Novel self-foaming drug delivery system for rectum and application

Abstract

The invention discloses a novel rectum self-foaming drug delivery system and application, and belongs to the technical field of medicine. The novel rectum self-foaming drug delivery system comprises a carrier material, a foaming agent and a foaming agent, when the drug delivery system or device is used for a rectum drug delivery route, particles carrying drugs can penetrate through an intestinal mucous layer and further penetrate through or directly act on mucous membranes, and the treatment effect is improved.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a novel self-foaming rectal drug delivery system and application. BACKGROUND

[0002] Diabetes is a common endocrine and metabolic disorder disease, which belongs to the category of "Xiaoke" in traditional Chinese medicine. With the aging of the world population, diabetes has become a common and frequently-occurring disease. The number of deaths caused by complications of diabetes is the third after cardiovascular and cerebrovascular diseases and cancer, which has attracted the attention of countries around the world, and they have carried out research on the pathogenesis, drug prevention and treatment of diabetes. From the currently used or already applied hypoglycemic drugs, the basic administration is by oral or injection route. Although the administration by oral or injection route is the most common target for the research and development of new drugs and dosage forms, the two administration methods cannot avoid the liver first-pass effect. Rectal administration is a common self-administration and non-invasive administration method for patients. After the drug is administered rectally, most of the drug is absorbed through the middle and lower rectal veins and the anal vein, collected in the inferior vena cava, and directly enters the systemic circulation to avoid the liver first-pass effect, which can significantly improve the bioavailability. In addition, a small part of the drug is absorbed through the upper rectal vein, reaches the liver through the portal vein, triggers the liver response signal, and then activates other organs in the body to produce a linkage effect and improve the drug efficacy.

[0003] At present, rectal drug delivery preparations are mainly used for local administration of intestinal inflammation and systemic delivery of small molecule drugs, but the advantages of rectal administration and the characteristics of drug absorption are not only suitable for the delivery of small molecule drugs, but also very suitable for the administration of biological macromolecules and their derivatives. At present, biological macromolecules and their derivative drugs have the disadvantages of poor absorption, easy degradation and inactivation, and most of them are administered by injection, which has poor patient compliance. For example, insulin commonly used by diabetic patients is administered by subcutaneous injection, and side effects such as pain, trauma, wound infection and purpura are common, which greatly reduces the quality of life of patients. In addition, recent studies have shown that the intestine not only can absorb drugs, but also has respiratory function, so intestinal oxygen supply has also attracted widespread attention. Therefore, on the basis of traditional rectal drug delivery dosage forms, a novel self-foaming rectal drug delivery system is designed for the delivery of small molecule, biological macromolecule and their derivative drugs and intestinal oxygen supply, which can improve the bioavailability of drugs, improve patient compliance, improve the convenience of oxygen supply, and has great application prospect.

[0004] Generally, the delivery of active agents via the rectal route (topical delivery) can be achieved by using suppositories, enemas, ointments, creams or foams. Traditional rectal administration dosage forms include suppositories, gels, enemas, etc. Due to the low drug loading, weak permeability, poor comfort and other shortcomings, the advantages of rectal administration cannot be fully exerted. Compared with traditional formulations, the retrograde rising effect and the structural characteristics of the foam can effectively deliver the drug to the inside of the intestinal folds. However, the mucus barrier formed by the mucus covering the intestinal mucosa limits the further absorption of the drug.

[0005] Pramlintide acetate is a synthetic analogue of amylin (Amykin, amylin), and is the second drug approved for the treatment of type 1 diabetes after insulin. Clinical studies have found that when pramlintide is used in combination with insulin, it can cause a modest weight loss in patients. However, according to the recommendations of the manufacturer of pramlintide, pramlintide and insulin should not be placed in the same syringe or administered at the same injection site, because the pharmacokinetics of pramlintide can be affected by conventional insulin, neutral protamine hyclase (NPH) and premixed 70 / 30 insulin formulations.

[0006] In addition, in clinical trials, the most common adverse reaction in the pramlintide treatment group is hypoglycemia. Pramlintide as a single drug does not cause hypoglycemia, but when pramlintide is used in combination with insulin, the risk of hypoglycemia caused by insulin increases. Generally, patients are most likely to experience severe hypoglycemia during the initial period of pramlintide treatment (such as within the first 4 weeks of treatment) and within the first 3 hours after injection. SUMMARY

[0007] 1. Problems to be solved

[0008] One of the purposes of the present application is to provide a novel rectal self-foaming drug delivery system and device, which can penetrate the intestinal mucus layer and further penetrate or directly act on the mucosa when used in the rectal administration route, thereby improving the therapeutic effect.

[0009] Meanwhile, the present application also provides a preparation method of the novel rectal self-foaming drug delivery system and the application of the novel rectal self-foaming drug delivery system.

[0010] The second purpose of the present application is to provide a drug delivery system for rectal administration containing a substance having a blood glucose lowering effect, and a method of rectal administration of a substance having a blood glucose lowering effect, which can effectively improve the bioavailability.

[0011] 2. Technical solutions

[0012] To solve the above problems, the technical scheme adopted by the present application is as follows:

[0013] According to one of the purposes of the present application, the present application provides a novel self-foaming drug delivery system for rectum, which comprises a carrier material, a foaming agent and a foaming promoter;

[0014] The carrier material comprises any one, two or more of liposomes, micelles, polymeric nanoparticles;

[0015] The foaming agent comprises a low-boiling point compound;

[0016] The foaming promoter comprises any one, two or more of Tween 80, benzalkonium 35, poloxamer P188, poloxamer P407, alkyl glycoside 0810 and alkyl glycoside 10;

[0017] The volume of the carrier material, the foaming agent and the foaming promoter is calculated;

[0018] The volume addition of the foaming agent is 1% to 10%;

[0019] The volume addition of the foaming promoter is 0.5% to 5%.

[0020] The low-boiling point compound as described herein refers to an organic compound with a boiling point lower than 100℃, and any one, two or three of perfluorocarbon, perfluorobutyl methyl ether and volatile silicone oil can be cited.

[0021] The novel self-foaming drug delivery system for rectum according to any one of the embodiments of the first aspect of the present application has a particle size of the drug-loaded substance of 50nm to 400nm.

[0022] The novel self-foaming drug delivery system for rectum according to any one of the embodiments of the first aspect of the present application has a particle size of the drug-loaded substance selected from any one of the following numerical ranges: 50nm to 400nm, 50nm to 350nm, 50nm to 300nm, 50nm to 250nm, 50nm to 200nm, 50nm to 150nm, 50nm to 100nm;

[0023] 100nm to 400nm, 100nm to 350nm, 100nm to 300nm, 100nm to 250nm, 100nm to 200nm, 100nm to 150nm;

[0024] 150nm to 400nm, 150nm to 350nm, 150nm to 300nm, 150nm to 250nm, 150nm to 200nm, 150nm to 150nm;

[0025] 200-400 nm, 200-350 nm, 200-300 nm, 200-250 nm;

[0026] 250-400 nm, 250-350 nm, 250-300 nm.

[0027] The second aspect of the present application provides a preparation of a novel self-foaming drug delivery system for rectal use, the preparation comprising the steps of:

[0028] S1. preparing a mixed solution containing a carrier material and a foaming agent;

[0029] S2. passing the mixed solution through at least two layers of porous membranes with different pore sizes in the order of decreasing pore size, and each layer of porous membrane is passed through for no less than 8 times;

[0030] S3. adding a foaming agent and stirring at low temperature to obtain the drug delivery system.

[0031] According to the preparation of the novel self-foaming drug delivery system for rectal use according to any one of the embodiments of the second aspect of the present application, in step S2, the preferred number of times of passing through each layer of porous membrane is preferably no less than 8, 9, 10, 11, 12, or 13, in turn.

[0032] According to the preparation of the novel self-foaming drug delivery system for rectal use according to any one of the embodiments of the second aspect of the present application, in step S2, the porous membrane has a pore size ranging from 50 nm to 400 nm.

[0033] According to the preparation of the novel self-foaming drug delivery system for rectal use according to any one of the embodiments of the second aspect of the present application, in step S2, the porous membrane comprises any two, three, or four or more of the following types of porous membranes: a porous membrane with a pore size of 50 nm, a porous membrane with a pore size of 100 nm, a porous membrane with a pore size of 150 nm, a porous membrane with a pore size of 200 nm, a porous membrane with a pore size of 250 nm, a porous membrane with a pore size of 300 nm, a porous membrane with a pore size of 350 nm, and a porous membrane with a pore size of 400 nm.

[0034] According to the preparation of the novel self-foaming drug delivery system for rectal use according to any one of the embodiments of the second aspect of the present application, in step S3, the stirring condition comprises stirring at 2-6°C for 1-3 h; preferably, the stirring condition comprises stirring at 4°C for 2 h.

[0035] According to the preparation of the novel self-foaming drug delivery system for rectal use according to any one of the embodiments of the second aspect of the present application, the novel self-foaming drug delivery system for rectal use according to any one of the embodiments of the first aspect of the present application can be prepared.

[0036] The third aspect of the present application provides a use of the novel self-foaming rectal administration system for preparing a medicament having a blood glucose lowering effect.

[0037] The use of the novel self-foaming rectal administration system according to any one of the embodiments of the third aspect of the present application, wherein the substance having a blood glucose lowering effect comprises any one, two, or more of insulin, an insulin analog, pramlintide, an amylin analog.

[0038] The use of the novel self-foaming rectal administration system according to any one of the embodiments of the third aspect of the present application, wherein the substance having a blood glucose lowering effect comprises insulin.

[0039] The use of the novel self-foaming rectal administration system according to any one of the embodiments of the third aspect of the present application, wherein the substance having a blood glucose lowering effect comprises pramlintide.

[0040] The use of the novel self-foaming rectal administration system according to any one of the embodiments of the third aspect of the present application, wherein the substance having a blood glucose lowering effect comprises insulin and pramlintide.

[0041] The use of the novel self-foaming rectal administration system according to any one of the embodiments of the third aspect of the present application, wherein the substance having a blood glucose lowering effect is insulin.

[0042] The use of the novel self-foaming rectal administration system according to any one of the embodiments of the third aspect of the present application, wherein the substance having a blood glucose lowering effect is pramlintide.

[0043] The use of the novel self-foaming rectal administration system according to any one of the embodiments of the third aspect of the present application, wherein the substance having a blood glucose lowering effect is insulin and pramlintide.

[0044] The fourth aspect of the present application provides a drug administration system for rectal administration comprising a substance having a blood glucose lowering effect, wherein the drug administration system comprises the novel self-foaming rectal administration system and the substance having a blood glucose lowering effect.

[0045] The drug administration system for rectal administration comprising a substance having a blood glucose lowering effect according to any one of the embodiments of the fourth aspect of the present application, wherein the novel self-foaming rectal administration system is present in an amount of 10 wt% to 60 wt% relative to the mass of the substance having a blood glucose lowering effect.

[0046] The use of the novel self-foaming rectal administration system according to any one of the embodiments of the third aspect of the present application, wherein the substance having a blood glucose lowering effect comprises any one, two, or more of insulin, an insulin analog, pramlintide, an amylin analog.

[0047] According to the use of the novel rectal self-foaming drug delivery system according to any embodiment of the fourth aspect of the present invention, the substance having the effect of lowering blood sugar includes insulin.

[0048] According to the use of the novel rectal self-foaming drug delivery system according to any embodiment of the fourth aspect of the present invention, the substance having the effect of lowering blood sugar includes pramlintide.

[0049] According to the use of the novel rectal self-foaming drug delivery system according to any embodiment of the fourth aspect of the present invention, the substance having the effect of lowering blood sugar includes insulin and pramlintide.

[0050] According to the use of the novel rectal self-foaming drug delivery system described in any embodiment of the fourth aspect of the present invention, the substance having the effect of lowering blood sugar is insulin.

[0051] According to the use of the novel rectal self-foaming drug delivery system according to any embodiment of the fourth aspect of the present invention, the substance having the effect of lowering blood sugar is pramlintide.

[0052] According to the use of the novel rectal self-foaming drug delivery system according to any embodiment of the fourth aspect of the present invention, the substances having the effect of lowering blood sugar are insulin and pramlintide.

[0053] A fifth aspect of the present invention provides a method for preparing a drug delivery system for rectal administration comprising a substance having a blood sugar lowering effect, comprising the steps of:

[0054] S1. Prepare a mixture containing a carrier material and a foaming agent;

[0055] Prepare an acidic solution containing a substance that has a hypoglycemic effect;

[0056] mixing the mixed solution with the acid solution to form a blended solution;

[0057] S2. In descending order of pore size, the blend is passed through at least two layers of a porous membrane having different pore sizes, and the number of passes through each porous membrane is not less than 8 times;

[0058] S3. Add a foaming agent and stir at low temperature to obtain the drug delivery system.

[0059] According to any embodiment of the fifth aspect of the present invention, in the preparation of the drug delivery system for rectal administration comprising a substance having a blood sugar lowering effect, in step S1, the pH of the acid solution is 1-5.

[0060] According to any embodiment of the fifth aspect of the present invention, in the preparation of the drug delivery system for rectal administration comprising a substance having a blood sugar lowering effect, the acid of the acid solution comprises any one of hydrochloric acid and acetic acid.

[0061] The preparation of the drug delivery system for rectal administration containing the substance with hypoglycemic effect according to any embodiment of the fifth aspect of the present application, in step S2, the preferred number of times of perforating each porous membrane is preferably not less than 8, 9, 10, 11, 12, or 13 times in turn.

[0062] The preparation of the drug delivery system for rectal administration containing the substance with hypoglycemic effect according to any embodiment of the fifth aspect of the present application, in step S2, the pore size of the porous membrane ranges from 50 nm to 400 nm.

[0063] The preparation of the drug delivery system for rectal administration containing the substance with hypoglycemic effect according to any embodiment of the fifth aspect of the present application, in step S2, the porous membrane comprises any two, three, or four or more of the following types of porous membranes: a porous membrane with a pore size of 50 nm, a porous membrane with a pore size of 100 nm, a porous membrane with a pore size of 150 nm, a porous membrane with a pore size of 200 nm, a porous membrane with a pore size of 250 nm, a porous membrane with a pore size of 300 nm, a porous membrane with a pore size of 350 nm, and a porous membrane with a pore size of 400 nm.

[0064] The preparation of the drug delivery system for rectal administration containing the substance with hypoglycemic effect according to any embodiment of the fifth aspect of the present application, in step S3, the stirring condition comprises stirring at 2-6℃ for 1-3h.

[0065] The preparation of the drug delivery system for rectal administration containing the substance with hypoglycemic effect according to any embodiment of the fifth aspect of the present application can prepare the drug delivery system for rectal administration containing the substance with hypoglycemic effect according to any embodiment of the fourth aspect of the present application.

[0066] The sixth aspect of the present application provides a device for administering the novel rectal self-foaming drug delivery system, or the drug delivery system for rectal administration containing the substance with hypoglycemic effect, which comprises:

[0067] A drug solution containing cavity;

[0068] A drug outlet conduit in communication with the drug solution containing cavity, the port of the drug outlet conduit having a drug outlet hole; and,

[0069] A foaming screen between the containing cavity and the drug outlet conduit.

[0070] The device according to any embodiment of the sixth aspect of the present application further comprises a dosing structure arranged between the foaming screen and the containing cavity.

[0071] Advantages

[0072] (1) Compared with common rectal administration preparations such as suppositories and gels, the novel rectal self-foaming administration system provided by the application can self-foam under the stimulation of intestinal peristalsis and body temperature after entering the intestinal tract, the administration foam is uniformly dispersed, can reversely rise and be widely distributed, and because the foam has a large specific surface area, the contact area of the drug with the rectal cavity is large, and thus the drug can effectively penetrate into the intestinal fold wall and the fold interior.

[0073] In addition, the novel rectal self-foaming administration system provided by the application can reduce the stimulation to the mucosa, and the intestinal tract is not uncomfortable, so that the patient is more willing to accept.

[0074] (2) The novel rectal self-foaming administration system provided by the application has a nanoscale carrier material particle size, has good penetration ability, can overcome the intestinal mucosal barrier, and improve the bioavailability.

[0075] (3) The novel rectal self-foaming administration system provided by the application is applied to the preparation of a drug having a blood glucose lowering effect, or the administration system provided by the application for rectal administration of a substance having a blood glucose lowering effect, can deliver the drug having a blood glucose lowering effect through the rectum, the physiological environment of the rectum avoids protein degradation, and most of the drug can avoid the liver first-pass effect to directly enter the systemic circulation, so that the drug is effectively absorbed and the bioavailability is effectively improved.

[0076] (4) According to the suggestion of the pramlintide manufacturer, pramlintide and insulin should not be placed in the same syringe or administered at the same injection site, because the pharmacokinetics of pramlintide can be affected by conventional insulin.

[0077] The novel rectal self-foaming administration system provided by the application is applied to the preparation of a drug having a blood glucose lowering effect, or the administration system provided by the application for rectal administration of a substance having a blood glucose lowering effect, can realize the stable existence of the two drugs in the same liquid environment or medicine bottle, and realize the simultaneous administration of the two drugs.

[0078] (5) Existing clinical trial data show that the most common adverse reaction in the pramlintide treatment group is hypoglycemia, and when pramlintide is used with insulin, the risk of hypoglycemia caused by insulin will increase.

[0079] The novel rectal self-foaming drug delivery system provided by the application is applied to the preparation of a drug with a blood sugar lowering effect, or the drug delivery system for rectal drug delivery containing a substance with a blood sugar lowering effect, and test results show that when two drugs are delivered simultaneously by using the rectal drug delivery system, due to the characteristics of intestinal absorption and the sustained release effect of liposomes, the hypoglycemic effect caused by the simultaneous administration of the two drugs can be effectively avoided. BRIEF DESCRIPTION OF DRAWINGS

[0080] Figure 1 The morphology of the drug-loaded liposomes prepared in Example 1 of the application under a transmission electron microscope;

[0081] Figure 2 The morphology of the foam modifier modified drug-loaded liposomes prepared in Example 1 of the application under a transmission electron microscope;

[0082] Figure 3 The structural schematic diagram of the novel rectal drug delivery device provided by the application;

[0083] Figure 4 The shape of the foam generated by the novel rectal self-foaming drug delivery system prepared in Example 1 of the application;

[0084] Figure 5 The effect evaluation diagram of the novel rectal self-foaming drug delivery system prepared in Example 1 of the application penetrating the mucus barrier and intestinal epithelial cells;

[0085] Figure 6 The hypoglycemic effect of the drug delivery system for rectal drug delivery containing a substance with a blood sugar lowering effect (insulin) prepared in Example 3 of the application for delivering insulin in mice;

[0086] Figure 7 The combined hypoglycemic effect of the drug delivery system for rectal drug delivery containing a substance with a blood sugar lowering effect (insulin and pramlintide) prepared in Example 4 of the application for delivering insulin and pramlintide in mice;

[0087] Figure 8 The weight loss effect of the drug delivery system for rectal drug delivery containing a substance with a blood sugar lowering effect (pramlintide) prepared in Example 3 of the application for delivering insulin and pramlintide in mice;

[0088] Figure 9 The oxygen supply effect of the novel rectal self-foaming drug delivery system prepared in Example 1 of the application for mice intestinal tract in an anoxic environment after oxygenation. DETAILED DESCRIPTION

[0089] The present disclosure can be more readily understood by reference to the following description, taken in conjunction with the accompanying drawings and examples, which constitute a part of this disclosure. It is understood that the present disclosure is not limited to the particular products, methods, conditions or parameters described and / or shown herein, unless otherwise specified. Further, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, unless otherwise specified.

[0090] It should also be understood that, for clarity, certain features of the present disclosure can be described in the context of separate embodiments, but can also be provided in combination in a single embodiment. That is, unless explicitly stated otherwise, each separate embodiment is considered to be combinable with any other embodiment, and such combinations are considered to represent another, different embodiment. Conversely, various features of the present disclosure described in the context of a single embodiment can also be provided separately or in any sub-combination, for the sake of conciseness. Finally, while a particular embodiment can be described as part of a series of steps or part of a more general structure, each step or sub-structure can itself be considered an independent embodiment.

[0091] Unless otherwise stated, it is to be understood that each individual element in a list and each combination of individual elements in that list are to be construed as a separate embodiment. For example, a list of embodiments recited as “A, B, or C” is to be construed as including the embodiments of “A,” “B,” “C,” “A or B,” “A or C,” “B or C,” or “A, B, or C.”

[0092] In this disclosure, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a substance” is a reference to at least one of such a substance and equivalents thereof.

[0093] Terms including ordinal numbers such as “first” and “second” can be used to explain various components or fluids, but the components, fluids are not limited by the terms. Thus, the terms are used only to distinguish the component / fluid from another component / fluid without departing from the teaching of the present disclosure.

[0094] When describing items by using conjunctive terms such as “and / or” and the like, the description should be understood to include any one of the associated listed items and all combinations of one or more of them; for example, A and / or B should be interpreted to include an embodiment of “A” but not “B,” an embodiment of “B” but not “A,” an embodiment of both “A” and “B.”

[0095] Generally, use of the term "about" indicates that a recited value or condition can vary from a preferred value or condition by a margin that is acceptable in the light of the particular characteristic being obtained by the disclosed subject matter and that the value or condition will be interpreted in a functionally dependent manner based on the context in which it is used. Thus, a person of ordinary skill in the art will be able to interpret a degree of variance on a case-by-case basis. In some cases, the number of significant digits used in expressing a particular value can be indicative of the degree of precision to which the term "about" allows a variance. In other cases, a range of values can be used to determine the range of variance that the term "about" allows. Further, all ranges in the present disclosure are inclusive and combinable, and a reference to a value in a range includes each value in the range.

[0096] Throughout the specification, when it is recited that a certain part "includes" a certain component, unless otherwise explicitly recited to the contrary, it does not mean that other components are excluded, but it means that other components can also be included.

[0097] Throughout the specification of the present application, when it is recited that a certain step is "above" or "before" other steps, it includes not only a case where a certain step has a direct time sequence relationship with other steps, but also a case where a time sequence of the order of two steps such as a mixed step after each step is changed.

[0098] Throughout the specification of the present application, when it is recited as "… according to any embodiment of the … aspect of the … object of the present invention", unless otherwise explicitly recited to the contrary, it does not mean that the components of the described scheme appearing before and after are excluded, but it means that other components can also be included.

[0099] The mice used in the following examples, male, weighing about 200g, can be made into a diabetic rat model with four oxygen pyrimidine as an inducing agent.

[0100] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs; the terminology used herein and / or any and all combinations of the listed items of one or more related items.

[0101] In order to make the technical solutions and advantages of the present application, the technical solutions in the embodiments of the present application will be described in detail below.

[0102] Example 1

[0103] This example provides a novel self-foaming drug delivery system for rectal use according to the following steps:

[0104] S1. Prepare a mixture containing a carrier material, a foaming agent; specifically:

[0105] Hydrogenated soybean lecithin and cholesterol were dissolved in chloroform at a mass ratio of 10:1, and completely dissolved by ultrasonication. The organic solvent was removed by evaporation under reduced pressure at 40°C to obtain a lipid film.

[0106] Deionized water was added as the hydration medium and hydrated at 37°C for 30 min to obtain lipid vesicles;

[0107] Perfluorocarbon was added at 4°C and pulverized using probe ultrasound;

[0108] S2. The mixture is passed through at least two porous membranes with different pore sizes in descending order; specifically:

[0109] The porous membranes are: cellulose membranes with a pore size of 400 nm, cellulose membranes with a pore size of 200 nm

[0110] The mixed solution was passed through 400 nm and 200 nm cellulose membranes in sequence, with each layer extruded 13 times, and the filtrate was collected after completion;

[0111] The liposomes prepared in step S2 have a uniform appearance, are opalescent, have a particle size of 250 nm to 300 nm, and a potential of -25 mV to -30 mV. The TEM electron microscope image is as follows: Figure 1 The TEM electron microscope image shown shows spherical nanoparticles with uniform particle size;

[0112] S3. Add poloxamer P407 to the filtrate, stir at 4℃ for 2h, and pour into Figure 3 In the specially prepared container shown;

[0113] Wherein, the volume of the carrier material, foaming agent and blowing agent is used for calculation;

[0114] The volume addition amount of the perfluorocarbon is 5%;

[0115] The volume addition amount of the poloxamer P407 is 1%.

[0116] like Figure 2 As shown in the TEM electron microscope image, it can be observed that after the addition of poloxamer P407, a hydration film is formed outside the liposome due to self-assembly.

[0117] like Figure 4 As shown, the novel rectal self-foaming drug delivery system is as follows Figure 3 After extrusion in the device shown, a dense foam is formed and can continuously self-foam.

[0118] Example 2

[0119] In this example, the effect of the novel rectal self-foaming drug delivery system on penetrating intestinal mucus and intestinal epithelium was evaluated:

[0120] The new self-foaming drug delivery system for rectal administration prepared in Example 1 was fluorescently labeled, and then the effect of penetrating the intestinal mucus and intestinal epithelium was verified by a Transwell co-culture experiment.

[0121] Caco-2 cells were inoculated in the upper chamber of a Transwell dish, and after 21 days of growth, 1-2 mm of artificial intestinal mucus simulation solution was laid on the cells, and after 2 h of co-culture, drug delivery was performed in the upper chamber of the Transwell dish. At 0 h, 2 h, 4 h, 6 h, 12 h, and 24 h, samples were taken from the upper chamber and the receiving pool below the Transwell dish, and an equal amount of fresh medium was supplemented. The samples were analyzed by fluorescence, and the fluorescence intensity was calculated.

[0122] As shown in Figure 5 , the new self-foaming drug delivery system for rectal administration prepared in Example 1 has good penetration ability, and about 60% of the material can penetrate the intestinal mucus and intestinal mucosa after 24 h, and the material retained in the intestinal mucus and intestinal epithelium is less than 20%.

[0123] Example 3

[0124] In this embodiment, the new self-foaming drug delivery system for rectal administration is used to prepare a drug with a hypoglycemic effect. Specifically, a drug delivery system for rectal administration containing insulin is provided, and the hypoglycemic effect is verified and evaluated. The preparation steps of the drug delivery system for rectal administration containing insulin are as follows:

[0125] S1.1, prepare a mixed solution containing a carrier material and a foaming agent; specifically:

[0126] Hydrogenated soybean phospholipid and cholesterol were dissolved in chloroform at a mass ratio of 10:1, ultrasonicated to completely dissolve, and the organic solvent was removed by evaporation at 40°C under reduced pressure to obtain a lipid film;

[0127] Deionized water was added as a hydration medium, and the lipid vesicles were hydrated at 37°C for 30 min;

[0128] Perfluorocarbon was added at 4°C, and the probe was used for ultrasonic crushing.

[0129] S1.2, disperse insulin in 0.01 mol / L HCL solution (insulin concentration is 1M) to obtain an acid solution containing insulin;

[0130] S1.3, mix the mixed solution with the acid solution to form a blended solution;

[0131] S2. In order from large to small, the mixed solution passes through at least two porous membranes with different pore sizes; specifically:

[0132] The porous membrane is: cellulose membrane with a pore size of 400 nm, cellulose membrane with a pore size of 200 nm

[0133] The mixed solution is sequentially passed through 400 nm and 200 nm cellulose membranes, and the extrusion times of each layer are 13 times, and the filtrate is taken after the end;

[0134] S3. Add poloxamer P407 to the filtrate, stir at 4°C for 2h, and pour into Figure 3 The special container as shown.

[0135] The volume of the carrier material, the foaming agent and the blowing agent is calculated.

[0136] The volume of the perfluorocarbon is added by 5%.

[0137] The volume of the poloxamer P407 is added by 1%.

[0138] The hypoglycemic effect of the drug delivery system for rectal administration containing insulin is verified by oral glucose tolerance test, as shown in Figure 6 Compared with the control group (Control), the blood glucose fluctuation of the drug delivery system group (lipo@ins foam group) is small, and the blood glucose control effect is good.

[0139] Example 4

[0140] In this embodiment, the new self-foaming drug delivery system for rectal administration is used to prepare a drug with hypoglycemic effect. Specifically, a drug delivery system for rectal administration containing pramlintide is provided, and its weight loss effect is verified and evaluated. The preparation steps of the drug delivery system for rectal administration containing pramlintide are basically the same as those of Example 3, and the only difference is that:

[0141] S1.2, disperse pramlintide in acetic acid buffer solution with pH 4 (pramlintide concentration is 1M) to obtain acid solution containing pramlintide;

[0142] The rest is the same as Example 3.

[0143] Example 5

[0144] In this embodiment, the new self-foaming drug delivery system for rectal administration is used to prepare a drug with hypoglycemic effect. Specifically, a drug delivery system for rectal administration containing pramlintide is provided, and its weight loss effect is verified and evaluated. The preparation steps of the drug delivery system for rectal administration containing pramlintide are basically the same as those of Example 3, and the only difference is that:

[0145] The drug delivery system for rectal administration containing insulin is prepared in the manner shown in Example 3;

[0146] A drug delivery system for rectal administration containing pramlintide was prepared in the manner as shown in Example 4;

[0147] After mixing the two, pour Figure 3 In the special container shown

[0148] The hypoglycemic effect of the drug delivery system for rectal administration containing insulin and pramlintide was verified by an oral glucose tolerance test. The novel self-foaming drug delivery system for rectal administration provided in Example 1 of the present invention can stabilize the two drugs in liposomes respectively, so that the two drugs can be stably present in the same solution, thereby achieving simultaneous administration of the two drugs. In addition, Figure 7 As shown, the results of the oral glucose tolerance test showed that compared with the control group (Control), when the rectal delivery system was used to deliver two drugs simultaneously (delivery system group: Co-formulation group), due to the characteristics of intestinal absorption and the sustained release effect of liposomes, the hypoglycemic effect caused by the simultaneous administration of the two drugs was avoided.

[0149] The weight loss effect of a drug delivery system for rectal administration containing pramlintide (drug delivery system group: Co-formulation group) was verified by experiments, such as Figure 8 As shown, the co-formulation group can slow down gastric emptying, suppress the appetite of diabetic patients, achieve the purpose of weight loss, and thus reduce the various complications caused by obesity in diabetic patients.

[0150] Example 6

[0151] In this example, the novel rectal self-foaming drug delivery system prepared in Example 1 was used to prepare an intestinal oxygen supply drug. Specifically, the preparation prepared in Example 1 was oxygenated in vitro for 30 to 60 seconds. After oxygenation, the drug was administered to mice, and the survival time was measured in an oxygen-deficient environment. Compared with the control group, the survival time of the mice in the drug-administered group was significantly prolonged. Figure 9 .

[0152] Compared to the control group (Control), the rectal administration system can effectively provide intestinal oxygen by utilizing the respiratory function of the intestine. Compared with traditional oxygen supply methods, the intestinal oxygen supply method provided by the present invention is more convenient, controllable, and concealed.

[0153] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A novel self-foaming delivery system for rectal use, characterized in that, The drug delivery system comprises a carrier material, a foaming agent and a foaming enhancer; The carrier material comprises any one, two or more of liposome, micelle, polymer nanoparticle; The foaming agent comprises a low-boiling compound; The foaming enhancer comprises any one, two or more of Tween 80, benzalkonium 35, poloxamer P188, poloxamer P407, alkyl glycoside 0810 and alkyl glycoside 10; The volume of the foaming agent is calculated based on the volume of the carrier material, the foaming agent and the foaming enhancer; The volume of the foaming agent is added by 1% to 10%; The volume of the foaming enhancer is added by 0.5% to 5%.

2. The novel self-foaming drug delivery system for rectal use as claimed in claim 1, wherein, The drug delivery system has a drug loading material with a particle size of 50nm to 400nm.

3. The preparation of a novel self-foaming drug delivery system for rectal use according to claim 1 or 2, characterized in that, The method comprises the steps of: S1. preparing a mixed solution containing a carrier material and a foaming agent; S2. passing the mixed solution through at least two layers of porous membranes with different pore sizes in the order of decreasing pore size, and the passing number of each layer of porous membrane is not less than 8 times; S3. adding a foaming enhancer and stirring at low temperature to obtain the drug delivery system.

4. The preparation of novel self-foaming drug delivery system for rectal use according to claim 3, characterized in that, In step S2, the pore size of the porous membrane ranges from 50nm to 400nm; And / or, In step S3, the stirring condition comprises stirring at 2 to 6℃ for 1 to 3h.

5. Use of a novel self-foaming drug delivery system for rectal use, characterized in that, The use for preparing a drug with a blood glucose lowering effect; Or, the use for preparing a drug with an intestinal oxygen supply effect.

6. A delivery system for rectal administration comprising a substance having a blood glucose lowering effect, characterized in that The drug delivery system comprises a novel self-foaming drug delivery system for rectal use and a substance with a blood glucose lowering effect; And / or, The novel self-foaming drug delivery system for rectal use has an addition mass ratio of 10wt% to 60wt% to insulin.

7. Use of the novel self-foaming drug delivery system for rectal administration according to claim 5, or the drug delivery system for rectal administration comprising a substance having a blood glucose-lowering effect according to claim 6, characterized in that, The substance with a blood glucose lowering effect comprises any one, two or more of insulin, insulin analog, pramlintide and amylin analog; The substance with a blood glucose lowering effect is preferably insulin and / or pramlintide.

8. The preparation of a drug delivery system for rectal administration comprising a substance having a blood sugar lowering effect, characterized in that, The method comprises the steps of: S1. preparing a mixed solution containing a carrier material and a foaming agent; S2. preparing an acid solution containing a substance with a blood glucose lowering effect; S3. mixing the mixed solution and the acid solution to form a blended solution; S4. passing the blended solution through at least two layers of porous membranes with different pore sizes in the order of decreasing pore size, and the passing number of each layer of porous membrane is not less than 8 times; S5. adding a foaming enhancer and stirring at low temperature to obtain the drug delivery system.

9. The preparation of a drug delivery system for rectal administration comprising a substance having a blood glucose-lowering effect according to claim 8, characterized by, In step S1, the pH of the acid solution is 1 to 5; And / or, In step S2, the pore size of the porous membrane ranges from 50nm to 400nm; And / or, In step S3, the stirring condition comprises stirring at 2 to 6℃ for 1 to 3h.

10. A device for rectal administration of a self-foaming drug delivery system containing a novel substance having a hypoglycemic effect, or a drug delivery system for rectal administration containing a substance having a hypoglycemic effect, characterized in that, The device comprises: a drug solution containing cavity; a drug outlet conduit in communication with the drug solution containing cavity, and the port of the drug outlet conduit has a drug outlet hole; and a foaming screen between the containing cavity and the drug outlet conduit.

Images