CN1488331A - A superporous hydrogel composite, its preparation method and its application in pharmacy - Google Patents

Abstract

The invention discloses an ultra-multiaperture hydrogel compound, making method and application in pharmacy. It contains cross-linked polymer and Carbomer. At least one unsaturated alkene monomer and polyene cross-linking agent polymerize to develop it. The making steps: mix at least one unsaturated alkene monomer, one polyene cross-linking agent, Carbomer and one foaming agent; the mixture develops it on the condition of polymerizing and foaming. It can be used in stomach floating preparation and protein polypeptide oral medicine supplying system.

Description

A superporous hydrogel composite, its preparation method and its application in pharmacy

technical field

The invention belongs to the technical field of polymer materials, and in particular relates to a superporous hydrogel compound, its preparation method and its application in pharmacy.

Background technique

Hydrogels are cross-linked hydrophilic polymers containing a network structure. It is insoluble in water but absorbs large amounts of water. The study of hydrogel began in the 1960s. Due to its biocompatibility and biodegradability, it can be widely used in the fields of medicine, biology and pharmacy. So far, a variety of hydrogels have been invented. gel.

As far as the swelling properties of hydrogels are concerned, they can be divided into the following two types: traditional hydrogels and new hydrogels. The most important difference between the two is their expansive nature. The swelling properties of hydrogel are mainly related to the elasticity of the network structure, the presence or absence of hydrophilic functional groups in the polymer chain segment, the degree of crosslinking and the porosity of the polymer. In addition, the interaction between ions and solvent-mediated effects also affect it. Conventional hydrogels swell very slowly due to their rigid crystalline structure and low elasticity of polymer chain segments. The time for a hydrogel of the size of an ordinary tablet (diameter 1 cm, thickness 0.5 cm) to reach swelling equilibrium is usually several hours or even several days. The hydrogel needs to be pre-swelled for application. The new superporous hydrogels (superporous gydrogels) greatly increase the internal surface area of the hydrogel due to the large number of cross-linked pores, which makes them absorb water very quickly, usually for a few seconds to several hours. However, its mechanical strength is poor.

U.S. Patent 6271278 discloses a superporous hydrogel composite, in the presence of a disintegrant and a foaming agent, by crosslinking one or more ethylenically unsaturated monomers and a polyene Formed by polymerization. The superporous hydrogel disclosed in the invention has a certain bioadhesion and protease inhibitory effect due to containing a large number of carboxylic acid groups. However, due to the addition of disintegrants, the superporous hydrogel composites have decreased bioadhesion and protease inhibition.

Contents of the invention

The object of the present invention is to provide a superporous hydrogel composite with fast expansion speed, high mechanical strength, good bioadhesion and protease inhibition and its preparation method, and its application in pharmacy to overcome Deficiencies and defects of the prior art.

Carbomer is a copolymer of polyalkyl sucrose and polyalkyl pentaerythritol with acrylic acid crosslinked polymer. Due to the presence of a large number of carboxylic acid groups in the molecule, it has very similar physical and chemical properties to polyacrylic acid, and at the same time, the weak cross-linking bonds in the structure make it have a similar water absorption phenomenon to cross-linked sodium polyacrylate. Carbomer swells rapidly in water but does not dissolve. And the gel formed by carbomer has certain strength and elasticity. The carboxylic acid groups in the carbomer molecule can form a large number of hydrogen bonds. On the one hand, it is easy to swell in water, which can produce a large adhesion area and maximize contact with mucous membrane proteins; on the other hand, acrylic acid The interaction between the polymer and the mucin through hydrogen bonds can cause a viscous interaction between the polymer and the mucin. And the faster the polymer swells, the faster it interacts with mucin, thus ensuring a strong stickiness.

The superporous hydrogel composite proposed by the present invention is prepared by adding carbolin into the superporous hydrogel. It not only has the property of rapid expansion of the superporous hydrogel, but also because of the addition of carbomer, The mechanical strength is increased, and it has good bioadhesive properties and inhibitory effect on protease, so that the hydrogel complex is beneficial for oral administration of protein polypeptide drugs and for gastric floating preparations.

The superporous hydrogel composite of the present invention contains a crosslinked polymer and carbomer, and has a superporous structure, and the polymer is formed by polymerization of at least one unsaturated ethylenic monomer and a polyene crosslinking agent; wherein the carbomer The weight ratio of foam to polymer is 0.05:100 to 15:100, and the weight ratio of crosslinking agent to monomer is 0.01:100 to 10:100.

Said unsaturated ethylenic monomers can be (meth)acrylic acid, (meth)acrylic acid salts, (meth)acrylic acid esters, (meth)acrylic acid ester salts or acids, (meth)acrylic acid N-alkylamides of (meth)acrylic acid, salts and acids of N-alkylamides of (meth)acrylic acid, N-vinylpyrrolidone, acrylamide, acrylamide derivatives, One or more of methacrylamide and methacrylamide derivatives.

Commonly used ethylenically unsaturated monomers are acrylamide, N-isopropylacrylamide, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, N-vinylpyrrolidone, acrylic acid, 2- One or more of acrylamide-2-methyl-1-propanesulfonic acid, 3-sulfopropyl-acrylic acid potassium salt.

Said cross-linking agent is N, N-methylene-bisacrylamide (Bis), ethylene glycol di(meth)acrylate, piperazine diacrylamide, glutaraldehyde, epichlorohydrin, containing 1, 2 Diol structure cross-linking agent, functional peptide-containing cross-linking agent and protein-containing cross-linking agent.

The superporous hydrogel composite of the present invention has an average pore diameter of 50 μm to 4000 μm. A preferred average pore size is 100 μm to 800 μm. Due to the existence of a large number of pores and their interconnection with each other, the hydrogel composite swells very quickly and its time to reach swelling equilibrium is also very short. The swelling ratio of the superporous hydrogel composite of the present invention is 5 to 2000, and the preferred swelling ratio is 5-800. The time to reach swelling equilibrium is 1 second to 2 hours, and the better swelling equilibrium time is 1 second to 30 minutes.

The above-mentioned superporous hydrogel composite that the present invention proposes, its preparation method is as follows:

(1) at least one unsaturated ethylenic monomer, a polyene crosslinking agent, carbomer and a foaming agent are mixed by weight;

(2) The above mixture forms a superporous hydrogel composite under the conditions of polymerization and foaming.

Wherein the ratio of carbomer to polymer (formed by polymerization of at least one ethylenically unsaturated monomer and polyene crosslinking agent) is in the range of 0.05:100 to 15:100. The amount of carbomer used is too large, and it cannot be completely included in the polymer during the polymerization process, and some carbomer does not gel. Said unsaturated ethylenic monomers are (meth)acrylic acid, (meth)acrylic acid salts, (meth)acrylic acid esters, (meth)acrylic acid ester salts or acids, (meth)acrylic acid Amides, N-alkylamides of (meth)acrylic acid, salts and acids of N-alkylamides of (meth)acrylic acid, N-vinylpyrrolidone, acrylamide, acrylamide derivatives, formaldehyde One or more of methacrylamide and methacrylamide derivatives.

Commonly used ethylenically unsaturated monomers are acrylamide, N-isopropylacrylamide, 2-hydroxyethyl methacrylate, 2-hydroxypropyl methacrylate, N-vinylpyrrolidone, acrylic acid, 2- One or more of acrylamide-2-methyl-1-propanesulfonic acid, 3-sulfopropyl-acrylic acid potassium salt.

Said cross-linking agent is N, N-methylene-bisacrylamide, ethylene glycol di(meth)acrylate, piperazine diacrylamide, glutaraldehyde, epichlorohydrin, containing 1,2 glycol Structural cross-linking agents, functional peptide-containing cross-linking agents and protein-containing cross-linking agents. The amount used is such that the ratio of crosslinker to monomer is in the range of 0.01:100 to 10:100. A preferred ratio of crosslinker to monomer is 1:100. Too high concentration of cross-linking agent caused the swollen superporous hydrogel composite to become brittle, resulting in a decrease in the swelling ratio. On the contrary, the concentration of cross-linking agent is too low, resulting in softer and brittle superporous hydrogel composites.

Said foaming agent is one or more of bicarbonate and carbonate or introduces bubbles from the outside. One or more of sodium bicarbonate, sodium carbonate and calcium carbonate are commonly used. Preferred is sodium bicarbonate. Its addition amount is 0.5-1.5 weight ratio of proton-giving monomer.

The two necessary conditions for the formation of superporous hydrogel composites are aggregation and foaming. The required water should be added prior to polymerization and foaming. In order to prepare homogeneous superporous hydrogel composites, polymerization and foaming should occur simultaneously. Because the foaming process is short and it is difficult to stabilize the bubbles for longer than a few minutes, in order to trap the bubbles in the polymer network, gelation must occur while the bubbles are stabilizing.

There are various methods of foaming, including chemical or mechanical methods such as thermal decomposition of chemical reagents, mechanical shaking, volatilization of low-boiling liquids, chemical reactions, and expansion of dissolved gases when pressure is released. The amount of foaming agent determines the pore size of the bubbles and the porosity of the superporous hydrogel composite. After the bubbles are generated, to stabilize them during the gelation process, foam stabilizers are used, which stabilize the foam by reducing the film-air interfacial tension and increasing the film viscosity. . An ideal foam stabilizer should stabilize the foam until the onset of the gelling process. Pluronic F127 (poloxamer) is a better foam stabilizer, which stabilizes the foam for a longer time. However, there are certain requirements for its dosage, too little can not provide a good foam stabilization effect, and more than a certain amount can not achieve the same foam stabilization effect. Generally speaking, its dosage is 0.4-0.7% (W/W). Carbosol is used in the present invention, and with the increase of the amount of carbose, it can be observed that the generation height of the bubbles increases. And if the amount of carbomer added is appropriate, the stability of the bubbles increases. Carbomer plays an auxiliary role in stabilizing the bubbles.

In the above method, before the polymerization and foaming, an initiator and a catalyst can also be added to the mixture to improve the polymerization speed.

In the present invention, sodium bicarbonate is selected as the foaming agent to prepare superporous hydrogel composites in the presence of acid, because the sodium bicarbonate-acid system has advantages that other gas injection techniques do not have. It is safe, inexpensive, easy to use, and allows artificial control of the time of foam formation and the amount of gas introduced during polymerization.

Rapid gelation can be achieved by controlling monomer (type and concentration), initiator (type and concentration), temperature and solvent. Generally, water-soluble acrylates, methacrylates, and acrylamides gel very quickly, so the above-mentioned monomers are preferred to prepare superporous hydrogel composites.

Ammonium persulfate is preferably used as the initiator, and N,N,N',N'-tetramethylethylenediamine (TMEDA) is used as the catalyst, and the amount of the initiator and the catalyst can affect the polymerization rate. Typically, the concentration of ammonium persulfate and N,N,N',N'-tetramethylethylenediamine is about 1.5-2.5% (W/W) of the monomer.

The measuring method of the swelling ratio, density and bioadhesion of superporous hydrogel composite of the present invention is as follows:

Determination of swelling ratio: The swelling ratio is defined as Q=(Ws-Wd)/Wd, wherein Ws is the weight of the swollen superporous hydrogel composite, and Wd is the weight of the dry superporous hydrogel composite. First weigh the dry superporous hydrogel composite to obtain Wd, place the sample in excess double-distilled water, take it out regularly with a container with a screen, remove the remaining water in the screen, and then weigh it to obtain Ws, namely The swelling ratio Q can be obtained.

Determination of density: the density is d=Wd/Vd, wherein Wd is the weight of the dry superporous hydrogel composite, and Vd is the volume of the superporous hydrogel composite. Among them, Vd is measured by solvent replacement method, that is, the superporous hydrogel composite is placed in a cylindrical test tube filled with n-hexane whose diameter and height have been measured, and the Vd is obtained through the change of height, thereby obtaining the density.

Determination of bioadhesive force: take fresh gastric mucosa and small intestinal mucosa of rats (do not damage the mucosal layer), put the superporous hydrogel in contact with the mucosa in a fixed volume, place it for 10 minutes, and measure it with an improved precision torque balance. The force required to separate the hydrogel from the mucosa is known as bioadhesion.

Table 1 Density, swelling ratio, swelling time and bioadhesion of superporous hydrogels (n=3)

Dried ultraporous hydrogel

Swrite time Biological adhesion sample

                         

Density of composite (g/cm ³ )

(min) (mg/mm ² )

1 0.84±0.05 138±16 10±3 23.6±10.2

2 0.68±0.02 146±11 8±4 25.3±12.5

3 0.98±0.02 75±8 90±14 32.6±13.1

4 0.80±0.06 149±21 12±5 24.5±11.3

5 0.73±0.09 131±9 9±3 28.3±12.9

6 0.96±0.01 83±11 86±18 35.4±15.6

^* : Samples 1-6 were prepared from Examples 1-6.

The superporous hydrogel composite provided by the invention has a porous structure inside and fewer pores outside, similar to traditional hydrogels, and thus has better mechanical strength.

The superporous hydrogel composite of the invention has better inhibitory effect on trypsin.

The superporous hydrogel composite of the present invention can be used in the preparation of gastric floating preparations because of its low density, rapid expansion, good mechanical strength and adhesion to gastric mucosa.

The superporous hydrogel complex of the present invention can be used for oral administration of protein polypeptide drugs because of its fast swelling, adhesion to small intestine mucosa and inhibition of protease.

The advantages of the present invention are:

(1) Carbopol has the effect of assisting the stabilization of bubbles, making the preparation of superporous hydrogel composites easier.

(2) The added carbomer has the characteristics of rapid swelling, and the composite formed with the superporous hydrogel still has the characteristics of rapid swelling;

(3) Due to the appearance of the exterior similar to traditional hydrogels, the mechanical strength of the superporous hydrogel composite is better;

(4) After adding an appropriate amount of carbomer, the density of the superporous hydrogel composite is small, which is beneficial to the gastric floating preparation;

(5) The addition of carbomer enables the superporous hydrogel complex to have bioadhesion and protease inhibition, which is beneficial to the oral administration of protein and polypeptide drugs.

Detailed ways

Embodiment 1, poly(acrylic acid and acrylamide)-carbomer superporous hydrogel composite

Add the following ingredients in turn to a tall weighing bottle: 300 μl 50% acrylamide; 200 μl 50% acrylic acid; 70 μl 2.5% Bis; 300 μl double distilled water; 30 μl 10% Pluronic F127; 25 μl 20% ammonium persulfate; 0.4% Carbopol 934P; 25 μl 15% TEMED. After the addition of each component, the solution was vortex mixed, 100 mg of sodium bicarbonate was added 2 minutes before gelling, and vortexed for 20 seconds. The superporous hydrogel composite was cured at room temperature for 10 minutes and dried at 55°C for 20 hours.

Embodiment 2, poly(acrylic acid and acrylamide)-carbomer superporous hydrogel composite

Add the following ingredients to a tall weighing bottle in turn: 300 μl 50% acrylamide; 200 μl 50% acrylic acid; 70 μl 2.5% Bis; 300 μl double distilled water; 30 μl 10% Pluronic F127; 25 μl 20% ammonium persulfate; 12 mg Carbopol 934P; 25 μl 15% TEMED. After the addition of each component, the solution was vortex mixed, 100 mg of sodium bicarbonate was added 2 minutes before gelling, and vortexed for 20 seconds. The superporous hydrogel composite was cured at room temperature for 10 minutes and dried at 55°C for 20 hours.

Embodiment 3, poly(acrylic acid and acrylamide)-carbomer superporous hydrogel composite

Add the following ingredients to a tall weighing bottle in turn: 300μl 50% acrylamide; 200μl 50% acrylic acid; 70μl 2.5% Bis; 700μl double distilled water; 30μl 10% Pluronic F127; 25μl 20% ammonium persulfate; 50mg Carbopol 934P; 25 μl 15% TEMED. After the addition of each component, the solution was vortex mixed, 100 mg of sodium bicarbonate was added 2 minutes before gelling, and vortexed for 20 seconds. The superporous hydrogel composite was cured at room temperature for 10 minutes and dried at 55°C for 20 hours.

Embodiment 4, poly(acrylic acid and acrylamide)-carbomer superporous hydrogel composite

Add the following ingredients in turn to a tall weighing bottle: 300 μl 50% acrylamide; 200 μl 50% acrylic acid; 70 μl 2.5% Bis; 300 μl double distilled water; 30 μl 10% Pluronic F127; 25 μl 20% ammonium persulfate; 0.4% Carbopol 974P; 25 μl 15% TEMED. After the addition of each component, the solution was vortex mixed, 100 mg of sodium bicarbonate was added 2 minutes before gelling, and vortexed for 20 seconds. The superporous hydrogel composite was cured at room temperature for 10 minutes and dried at 55°C for 20 hours.

Embodiment 5, poly(acrylic acid and acrylamide)-carbomer superporous hydrogel composite

Add the following ingredients to a tall weighing bottle in turn: 300 μl 50% acrylamide; 200 μl 50% acrylic acid; 70 μl 2.5% Bis; 300 μl double distilled water; 30 μl 10% Pluronic F127; 25 μl 20% ammonium persulfate; 12 mg Carbopol 974P; 25 μl 15% TEMED. After the addition of each component, the solution was vortex mixed, 100 mg of sodium bicarbonate was added 2 minutes before gelling, and vortexed for 20 seconds. The superporous hydrogel composite was cured at room temperature for 10 minutes and dried at 55°C for 20 hours.

Embodiment 6, poly(acrylic acid and acrylamide)-carbomer superporous hydrogel composite

Add the following ingredients to a tall weighing bottle in turn: 300μl 50% acrylamide; 200μl 50% acrylic acid; 70μl 2.5% Bis; 700μl double distilled water; 30μl 10% Pluronic F127; 25μl 20% ammonium persulfate; 50mg Carbopol 974P; 25 μl 15% TEMED. After the addition of each component, the solution was vortex mixed, 100 mg of sodium bicarbonate was added 2 minutes before gelling, and vortexed for 20 seconds. The superporous hydrogel composite was cured at room temperature for 10 minutes and dried at 55°C for 20 hours.

Embodiment 7, polyacrylamide-carbomer superporous hydrogel composite

Add the following components to a tall weighing bottle in turn: 500 μl 50% acrylamide; 100 μl 2.5% Bis; 300 μl double distilled water; 40 μl 10% Pluronic F127; 10 μl acrylic acid; 20 μl 20% ammonium persulfate; %TEMED. After the addition of each component, the solution was vortex mixed, 50 mg of sodium bicarbonate was added 2 minutes before gelling, and vortexed for 20 seconds. The superporous hydrogel composite was cured at room temperature for 10 minutes and dried at 55°C for 20 hours.

Embodiment 8, polyacrylic acid-carbomer superporous hydrogel composite

Add the following ingredients to a tall weighing bottle in turn: 300μl 50% acrylic acid (neutralized); 100μl 2.5% Bis; 300μl double distilled water; 40μl 10% Pluronic F127; 20μl 20% ammonium persulfate; 12mgCarbopol934P; 15% TEMED. After the addition of each component, the solution was vortex mixed, 100 mg of sodium bicarbonate was added 2 minutes before gelling, and vortexed for 20 seconds. The superporous hydrogel composite was cured at room temperature for 10 minutes and dried at 55°C for 20 hours.

Example 9, 2-hydroxyethyl methacrylate-carbomer superporous hydrogel composite

Add the following components to a tall weighing bottle in turn: 300μl 2-hydroxyethyl methacrylate; 60μl 2.5% Bis; 60μl 10% Pluronic F127; vortex mixing; keep warm at 60°C, add 20μl 20% ammonium persulfate ; 12 mg Carbopol 934P; 20 μl 15% TEMED. After the addition of each component, the solution was vortex mixed, 50 mg of sodium bicarbonate was added 2 minutes before gelling, and vortexed for 20 seconds. The superporous hydrogel composite was cured at room temperature for 10 minutes and dried at 55°C for 20 hours.

The superporous hydrogel composites prepared in the above examples all have good physical and biological properties, as shown in Table 1 for details.

Embodiment 10 aspirin gastric flotation preparation

Prepare a 2mg/ml aqueous aspirin solution; take out 20ml, add the sample obtained in Example 5 into it; wait for it to completely absorb the aspirin aqueous solution, dry it at room temperature for 2 days; pack it into a No. 0 capsule.

Embodiment 11 Oral insulin delivery system

Insulin was first dissolved with 0.1N HCl, and water was added to obtain a 2mg/ml solution; 15ml was taken out, and the sample obtained in Example 5 was added to it; after it completely absorbed the insulin solution, it was dried at room temperature for 2 days; Dissolve the capsules.

Claims (15)

1, a kind of Superporous hydrogels complex is characterized in that containing cross linked polymer and CBP, and has super loose structure, and this polymer is formed by at least a ethylenic unsaturation monomer and polyene cross-linking agent polymerization; Wherein, the part by weight of CBP and polymer is 0.05: 100 to 15: 100; Cross-linking agent and monomeric part by weight are 0.01: 100 to 10: 100.

2, Superporous hydrogels complex according to claim 1, it is characterized in that said ethylenic unsaturation monomer in the salt of the salt of (methyl) acrylic acid, (methyl) acrylic acid salt, (methyl) esters of acrylic acid, (methyl) acrylate or acids, (methyl) acrylic acid amide-type, (methyl) acrylic acid N-alkylamide, (methyl) acrylic acid N-alkylamide and acids, N-vinyl pyrrolidone, acrylamide, acrylamide derivative, Methacrylamide, the methacrylamide derivatives one or more.

3, Superporous hydrogels complex according to claim 1 is characterized in that used ethylenic unsaturation monomer is one or more in acrylamide, N-N-isopropylacrylamide, 2-hydroxyethyl meth acrylate, 2-hydroxypropyl methyl acrylate, N-vinyl pyrrolidone, acrylic acid, 2-acrylamide-2-methyl isophthalic acid-propane sulfonic acid, the 3-sulfopropyl-acrylic acid potassium salt.

4, Superporous hydrogels complex according to claim 1, it is characterized in that used cross-linking agent is N, N-methylene-bisacrylamide (Bis), two (methyl) acrylic acid glycol ester, piperazine diacrylamine, glutaraldehyde, chloropropylene oxide, the cross-linking agent that contains 1,2 diol structure, the cross-linking agent that contains Functional Polypeptides and proteinaceous cross-linking agent.

5,, it is characterized in that its average pore size is 50 μ m to 4000 μ m according to the described Superporous hydrogels complex of one of claim 1-4.

6, Superporous hydrogels complex according to claim 5 is characterized in that its average pore size is 100 μ m to 800 μ m.

7, Superporous hydrogels complex according to claim 1 is characterized in that its swelling ratio is 5 to 2000, and the time that reaches swelling equilibrium is 1 second to 2 hours.

8, a kind of preparation method as the described Superporous hydrogels complex of one of claim 1-7 is characterized in that concrete steps are as follows:

(1) at least a ethylenic unsaturation monomer, a kind of polyene cross-linking agent, CBP and a kind of foaming agent are mixed by weight proportion;

(2) said mixture forms the Superporous hydrogels complex under polymerization and blistered condition.

9, the preparation method of Superporous hydrogels complex according to claim 8, it is characterized in that said foaming agent be bicarbonate, carbonate one or more or from outer importing bubble.

10, the preparation method of Superporous hydrogels complex according to claim 9 is characterized in that said foaming agent is a sodium bicarbonate.

11, the preparation method of Superporous hydrogels complex according to claim 8 is characterized in that adding entry in mixture before polymerization and bubbling.

12, the preparation method of Superporous hydrogels complex according to claim 8 is characterized in that adding foam stabiliser in mixture before polymerization and bubbling.

13, the preparation method of Superporous hydrogels complex according to claim 8 is characterized in that adding initiator and catalyst in mixture before polymerization and bubbling.

14, each the application of Superporous hydrogels complex in the stomach floating preparation among the claim 1-7.

15, each the application of Superporous hydrogels complex in the protein and peptide oral administration system among the claim 1-7.