colloidal emulsion is through 40 ℃, and the long-term examination in 2 years of relative humidity 75%, 6 month and room temperature all can be at 60 minutes with interior complete disintegrate.Because disintegrate is fast, soft capsule is the energy fast Absorption in body, and the peak time of medicine is shortened, and brings into play the curative effect of medicine quickly or improves medicine in the intravital bioavailability of machine.

The specific embodiment

Component among the embodiment all is weight percentage.

Embodiment 1

Gelatin 45%, glycerol 13%, phosphatidase 11 %, soybean oil 3%, ethyl hydroxybenzoate 0.3%, water 37.7%.

The preparation of colloidal emulsion:

Phospholipid is joined in an amount of water, make dissolving, add soybean oil while stirring, make into emulsion, handle to the Emulsion of average breast grain size about 1 micron through high pressure homogenizer again.

Gelatin, glycerol, ethyl hydroxybenzoate are added to the water, stir into uniform glue after, add above-mentioned Emulsion, stir, the degassing, colloidal emulsion.

Embodiment 2

Gelatin 45%, glycerol 13%, Tween 80 3%, Oleum Arachidis hypogaeae semen 5%, benzoic acid 0.3%, water 35.7%.

The preparation of colloidal emulsion:

Tween 80 is joined in an amount of water, make dissolving, add soybean oil while stirring, make into emulsion, handle to the Emulsion of average breast grain size about 5 microns through high pressure homogenizer again.

Gelatin, glycerol, benzoic acid are added to the water, stir into uniform glue after, add above-mentioned Emulsion, stir, the degassing, colloidal emulsion.

Embodiment 3

Gelatin 45%, glycerol 13%, Tween 80 2%, sorbester p17 0.5%, soybean oil 4%, domiphen bromide 0.3%, water 35.2%.

The preparation of colloidal emulsion:

Tween 80 and sorbester p18 are joined in an amount of water, make dissolving, add soybean oil while stirring, make into emulsion, handle to the Emulsion of average breast grain size about 5 microns through high pressure homogenizer again.

Gelatin, glycerol, domiphen bromide are added to the water, stir into uniform glue after, add above-mentioned Emulsion, stir, the degassing, colloidal emulsion.

Embodiment 4

Gelatin 45%, glycerol 13%, sodium lauryl sulphate 2%, soybean oil 4%, ethyl hydroxybenzoate 0.3%, water 35.7%.

The preparation of colloidal emulsion:

Sodium lauryl sulphate is joined in an amount of water, make dissolving, add soybean oil while stirring, make into emulsion, handle to the Emulsion of breast grain size about 5 microns through high pressure homogenizer again.

Gelatin, glycerol, ethyl hydroxybenzoate are added to the water, stir into uniform glue after, add above-mentioned Emulsion, stir, the degassing, colloidal emulsion.

Embodiment 5

Gelatin 45%, glycerol 13%, pluronic F68 2%, soybean oil 4%, ethyl hydroxybenzoate 0.3%, water 35.7%.

The preparation of colloidal emulsion:

Pluronic F68 joins in an amount of water, makes dissolving, adds soybean oil while stirring, makes into emulsion, handles to the Emulsion of breast grain size about 5 microns through high pressure homogenizer again.

Gelatin, glycerol, ethyl hydroxybenzoate are added to the water, stir into uniform glue after, add above-mentioned Emulsion, stir, the degassing, colloidal emulsion.

Embodiment 6

Gelatin 45%, glycerol 13%, soybean phospholipid 2%, liquid paraffin 3%, ethyl hydroxybenzoate 0.3%, water 36.7%.

The preparation of colloidal emulsion:

Soybean phospholipid joins in an amount of water, makes dissolving, adds liquid paraffin while stirring, makes into emulsion, handles to the Emulsion of breast grain size about 5 microns through high pressure homogenizer again.

Gelatin, glycerol, ethyl hydroxybenzoate are added to the water, stir into uniform glue after, add above-mentioned Emulsion, stir, the degassing, colloidal emulsion.

Embodiment 7

The mensuration of soft capsule disintegration

Trial target: the digoxin soft capsule that this colloidal emulsion is made

The content prescription:

Digoxin 0.1g, dehydrated alcohol 20g, propylene glycol 30g, PEG400 170g

Colloidal emulsion adopts the prescription of embodiment 1:

The digoxin preparation of soft capsule:

Adopt revolving die formula encapsulating machine, with the perfusion of digoxin content and be wrapped in the rubber that this colloidal emulsion makes, make every and contain digoxin 0.1mg soft capsule.

Reference substance: commercially available vitamin E soft gelatin capsule, Radix agastaches healthy energy soft capsule, Oleum Bulbus Allii soft gelatin capsule, Squalene soft gelatin capsule, lecithin soft gelatin capsule.

Instrument: ZBS-6G intelligence disintegration tester (Radio Factory of Tianjin Univ.)

Disintegrate medium: distilled water

Test method: press Chinese Pharmacopoeia version in 2000 inspection technique two disintegrations, measure the disintegration of digoxin soft capsule and vitamin E soft gelatin capsule, Radix agastaches healthy energy soft capsule, Oleum Bulbus Allii soft gelatin capsule, Squalene soft gelatin capsule, lecithin soft gelatin capsule respectively, measurement result sees Table.

	The digoxin soft capsule	The vitamin E soft gelatin capsule	HUOXIANG ZHENGQI RUANJIAONANG	The Oleum Bulbus Allii soft gelatin capsule	The Squalene soft gelatin capsule	The lecithin soft gelatin capsule
							Original	7min	-	-	-	-	-
40 ℃, 3 months	20min	-	-	-	-	-
							40 ℃, 6 months	37min	-	-	-	-	-
Room temperature, 6 months	9min	-	-	-	-	-
							Room temperature, 12 months	12min	40min	-	-	-	65min
Room temperature, 18 months	17min	-	120min does not collapse	120min	120min does not collapse	-
							Room temperature, 24 months	28min	-	-	-	-	-

The result shows, no matter the digoxin soft capsule made from colloidal emulsion of the present invention is 40 ℃, stored 6 months, still room temperature storage is 2 years, all meets standards of pharmacopoeia (60 minutes) disintegration, and some commercially available products, except that vitamin E soft gelatin capsule and lecithin soft gelatin capsule meet the pharmacopeia regulation storing 1 year fashion, remaining soft capsule is in the time of 1.5 years, and yet not disintegrate in 2 hours does not all meet the pharmacopeia requirement.

Claims (6)

1. a soft capsule shell colloidal emulsion is characterized in that, contains the breast grain of o/w type in this colloidal solution, and the size of its breast grain is between 0.1～20 micron, on average below 5 microns;

The component of colloidal emulsion and weight percent content are:

Gelatin 30～60%

Glycerol 5～25%

Surfactant 0.1～10%

Antibacterial 0～1%

Oils and fats 0.1～10%

Water surplus.

2. soft capsule shell colloidal emulsion according to claim 1, it is characterized in that, said surfactant is selected from polyglyceryl fatty acid ester, the sucrose high-grade aliphatic ester, the sorbitol high-grade aliphatic ester anhydrates, the anhydrate condensation substance of Span of polyoxyethylene, polyoxyethylene higher fatty acids ester condensates, polyoxyethylene high fatty alcohol condensation substance, the polyoxyethylene castor oil condensation substance, the polyoxyethylene hydrogenated Oleum Ricini condensation substance, phospholipid, hydrogenated phospholipid, arabic gum, the tragakanta, sodium alginate, in sodium lauryl sulphate or the sodium stearyl sulfate one or more, said antibacterial is selected from ethyl hydroxybenzoate, in benzoic acid or its salt or the domiphen bromide one or more.

3. soft capsule shell colloidal emulsion according to claim 2 is characterized in that said oils and fats is selected from one or more in soybean oil, Oleum Arachidis hypogaeae semen, liquid paraffin or the animal oil.

4. soft capsule shell that is prepared into by each described colloidal emulsion of claim 1～3.

5. the preparation method of soft capsule shell colloidal emulsion according to claim 1 is characterized in that, comprises the steps:

(1) surfactant, oils and fats and water are prepared into Emulsion;

(2) gelatin, glycerol, the antibacterial with recipe quantity joins in an amount of water, heating, stir into uniform glue after, add above-mentioned Emulsion, continue to stir and to make evenly, the degassing, colloidal emulsion.

6. the preparation method of soft capsule shell colloidal emulsion according to claim 5 is characterized in that, adopts paddling process, colloid milling, high pressure homogenization method and supercritical ultrasonics technology to be prepared into Emulsion.