CN1034858A - The delivery systme of medicament - Google Patents

Abstract

Narrated the method that a kind of a certain in animal body target place discharges activated medicament, it is to realize by taking this medicament that is encapsulated in the microsphere that albuminoid makes.This proteinoid microsphere until they move in the way of Target organ, liquid or cell of health is stable in the residing environment, and is unsettled in the target area at the position of introducing.

Description

The delivery systme of medicament

The present invention relates to be encapsulated in the protectiveness proteinoid microsphere pharmaceutically-active preparation and to the method for homoiothermic animal administration.The present invention be more particularly directed to the oral microsphere that contains medicament, these medicaments all will lose efficacy in gastrointestinal tract when adopting other administering modes.

Give the available means of medicament and therapeutic preparation, limited by the chemistry of health generation or the strictness of physical barrier or the two common obstacle.For example, if not because these medicaments run into many obstacles when adopting oral ways, then usually they are selected oral mode.Whether permeability and other factors of existence, gastrointestinal membranes and the tissue of unsuitable pH condition in the gastrointestinal tract, efficient digestive enzyme can adopt oral way to deliver to aspect the target site active ingredient in decision, all play an important role.In numerous medicaments, knownly when oral, affect adversely or become invalid having: bioactive polypeptide and protein, as insulin.These preparations be subjected to acid hydrolysis under one's belt and in the gastrointestinal tract of bottom, be subjected to dividing peptide bond enzyme effect and destroy rapidly, and their are difficult to see through gastrointestinal wall.

Therefore, still need to improve in vivo method at target release of pharmacologically active ingredient, especially need be under the gastrointestinal tract condition the more gratifying method of oral administration medicine supplying of unsettled medicament.

In a broad sense, a content of the present invention is a kind of system of pharmaceutically-active preparation, comprise said medicament sealed or encapsulate in proteinoid microsphere.

Second broad context of the present invention is a kind of encapsulating method, being about to said active agents mixes with a kind of pharmaceutically acceptable liquid phase, this mixture is contacted with a kind of albuminoid, this albuminoid and this mixture interact again, and form hollow microsphere.

The 3rd broad context of the present invention, it is the method that realizes that a kind of pharmaceutically-active preparation discharges in an animal body, comprise give described animal effective dose, be encapsulated in the said active agents in the proteinoid microsphere, this microsphere is stable for the introducing position that enters this animal to residing environment between the release district that elects target as, and is unsettled in this release district.

Form the capsular albuminoid of protection of the present invention, once be described to artificial polypeptide, because they are by natural or synthesizing amino acid and/or little peptide chain at random or directed combination and the artificial condensation polymer that generates.Found that since nineteen fifty end the linear condensation polymer that mixes natural amino acid can react with water, generated since the hollow microsphere that albuminoid just becomes the problem of broad research origin of life.About one piece of these researchs outstanding summary and bibliography widely, all can be at Fox, S.W. and Dose, K. show " molecular evolution and origin of life " (Mercel Dekker, Inc., New York, 1977) find in the book, above-mentioned discovery comprises in this manual with for referencial use.

As the result of these and other research, accumulated many about the preparation of various types of albumen and proteinoid microsphere and the knowledge of character.For example, the known albuminoid that derives from natural a-amino acid (in animal and plant albumen, finding) and with the deutero-albuminoid of material (for example, polynucleotide, phosphoric acid, ferrum and calcium) of other natural origins all be nontoxic.Find also, contain that form a kind of acid class albumen, this albuminoid is insoluble in the acid medium, and is dissolved in the alkaline medium above the acidity two of stoichiometric amount or these polymer of many carboxyaminos acid; When containing excessive alkalescence two or polyamino monomer in the high polymer, then form a kind of alkaline species albumen, this albuminoid is dissolved in acid medium, and does not dissolve when pH is high.Thereby can do very tiny adjusting to this dissolubility property.Similarly, albuminoid contacts with water or other liquid phases and the size of the microsphere that forms, can be by regulating the physics or the chemical parameters such as pH, osmotic pressure or salt content of this liquid, be controlled at by about below half micron in about scope more than 10 microns.Also observe, these albuminoids are more much higher than protein to the stability of digestion enzymatic lysis effect.

The present invention results from following discovery: can form in the pharmaceutically acceptable liquid of microsphere with such protein-interacting by pharmaceutically-active preparation being dissolved or suspended in easily water or dimethyl sulfoxine etc., be encapsulated in the microsphere.

Found that also this encapsulating method can not change the pharmacological properties of this active ingredient, and this method can improve the storage stability of said preparation often as the situation of insulin solution, even can be freezing.Diameter microsphere about 10 microns, the carrying active preparation is little as to be enough to enter in the blood flow by gastrointestinal mucosa smoothly.The preferred microsphere diameter range that is suitable for diffusion rapidly is about 0.5 to 5.0 micron, because littler size presents less stability and forms active lower preparation, and the difficult diffusion of bigger size.But by about 5.0 to about 10 microns granule, can mix use, because their slower diffusions can make the active agents time-delay discharge with the granule in the above-mentioned preferable range.

Find when adopting known method to adjust the granularity of acid class albumen solubility characteristic and microsphere, can be manufactured on (normal pH is by about 4 to about 6.8) stable load microsphere in the oral cavity, it can see through oral mucosa rapidly and enter in the blood flow, and (normal pH is by about 7.35 to about 7.45) discharge active ingredient in blood.This system is applicable to the sublingual administration pharmaceutically-active preparation, for example, and the growth hormone of people or cattle, interferon or interleukin-II etc.

Similarly, can be used in (normal pH is by about 2 to about 6) in the stomach of highly acidic stable but dissolve in microsphere near the diffusion easy to manufacture of the acid class albumen in the neutral blood.This system is applicable to oral peptide hormone, for example insulin or heparin, otherwise they will be destroyed rapidly under one's belt.They are applicable to that also the protection stomach is not subjected to the stimulation of stomachics such as aspirin.After this microsphere oral administration that contains aspirin, can see through coat of the stomach and in blood, discharge aspirin, it is faster to enter blood than traditional enteric-coated aspirin, because the latter at first must pass through stomach, also must only after the enteric coating dissolving, just can enter in the blood flow then by intestinal wall.

It is stable can also being used in the weakly alkaline lower intestine (normal pH is about 8), and the alkaline species albumen that then discharges active ingredient in blood is made similar system.This system is applicable to some medicament, for example the redox carrier of calcium regulator and dopamine or γ-An Jidingsuan.

Except that these bags taking the system with enteric coating, can also make a kind of near neutral proteinlike granule system, make it stable in blood flow, and (for example higher or lower pH or the existence of specific enzymes is arranged) discharge contained medicament in the environment of Target organ.Thisly must introduce with intravenous injection near neutral system, only this microsphere is little as can be encapsulated in completely in the bigger proteinoid microsphere, and the latter can spread through gastrointestinal mucosa, and is stable before arriving blood flow always.

Though any medicament all can be encapsulated in the proteinoid microsphere, clearly, this method is specially adapted to protect those just to be destroyed or render a service the medicament that reduces by environment on every side before no show target area in animal body when adopting additive method.

The following examples 1 have illustrated the preparation method of the hot albuminoid of a kind of acidity, and this albuminoid can interact with a kind of aqueous solution of pharmaceutically-active preparation, and this medicament is sealed and protected in hollow microsphere.This microsphere presents stability in the presence of digestive enzyme and gastric acid, and because its diameter, enters in the alkalescence blood flow dissolving and discharge medicament in blood flow mostly less than 5.0 microns so solution sees through coat of the stomach.

Embodiment 1a

Will be in stirring by 52.3 gram aspartic acids (0.4 mole), 42 gram arginine monohydrochlorides (0.2 mole), 26 gram isoleucine (0.2 mole) and 50 milliliters of mixture that glycerol is formed, under nitrogen protection, be heated to 160 ℃, emit gas simultaneously.Temperature was kept 23 hours at 155 ℃, then with the mixture cool to room temperature, with 200 milliliters of 10%(weight) sodium bicarbonate aqueous solution extract, extract was carried out dialysis 26 hours by collodion membrane to distilled water, changed water once in per 6 hours.Then the material in the dialysis tube is evaporated to driedly under 50 ℃ and vacuum, generates a kind of glassy acid class protein solid material, it is ground be fine powder again.

Embodiment 1b

35 milligrams of these Powdered albuminoids are joined in the mixture of being made up of 50 milligrams of Iletin II (Lilly) crystallizations and 2 ml distilled waters, then this mixture at room temperature is placed into the formation microsphere.Isolate the microsphere that is loaded with insulin with Filtration, the acetic acid aqueous solution washing with pH5.4 is suspended in the acetic acid aqueous solution of 2 milliliters of pH5.4 then again.When being carried out microexamination, this suspension finds that the diameter great majority of stable microsphere are between 0.1 to 5.0 micron.When a part of suspension being neutralized pH7.4, then obviously find out the microsphere dissolving at once with dense ammonium hydroxide.

Embodiment 1c

With 0.35 milliliter of dosage, among the embodiment 2b, as to be loaded with insulin microsphere suspension, inject three adult, normal white mouse gastric of blood sugar concentration by the oral cavity with syringe.After the dispensing, according to the mensuration of being done by afterbody institute blood sampling, every white mouse all only shows the obvious reduction of blood glucose.Should be noted that as laboratory animal and people during, the obvious reduction of blood sugar concentration does not take place by much bigger unshielded pig of per unit body weight oral dose or bovine insulin.

Though be applicable to that the hollow microsphere of sealing medicament can be by single acidity or basic amino acid and few to only generating with another kind of aminoacid, but used amino acid whose kind more for a long time, then often is that diameter productive rate in desired 0.5 to 5.0 micrometer range, microsphere of uniform size is higher.Embodiment 2 set forth oral be encapsulated in 18 kinds of different aminoacid the insulin in the deutero-proteoplast, the effectiveness of the effect of the blood sugar lowering that in mammal, is produced.

Embodiment 2 has also set forth a good especially method of producing the proteinoid microsphere of load insulin.This method can make the microsphere productive rate height of diameter in 0. to 5.0 required micrometer range reliably, and dissolves easily under as the difficult He of order rice steamer Xie Ou H condition.

Embodiment 2a

A flask that fills 2 parts of (weight) anhydrous 1-glutamic acid under the nitrogen current protection, in oil bath, is heated to the fusion of vial matter at about 175 ℃.The molar mixture such as anhydrous of 16 kinds of neutrality that adds in bottle that 2 parts of (weight) anhydrous 1-aspartic acids and 1 part (weight) finds in animal protein and basic amino acid.The gained mixture stirred with Glass rod and under 175 ℃ and nitrogen protection, kept 3 hours.After the cooling, extract dark amber product, and extract was at room temperature carried out dialysis 24 hours through collodion membrane to distilled water, changed water once in per 4 hours with saturated sodium bicarbonate aqueous solution.Then the total material in the dialysis tube is carried out drying under the condition of vacuum and 65 ℃, residual solids is ground with mortar and pestle be fine powder.

Embodiment 2b

By purgation preparation albuminoid aqueous solution: the powder among the embodiment 2a is mixed with 1 milliliter of water for per 35 milligrams, with pH regulator to 7.4, and remove insoluble matter with Filtration with dense sodium bicarbonate aqueous solution.Then with a (volume) no solid albuminoid aqueous solution rapidly injection isopyknic, new preparation, be dissolved in (concentration is 25 mg/ml) solution that the acetic acid aqueous solution of pH forms by Iletin II (Lilly).PH is about 3.5 said mixture and in ice bath, stirred 15 minutes, filter then, by separating in the filtrate, then filtrate is discarded with the microsphere that will be loaded with insulin.After the acetic acid aqueous solution washed twice with pH3.5, microsphere is suspended in the acetic acid aqueous solution of 10 parts of (volume) pH3.5.Microexamination to this suspension of a part finds that diameter is the dominant microsphere productive rate of person height in 0.5 to 5.0 micrometer range.When adding dense sodium bicarbonate when suspension is neutralized pH7.4 or when joining this microsphere in a large amount of human serums, then this microsphere is dissolving rapidly.

Among the embodiment 2c below, the microsphere suspension medicament that is loaded with insulin among the embodiment 2b is called " microsphere that is filled with insulin ".The program that does not contain the microsphere repetition embodiment 3b of insulin makes, different just in forming the microsphere process, do not add insulin, and it is that the Iletin II (Lilly) of 2.5 mg/ml is in distilled water in the formed solution, rather than in acetic acid,diluted that these microspheres are suspended in concentration.Generated, the suspension medicament of insulin-containing is not called " microsphere of outer attached insulin " in microsphere.Only containing concentration is the medicament of the Iletin II (Lilly) solution of 2.5 mg/ml, then is called " Proinsulin ".

Embodiment 2c

With 12 body weight respectively is about 500 gram and normal male white mouse of blood sugar concentration, is divided into each arbitrarily by two groups of 3 white mouse with by 6 the 3rd groups of forming.3 white mouse to the A group are taken the microsphere that insulin is housed with gavage; Take the microsphere of outer attached insulin with similar fashion to 3 white mouse of B group.6 white mouse of C group are accepted Proinsulin with similar fashion.All dosage all is 1 milliliter/500 gram body weight, and all white mouse are checked blood glucose immediately after taking medicine, and makes regular check on subsequently.Each is organized the average blood sugar concentration of white mouse and lists in the table 1.

Table 1

The intravital blood glucose of white mouse (milligram/decilitre)

Time A group B group C group

(hour) (dress insulin microsphere body) (outer attached insulin microsphere body) (Proinsulin)

0 109.7 92 92.7

0.5 54.7 89.3 95.5

1 59 84.3 98.2

2 50 80.7 95.8

3 57.7 86.7 86.2

4 64.7 84 91

6 76 83.7 89.8

8 65.7 88.7 91

12 81.7 92.3 92

24 94.3 95.7 92

These experiments show that the microsphere of Proinsulin or outer attached insulin does not have obvious influence for blood sugar concentration.In contrast, it is about 50% that the microsphere that insulin is housed causes that blood sugar concentration falls sharply, and produce persistent influence.This confirms that acid proteinoid microsphere does not have influence to blood sugar concentration, and they only comprise the insulin of sealing and are not subjected to the influence of gastric hostile environment, thereby the insulin of sealing can be entered in the blood flow with the form of pharmacologically active.

Embodiment 3a

To every 75 milligrams/kg body weight of each intravenous injection streptozotocin of mouse that nearly weighs 300 grams, to cause diabetes.Can observe mouse and present obstinate hyperglycemia concentration, polyuria and excessive thirst, and must could preserve life, be selected in this experiment at the subcutaneous injection Iletin II (Lilly).

Embodiment 3b

6 patient of diabetes Mus are divided into three groups arbitrarily, 2 every group.Take 1 milliliter of the aqueous suspension of the acid proteinoid microsphere that is loaded with Iletin II (Lilly) among the embodiment 2b for gavage first group of mouse.The trouble Mus of second group and the 3rd group 0.25 milligram of (6.5 iu) Iletin II (Lilly) that then gets an injection under the skin respectively.All trouble Mus are measured blood sugar concentration, periodic measurement then before facing administration.Each group is suffered from Mus and is exchanged twice week about, handles so that all trouble Mus all are subjected to every kind of insulin.Blood sugar concentration is listed in the table 2 by the percentage rate that baseline reduces in the various processing.

Table 2

Suffer from the Mus % that blood glucose is reduced by baseline after insulin is handled

Insulin handle after the administration institute through the time (hour)

0.5 1 1.5 2 3 4 6 8 12 24 48

Oral microsphere body 29 38 45 44 48 50 51 40 37 24-27

0.25 milligram subcutaneous injection 28 55 72 77 84 79 34 4 3-7-5

0.125 milligram subcutaneous injection 5 17 27 45 47 29 8-8-8-8-8

These results confirm, oral tremendous influence of filling the microsphere of insulin to the patient of diabetes Mus is similar with the situation of 0.125 milligram of insulin of subcutaneous injection, and its influence time is obviously long than the influence time of 0.125 milligram of subcutaneous injection or 0.25 milligram.

Embodiment 4a

In the aqueous solution that contains heparin 250 mg/ml, add spirit acid, make pH regulator to 4.5.In the powdered acid class albumen among the ratio adding embodiment 2a of 35 mg/ml, this mixture is left standstill in room temperature form microsphere more then.Then with the centrifugalize of portion (volume) mixture, and after discarding supernatant liquid, will be loaded with of the acetic acid aqueous solution washing of the microsphere of heparin, be suspended in after the filtration in the acetic acid aqueous solution of pH4.5, the volume of suspension also will be made into portion with pH4.5.Microexamination finds that the diameter great majority of microsphere are to arrive in about 5 micrometer ranges about 0.1, wherein are in the great majority between 1 and 2 micron.

Embodiment 4b

Began to test preceding 12 hours, and stopped male white mouse feeding 7 each heavily about 600 grams.No. 1 white mouse is not handled.Accept intravenous injection for No. 2 and be dissolved in 250 milligrams of heparin in 1 ml distilled water.3-7 number each Mus accepted respectively directly to introduce 1 milliliter of the microsphere aqueous suspension that is loaded with heparin among the embodiment 4a in the stomach with gavage.With the effect that activates partial thromboplastin time (APTT) test method determination heparin.This test determination is taken from tail venous blood serum sample and is formed the required time of fibrin clot.Each Mus result of the test of different time after administration is listed in the table 3.

Table 3

Setting time (second) in the APTT test

The heparin of Mus

Numbering is handled administration preceding 1 hour 2 hours 3 hours 4 hours 5 hours

1 nothing 28 26 27---

2 Ⅳ 25 54 ＞300 - - -

3 microspheres 24 35＞300---

4 microsphere 26 35 59 118＞300 21

5 microspheres 29 41 63 106 248 26

6 microsphere 25 37 66 121＞300 23

7 microsphere 24 31 62 111＞300 37

Be loaded with in the white mouse of microsphere of heparin in all acceptance, extend to setting time with the intravenous injection heparin after similar level.Go out after obviously by these data; in heparin is encapsulated in acid proteinoid microsphere by after oral; it is by with meaningful on the pharmacology and be that active form is sent in the blood flow; should be understood that; behind experiment white mouse and human oral the heparin, do not cause obviously to prolong setting time without protection by the much bigger dosage of unit bodies restatement.

Except the medicament that is encapsulated in the acid proteinoid microsphere of protectiveness that enumerate in the various embodiments described above, oral; outside the particular agent that discharges in blood flow with the pharmacologically active form, this microsphere system is all similarly effective for other vast unsettled medicaments (comprising physostigmine, nitroglycerin, cringle Ke Shi poliomyelitis vaccine, rubella vaccine and hepatitis B vaccine) in the environment of stomach then.But, also have many other medicaments, even, also can affect adversely it being encapsulated in the acid proteinoid microsphere in the residing slightly acidic environment.

Following experiment confirm alkaline species have form microsphere will be this to the acid medicament (dopamine derivant) of the sensitivity ability sealing and protect extremely; make this medicament not be subjected to the influence of hostile environment in the gastrointestinal tract; and this medicament delivered to blood circulation; again by blood brain barrier, in brain, discharge dopamine thus.The dopamine derivant of using in this experiment is PR-21, and it is that an acidylate dopamine is connected to the patent compositions that forms on a reductive dihydropyridine/pyridinium salt type redox carrier, is by Pharmatek; Icn. develop; at U.S.Patent4, introduction is arranged in 479,932.PR-21 compositions any position in gastrointestinal tract without protection is all unstable, and responsive especially to sour environment.After intravenous injection is in the mouse body, the deacylated tRNA quaternary ammonium precursor of a large amount of dopamine, available Journal of Medicinal Chemistry, 26,528(1983) method that proposes of contained Bao Diai and method Roger is determined in the Mus brain of homogenize.

Embodiment 5a

Will with nitrogen purging cross by those Min ostriches of the loyal ㄖ QiJun of the loyal ㄖ QiJun of  ┚  that curtain ⒍  ├ egg encircle the humorous  mace of loyal ㄖ QiJun ┰ saddle word hands Eriocheir sinensis 6 kinds of neutrality of ⑾ value and acidic amino acid etc. the mixture formed of molar mixture, 180 ℃ of following agitating heating 3 hours.The acetic acid aqueous solution of cooled reactant mixture with pH2.25 extracted, and at room temperature extract was carried out dialysis 48 hours through collodion membrane to a large amount of distilled water, changed water once in per 6 hours.Then with the material in the dialysis tube in vacuum and 65 ℃ heating down, generate powdered alkaline species albumen.When waiting until in the strong alkaline liquid medium during this Powdered albuminoid is suspended in, can form heart microsphere automatically, they are stable in this medium, and dissolving in the approaching neutral blood of pH.

Embodiment 5b

The alcoholic solution (360 mg/ml) of 1 part of (volume) PR-21 is used isopyknic distilled water diluting, and add saturated potassium dihydrogen phosphate aqueous buffer solution, with the pH regulator to 8 of this solution.The buffer of this PR-21 of containing 180 mg/ml of a part is put aside, claim that below this medicament is " without the PR-21 of protection ".

Remaining buffer solution and the described powdered alkaline species of embodiment 5a albumen are by the mixed of 25 mg/ml, and is freezing to forming microsphere in ice bath then.The suspension medicament that is generated, hereinafter referred to as " microcapsule PR-21 ", the most of diameters of microsphere wherein are 0.1 to 5 micron.

Embodiment 5c

The mouse (DA-1 and DA-2 Mus) of two each heavily about 500 grams is anaesthetized, dissect and expose jejunum, the sphincter that ligatures returns in the stomach to prevent backwash.Then 2 milliliters of microcapsule PR-21 are injected in the jejunum of every mouse.Two contrast Mus (DA-5 number and DA-6 Mus) are also done similarly to prepare, just 2 milliliters of PR-21 of injection in jejunum without protection.At last, to 22 milliliters of PR-21 of intravenous injection that similarly contrast Mus (DA-3 number and DA-4 Mus) without protection.Be listed in the quantity of the dopamine deacylated tRNA quaternary ammonium precursor of checking out in the homogenize brain of six mouse that are put to the test in the table 4.

Table 4

Dopamine quaternary ammonium precursor in the mouse brain

Mus

Numbering processing mode parent (microgram/gram)

DA-1 enteral injection microcapsule PR-21 1

DA-2 enteral injection microcapsule PR-21 10

The injection of DA-3 IV is without the PR-21 3 of protection

The injection of DA-4 IV is without the PR-21 4.5 of protection

The injection of DA-5 enteral is without the PR-21 0 of protection

The injection of DA-6 enteral is without the PR-21 0 of protection

These results have confirmed that alkaline proteinoid microsphere can seal and protect the dopamine derivant not to be subjected to the influence of enteral digestive enzyme and alkaline environment; also confirmed the following fact: this microsphere sees through intestinal wall and enters near in the neutral blood flow, and the dopamine derivant of sealing there just discharges.In order to make the oral drug of sealing so effective, by the oral cavity stomach function regulating time, the alkaline proteinoid microsphere of acid labile must be protected.In order to accomplish this point, preferably adopt the common method of wrapping enteric coating, enteric coating can not dissolve before arriving intestinal portion.

Embodiment 6

With in stirring by 2 parts of (mole) anhydrous glutaminic acids, 2 parts of (mole) lysine and 1 part of (mole) various neutral amino acid (alanine, glycine, leucine, phenylalanine, proline, tyrosine and valine) etc. the mixture formed of molar mixture, under nitrogen protection, heated 4 hours in 170 ℃.With of the acetic acid aqueous solution extraction of cooled product with pH2.25, then extract was carried out dialysis 24 hours by collodion membrane to distilled water, changed water once in per 4 hours.With the evaporate to dryness under 65 ℃ and vacuum of the material in the dialysis tube, remaining solid is ground be fine powder then.This neutral powder shape albuminoid forms a large amount of hollow microsphere after being added in the aqueous solution of medicament of pH7.4 or the suspension automatically, and this solution or suspension are sealed.

This microsphere is stable in human serum, but dissolves in the acids aqueous solution of pH2.5 and discharge the material that is comprised.This neutral proteinoid microsphere is when being exposed in the less environment of pH; when for example being eaten in macrophage; promptly become unstable; therefore be applicable to medicaments such as intravenous injection azidothymidine AZT diphosphonic acid; these medicaments can be by many non-target machine somas and cell under without the form of protection, and goes to the elegant  hand hay cutter of  bar as target wood on strong

The people that this professional technique is skilled can both find out, can do many changes and improvement in the illustrative embodiment of the invention described above, and still meet the spirit and scope of the present invention that propose in following claim.

Claims (10)

1, a kind of encapsulating method of pharmaceutically-active preparation comprises said preparation is mixed with a kind of pharmaceutically acceptable liquid phase, and this mixture is contacted with a kind of albuminoid, and this albuminoid and this mixture interact, and forms hollow microsphere.

2, a kind of method that pharmaceutically-active preparation is got up and discharges to target with in selected pH scope with microencapsulation, seal said preparation and a kind of pharmaceutically acceptable liquid are formed a kind of mixture, the pH that this mixture had is outside above-mentioned selected scope; Again with this chemical compound and a kind of in above-mentioned selected pH scope solubilized, and undissolved albuminoid contacts in this mixture.

3, according to the method for claim 2, wherein said pharmaceutically acceptable liquid is water.

4, according to the method for claim 2, comprise described albuminoid is mixed with water in described selected pH scope, again such the proteic aqueous solution that is generated is separated with any insoluble matter, thereby this albuminoid is purified in advance.

5, according to the method for claim 2, wherein said albuminoid is tart.

6, according to the method for claim 2, wherein said albuminoid is alkaline.

7, according to the method for claim 2, wherein said albuminoid is neutral.

8, a kind of produce can with the pharmacologically active form will to the unsettled medicament of stomach deliver in the blood flow can be oral method for compositions, comprise this medicament is contacted with a kind of acid class albumen with the mixture of water.

9, method according to Claim 8, wherein said medicament is a kind of peptide hormone, is selected from insulin, heparin and physostigmine.

10, method according to Claim 8, wherein said medicament is a kind of vaccine, is selected from cringle Ke Shi poliomyelitis vaccine, rubella vaccine and hepatitis B vaccine.