CN102028936A - Method for preparing oral protein medicament - Google Patents

Method for preparing oral protein medicament Download PDF

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CN102028936A
CN102028936A CN2010105880052A CN201010588005A CN102028936A CN 102028936 A CN102028936 A CN 102028936A CN 2010105880052 A CN2010105880052 A CN 2010105880052A CN 201010588005 A CN201010588005 A CN 201010588005A CN 102028936 A CN102028936 A CN 102028936A
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solution
chitosan
propanedicarboxylic acid
oral protein
weight concentration
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CN102028936B (en
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龚仁敏
李程程
张银叶
何所惧
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Tonghua Anruite Biopharmaceutical Co ltd
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Anhui Normal University
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Abstract

The invention discloses a method for preparing an oral protein medicament. The method comprises the following steps of: (a) synthesizing N-alpha-chitosan glutarate; and (b) preparing dual crosslinking hydrogel, namely, regulating pH of solution of N-alpha-chitosan glutarate to be 0.5 to 6.5 by using solution of sodium hydroxide, adding solution of sodium alga acid and mixing uniformly, adding the oral protein medicament and dripping into solution of calcium chloride; after dripping is completed, stirring and crosslinking for 0.5 to 3 hours, filtering, washing, soaking in solution of sodium sulfate and stirring and crosslinking for 0.5 to 4 hours, and filtering, washing and drying at room temperature until the mixture has constant weight. Compared with the prior art, the method has the advantages that: the prepared medicament carrier is hardly disintegrated under an acid condition, and the medicament is easily absorbed.

Description

A kind of preparation method of oral protein class medicine
Technical field
The present invention relates to the preparation method of oral protein class medicine, particularly modification of chitosan is as the oral protein class process for preparing medicine of pharmaceutical carrier.
Background technology
Along with the development of DNA recombinant technique, bioactive molecules such as a lot of protein, enzyme, polypeptide become commercial medicine and drop into clinical practice.Though oral is protein drug most convenient, the easiest administering mode of being accepted by patient, but because protein drug very easily sour degeneration and enzymatic degradation in digestive tract, the protein macromolecule medicine is difficult to go into blood through the intestinal wall mucosa absorption in addition, so protein and polypeptide drugs are still mainly by the injection system administration, even this administering mode brings misery to patient and causes easily infecting at present.Oral protein class pharmaceutical carrier becomes the research focus of pharmaceutics in recent years, and the natural polymer hydrogel material of pH sensitivity has received great concern.
Chitosan is a kind of natural polysaccharide of commercial large-scale production, because the biocompatibility of its height, nontoxic, biodegradable, intestinal mucosa adhesiveness and open closely performance such as connection of enterocyte, chitosan is widely used in pharmaceutical field.Chitosan has been used as the carrier of hormone, protein, enzyme and gene.Because its apparent pKa=5.6, chitosan is only soluble in the sour environment, and this has limited its application as the protein drug oral carrier.
Sodium alginate is a kind of soluble-salt of alginic acid, can or form gel under lower sour environment in polyvalent cation such as calcium ion existence.Because sodium alginate gel is easy to preparation, add its inherent attributes such as porous, biocompatibility and mucosa-adherent, the sodium alginate derivant is widely used in field of medicaments.Various sodium alginates, chitosan complexes also have been used as the carrier of drug targeting conveying and controlled release.
At present, both at home and abroad so long as chitosan and sodium alginate are directly prepared hydrogel with methods such as emulsification and cross linkeds, hydrogel disintegrate easily under sour environment that this method is prepared.
Summary of the invention
Technical problem to be solved by this invention provide a kind of under the gastric juice environment swelling and not at the swollen process for preparing medicine of small intestinal environment.
The technical scheme of technical solution problem of the present invention is: a kind of preparation method of oral protein class medicine comprises the synthesis step of (a) N-α-1,3-propanedicarboxylic acid chitosan, the preparation process of (b) dual cross-linked hydrogel;
The preparation process of described (b) dual cross-linked hydrogel is:
With weight concentration is N-α-1,3-propanedicarboxylic acid chitosan solution of 0.5-3%, regulate the pH to 0.5-6.5 of N-α-1,3-propanedicarboxylic acid chitosan solution with the sodium hydroxide solution of 0.5-2M, adding weight concentration again is the sodium alginate soln mixing of 0.5-3%, add oral protein class medicine, splash in the weight concentration 1.5-2% calcium chloride solution, after dropwising, stir crosslinked 0.5-3h, filter, washing, the % metabisulfite solution that is immersed in weight concentration 1.5-2 again stirs crosslinked 0.5-4h, filters, washing, be dried to constant weight under the room temperature, sodium alginate, N-α-1,3-propanedicarboxylic acid chitosan, the mass ratio of oral protein class medicine is 1: 0.3-0.9: 0.5-1.5.
Described oral protein class medicine is insulin, bovine serum albumin.
The synthesis step of described (a) N-α-1,3-propanedicarboxylic acid chitosan:
In 1-2% (v/v) acetic acid solution that chitosan is dissolved in, add α-Tong Wuersuan again, the pH value of regulating above-mentioned solution with the 0.5-2M sodium hydroxide solution is 3.5-5.5, room temperature reaction 2-6 hour, add sodium borohydride again, the pH value of regulating said mixture with the 0.1-1M hydrochloric acid solution is 4.5-7.5, reaction is not less than 24 hours, add 90-95% (v/v) ethanol cessation reaction, filter washing, drying, promptly obtain N-α-1,3-propanedicarboxylic acid chitosan, the mass ratio of chitosan, α-Tong Wuersuan, sodium borohydride is 1: 1.5-3.5: 0.3-1.5.
As shown in Figure 1: use the α-Tong Wuersuan beautify chitosan, can improve its water solublity, and chitosan has the biocompatibility of height, the sticking tack of nontoxic, biodegradable, intestinal mucosa and open closely performance such as connection of enterocyte, sodium alginate is a kind of soluble-salt of alginic acid, can or form gel under lower sour environment in polyvalent cation such as calcium ion existence.After both mixings, dually more crosslinkedly may access acid condition swelling not substantially, and under alkali condition swelling behavior.
The present invention compared with prior art, drug prepared carrier, easy disintegrating not under acid condition, and medicine is absorbed easily.
Description of drawings
Fig. 1 is N-α-synthetic principles of chemistry figure of 1,3-propanedicarboxylic acid chitosan.
Fig. 2 is the infrared spectrum of sodium alginate/N-α-1,3-propanedicarboxylic acid chitosan gel rubber pearl, sodium alginate and N-α-1,3-propanedicarboxylic acid chitosan.
Fig. 3 is the swelling character of gel beads ( embodiment 1,2,3,4,5) under the pH environment of simulation stomach.
Fig. 4 is the swelling character of gel beads ( embodiment 1,2,3,4,5) under the pH environment of simulation small intestinal.
Fig. 5 is the swelling character of gel beads ( embodiment 1,2,3,4,5) under the pH environment of simulation colon.
Fig. 6 is that the bag of bovine serum albumin BSA carries rate.
Fig. 7 is in the gel beads, and BSA is cumulative release in the buffer of simulation stomach (pH1.2).
Fig. 8 is in the gel beads, and BSA is cumulative release in the buffer of simulation small intestinal (pH6.8).
Fig. 9 is in the gel beads, and BSA is cumulative release in the buffer of simulation colon (pH7.4).
Figure 10 is that gel beads is put into simulation stomach (SGF) buffer 3h, and then puts into simulation colon (SCF) buffer 4h, BSA cumulative release rate.
The specific embodiment
Be described further below in conjunction with the technical scheme of specific embodiment invention.
Embodiment 1
(a) N-α-1,3-propanedicarboxylic acid chitosan is synthetic:
The synthesis step of N-α-1,3-propanedicarboxylic acid chitosan: the chitosan of 4.5 grams is dissolved in 1% (v/v) acetic acid solution of 100ml, the α-Tong Wuersuan that adds 7.2 grams again, pH value with 1M sodium hydroxide solution regulator solution is 5, stirring at room 4 hours, add 2 gram sodium borohydrides again, after stirring, the pH value of regulating said mixture with the 1M hydrochloric acid solution is 6.5, stirring reaction 24 hours, adding volume ratio is 95% ethanol cessation reaction.Filter and obtain N-α-1,3-propanedicarboxylic acid chitosan polymer, wash 3 to 4 times with ethanol and ether respectively, in infrared drier, be dried to constant weight.
(b) preparation of dual cross-linked hydrogel
With weight concentration N-α-1,3-propanedicarboxylic acid chitosan solution 30ml of 2%, regulate the pH to 5.0 of N-α-1,3-propanedicarboxylic acid chitosan solution with the sodium hydroxide solution of 1M, add weight concentration again and be 2% sodium alginate soln 70ml mixing, splash in excessive weight concentration 2% calcium chloride solution, after dropwising, stirred crosslinked 0.5 hour, filter, remove the unreacted calcium chloride in gel beads surface for 3 to 4 times with distilled water flushing, the metabisulfite solution that is immersed in excessive weight concentration 2% again stirs crosslinked 1h, filter, wash repeatedly 3 to 4 times, be dried to constant weight under the room temperature with distilled water.
The infrared spectrum of sodium alginate/N-α-1,3-propanedicarboxylic acid chitosan gel rubber pearl, sodium alginate and N-α-1,3-propanedicarboxylic acid chitosan as shown in Figure 2, three's infrared spectrum relatively, wave number 1609cm in the made gel beads infrared spectrum of embodiment 1 -1The asymmetric shock absorbing peak of place's sodium alginate carboxyl obviously weakens and moves (blue shift) to high wave number, in addition wave number 1568cm -1The characteristic of place's amino of chitosan is sheared the shock absorbing peak and is obviously weakened.
Embodiment 2:
Remove in the preparation of (b) dual cross-linked hydrogel,
" with weight concentration is N-α-1,3-propanedicarboxylic acid chitosan solution 10ml of 2%, regulates the pH to 4.5 of N-α-1,3-propanedicarboxylic acid chitosan solution with the sodium hydroxide solution of 1M, adds weight concentration again and be 2% sodium alginate soln 90ml mixing, "
Outward, all the other are identical with embodiment 1.
Embodiment 3:
Remove in the preparation of (b) dual cross-linked hydrogel,
" with weight concentration is N-α-1,3-propanedicarboxylic acid chitosan solution 20ml of 2%, regulates the pH to 4.8 of N-α-1,3-propanedicarboxylic acid chitosan solution with the sodium hydroxide solution of 1M, adds weight concentration again and be 2% sodium alginate soln 80ml mixing, "
Outward, all the other are identical with embodiment 1.
Embodiment 4:
Remove in the preparation of (b) dual cross-linked hydrogel,
" with weight concentration is N-α-1,3-propanedicarboxylic acid chitosan solution 40ml of 2%, regulates the pH to 4.5 of N-α-1,3-propanedicarboxylic acid chitosan solution with the sodium hydroxide solution of 1M, adds weight concentration again and be 2% sodium alginate soln 60ml mixing, "
Outward, all the other are identical with embodiment 1.
Embodiment 5:
Remove in the preparation of (b) dual cross-linked hydrogel,
" with weight concentration is N-α-1,3-propanedicarboxylic acid chitosan solution 50ml of 2%, regulates the pH to 4.5 of N-α-1,3-propanedicarboxylic acid chitosan solution with the sodium hydroxide solution of 1M, adds weight concentration again and be 2% sodium alginate soln 50ml mixing, "
Outward, all the other are identical with embodiment 1.
Embodiment 6
1. the swelling of gel beads is measured
Take by weighing a certain amount of (W 0) the xerogel pearl place the buffer solution of 37 ℃ of slow joltings respectively, buffer solution is simulated the pH environment of stomach, small intestinal and colon respectively.Take out gel beads in particular time interval, inhale with paper and remove the unnecessary water in gel beads surface, at scales/electronic balance weighing (W t).Experiment repeats 3 times.The swelling ratio of gel beads calculates with following formula:
S(t)=(W t-W 0)/W 0
Wt and W 0Be respectively is gel beads weight in wet base and dry weight.
2. the swelling character of gel beads
The swelling character of embodiment 1,2,3,4,5 is shown in Fig. 3,4,5 under the pH environment of simulation stomach, small intestinal and colon, the swelling ratio of gel pearl increases along with the increase of the ratio of N-α-1,3-propanedicarboxylic acid chitosan in sodium alginate/N-α-1,3-propanedicarboxylic acid chitosan, and embodiment 5 made gel beads behind 45min with regard to disintegrate, this phenomenon is because N-α-1,3-propanedicarboxylic acid chitosan has more negative charge than sodium alginate, and chitosan side-chain radical α-1,3-propanedicarboxylic acid has weakened the active force between the polymer.The high swelling ratio of the gel beads that embodiment 5 is made and disintegration rate cause being difficult to the protection medicine under the low pH environment on gastrointestinal top, the medicine that bag carries can rapid release in the gastrointestinal bottom.
The result shows 6 times and 11 times the when swelling ratio of embodiment 1,2,3,4 pH6.8 and is pH1.2 respectively at 7.4 o'clock.This is because in sodium alginate/N-α-1,3-propanedicarboxylic acid chitosan, and carboxyl is a main functional group, is in the nonionic state in pH1.2, electrostatic repulsion a little less than, so the expansion ratio is less.Along with pH value is increased to 6.8 and 7.4, be higher than its pKa=4.75, carboxyl (COOH) becomes ionic species (COO fully -).At COO -Between have powerful electrostatic repulsion to cause high-hydroscopicity and high swelling ratio.
Embodiment 7
Bag carries the preparation of the dual cross-linked gel pearl of bovine serum albumin
(a) N-α-1,3-propanedicarboxylic acid chitosan is synthetic:
The synthesis step of N-α-1,3-propanedicarboxylic acid chitosan: the chitosan of 4.5 grams is dissolved in 1% (v/v) acetic acid solution of 100ml, the α-Tong Wuersuan that adds 7.2 grams again, pH value with 1M sodium hydroxide solution regulator solution is 5, stirring at room 4 hours, add 2 gram sodium borohydrides again, after stirring, the pH value of regulating said mixture with the 1M hydrochloric acid solution is 6.5, stirring reaction 24 hours, adding volume ratio is 95% ethanol cessation reaction.Filter and obtain N-α-1,3-propanedicarboxylic acid chitosan polymer, wash 3 to 4 times with ethanol and ether respectively, in infrared drier, be dried to constant weight.
(b) preparation of dual cross-linked hydrogel
With weight concentration N-α-1,3-propanedicarboxylic acid chitosan solution 30ml of 2%, regulate the pH to 5.0 of N-α-1,3-propanedicarboxylic acid chitosan solution with the sodium hydroxide solution of 1M, add weight concentration again and be 2% sodium alginate soln 70ml mixing, then 0.4 bovine serum albumin (BSA) that restrains is added in the mixed solution and dissolve, splash in excessive weight concentration 2% calcium chloride solution, after dropwising, stirred crosslinked 0.5 hour, filter, remove the unreacted calcium chloride in gel beads surface for 3 to 4 times with distilled water flushing, the metabisulfite solution that is immersed in excessive weight concentration 2% again stirs crosslinked 1h, filters, wash repeatedly 3 to 4 times with distilled water, be dried to constant weight under the room temperature.
Embodiment 8
Remove in the preparation of (b) dual cross-linked hydrogel,
" being N-α-1,3-propanedicarboxylic acid chitosan solution 10ml of 2% with weight concentration; regulate the pH to 4.5 of N-α-1,3-propanedicarboxylic acid chitosan solution with the sodium hydroxide solution of 1M; add weight concentration again and be 2% sodium alginate soln 90ml mixing; the bovine serum albumin (BSA) of 0.4 gram is added in the mixed solution dissolve then, "
Outward, all the other are identical with embodiment 7.
Embodiment 9
Remove in the preparation of (b) dual cross-linked hydrogel,
" being N-α-1,3-propanedicarboxylic acid chitosan solution 20ml of 2% with weight concentration; regulate the pH to 4.5 of N-α-1,3-propanedicarboxylic acid chitosan solution with the sodium hydroxide solution of 1M; add weight concentration again and be 2% sodium alginate soln 80ml mixing; the bovine serum albumin (BSA) of 0.4 gram is added in the mixed solution dissolve then, "
Outward, all the other are identical with embodiment 7.
Embodiment 10
Remove in the preparation of (b) dual cross-linked hydrogel,
" being N-α-1,3-propanedicarboxylic acid chitosan solution 40ml of 2% with weight concentration; regulate the pH to 4.5 of N-α-1,3-propanedicarboxylic acid chitosan solution with the sodium hydroxide solution of 1M; add weight concentration again and be 2% sodium alginate soln 60ml mixing; the bovine serum albumin (BSA) of 0.4 gram is added in the mixed solution dissolve then, "
Outward, all the other are identical with embodiment 7.
Embodiment 11:
The BSA bag carries the mensuration of rate (LE)
25mg embodiment 7,8,9,10 made gel beads are pulverized, poured in 50ml, the PH6.8 phosphate buffered solution, room temperature condition stirs 24h down.Will be behind the solution centrifugal with the burst size of ultraviolet spectrophotometer BSA in 280nm place mensuration supernatant, compare with the supernatant of the made gel beads of embodiment 1.Suppose that in the time of 24h the BSA that bag carries in the pearl all discharges.
Bag carries rate (LE) and is calculated as follows:
LE (%)=(total amount of the BSA that uses in total amount/experiment of the BSA that bag carries in the pearl) * 100%
The bag of BSA carries rate (LE)
The bag of BSA carries rate as shown in Figure 6.We can see from figure, when the weight of BSA account for the gel beads quality 20% the time, bag carries a rate and can reach more than 92%.Simultaneously, along with the N-α-increase of 1,3-propanedicarboxylic acid chitosan in the gel beads total amount, the bag of BSA carries rate and also can constantly rise, because the BSA bag acid condition (pH5.0) when carrying gel beads is higher than the isoelectric point, IP (4.7) of BSA, but is lower than pKa value (6.3) amino on the chitosan chain.In this case, electronegative BSA will finish bag by electrostatic attraction with positively charged amino on the chitosan chain
Embodiment 12:
The mensuration of BSA release in vitro rate
At the external release rate of measuring BSA in the following method: 100mg embodiment 7,8,9,10 made gel beads are added respectively in the buffer of 20ml simulation stomach (pH1.2), simulation small intestinal (pH6.8), simulation colon (pH7.4), continue slow jolting under 37 ℃ of conditions.Every 15 minutes, get 5ml supernatant (simultaneously in solution, mending the fresh buffer of equal volume) with ultraviolet spectrophotometer at the 280nm place, measure the amount of wherein contained BSA.The cumulative release amount of BSA is calculated by standard curve.The experiment triplicate.
Its result is shown in Fig. 7,8,9, in the pH1.2 buffer, the release rate of BSA is relatively low, the BSA of 14-18% of only having an appointment in the 75min discharges from gel beads, and its cumulative release amount reaches balance subsequently, and this is low relevant with gel beads expansion rate in the solution of pH1.2, when pH reaches 6.8 and 7.4, along with gel beads constantly expands, the release rate of BSA improves rapidly, reaches about 100% in three hours.
Embodiment 13:
Embodiment 7,8,9,10 made gel beads are put into simulation stomach (SGF) buffer (pH1.2) 3h, and then put into simulation colon (SCF) pH of buffer 7.4 4h, measure BSA cumulative release rate.The cumulative release rate of BSA in SCF is higher than in SGF, as Figure 10.This is that medicine is to diffuse out from the hole of swollen gel beads because the swelling with gel beads that BSA discharges is relevant.

Claims (3)

1. the preparation method of an oral protein class medicine is characterized in that: comprise the synthesis step of (a) N-α-1,3-propanedicarboxylic acid chitosan, the preparation process of (b) dual cross-linked hydrogel;
The preparation process of described (b) dual cross-linked hydrogel is:
With weight concentration is N-α-1,3-propanedicarboxylic acid chitosan solution of 0.5-3%, regulate the pH to 0.5-6.5 of N-α-1,3-propanedicarboxylic acid chitosan solution with the sodium hydroxide solution of 0.5-2M, adding weight concentration again is the sodium alginate soln mixing of 0.5-3%, add oral protein class medicine, splash in the weight concentration 1.5-2% calcium chloride solution, after dropwising, stir crosslinked 0.5-3h, filter, washing, the % metabisulfite solution that is immersed in weight concentration 1.5-2 again stirs crosslinked 0.5-4h, filters, washing, be dried to constant weight under the room temperature, sodium alginate, N-α-1,3-propanedicarboxylic acid chitosan, the mass ratio of oral protein class medicine is 1: 0.3-0.9: 0.5-1.5.
2. the preparation method of a kind of oral protein class medicine according to claim 1 is characterized in that: described oral protein class medicine is insulin, bovine serum albumin.
3. the preparation method of a kind of oral protein class medicine according to claim 1 is characterized in that: the synthesis step of described (a) N-α-1,3-propanedicarboxylic acid chitosan:
In 1-2% (v/v) acetic acid solution that chitosan is dissolved in, add α-Tong Wuersuan again, the pH value of regulating above-mentioned solution with the 0.5-2M sodium hydroxide solution is 3.5-5.5, room temperature reaction 2-6 hour, add sodium borohydride again, the pH value of regulating said mixture with the 0.1-1M hydrochloric acid solution is 4.5-7.5, reaction is not less than 24 hours, add 90-95% (v/v) ethanol cessation reaction, filter washing, drying, promptly obtain N-α-1,3-propanedicarboxylic acid chitosan, the mass ratio of chitosan, α-Tong Wuersuan, sodium borohydride is 1: 1.5-3.5: 0.3-1.5.
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Cited By (1)

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