CN111297797A - Long-acting sustained-release drug delivery system suitable for subcutaneous drug delivery and preparation method thereof - Google Patents
Long-acting sustained-release drug delivery system suitable for subcutaneous drug delivery and preparation method thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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- Engineering & Computer Science (AREA)
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- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a long-acting sustained-release drug delivery system suitable for subcutaneous drug delivery, which is in a gel state and comprises porous microspheres for loading therapeutic drugs, and sodium alginate and calcium chloride which are mixed with the porous microspheres loaded with the therapeutic drugs and used as in-situ gel materials; the weight ratio of the porous microspheres to the sodium alginate to the calcium chloride is (1-90) to (10-100), and the porous microspheres contain phosphorus and/or calcium components, so that the therapeutic drug can be slowly released under the skin of a human body. The invention uses the porous microspheres containing phosphorus and/or calcium components as carriers of therapeutic drugs, the obtained drug delivery system not only can realize loading and slow release of the drug with super-large dose, but also can not generate the phenomenon of drug burst release, and has relatively low use cost and no toxic or side effect on patients when in use, therefore, the invention well solves the defects of the prior art, and is very suitable for large-scale popularization and application in the aspect of disease treatment by subcutaneous drug delivery.
Description
Technical Field
The invention relates to the field of long-acting sustained-release drug systems/preparations, in particular to a long-acting sustained-release drug delivery system suitable for subcutaneous drug delivery.
Background
There are many diseases in humans that require long-term administration to inhibit disease progression and to sustain life. Current administration to such patients is primarily oral or injection over a specific period of time or periodically. However, there are limitations to the current administration of this drug. Firstly, the administration mode brings great inconvenience, pain and psychological pressure to patients; secondly, the medicine is intermittently administrated for a short time, the medicine concentration has the characteristics of wave crest and wave trough in the body of a patient, and the change of the blood medicine concentration is large, so that the bioavailability of the medicine in the body of the patient is low, and meanwhile, the fluctuation is generated on the stability of the state of illness of the patient; thirdly, the stability of the drug in vivo is poor, a significant first-pass effect exists, the biological half-life is short, and the drug elimination is fast. In addition, for some specific patients, such as psychosis and Alzheimer's disease patients, there are cases where the intermittent administration of the drug is unwilling or forgotten, which may aggravate the patient's condition and even threaten life.
In order to improve the disadvantages of intermittent administration, the development of long-acting sustained-release administration systems is becoming a goal pursued by human beings. The long-acting sustained-release administration mode has a plurality of advantages. Most obviously, the medicine can reduce the administration times and improve the compliance of patients; secondly, the blood concentration of the medicine in the body of a patient is stable, and the wave crest and wave trough phenomena of the medicine can be avoided; third, long-acting sustained release administration can greatly reduce the cost to the patient.
It follows that due to the advantages of long acting sustained release drug delivery systems, many long acting sustained release drug delivery systems have been developed and commercialized, for example, the commercial products are Eligard, Atrigel, atriorb, etc. However, these long acting sustained release drug delivery systems are mainly composed of PLGA and NMP. As is known, PLGA is a high-viscosity polymer, which is not easy to be injected transdermally, and the phenomenon of drug burst is severe, and meanwhile, such long-acting sustained-release materials contain organic solvents, and acidic toxic substances are generated due to material degradation during use.
In order to avoid the defects of polyester long-acting sustained-release drug delivery systems such as PLGA, other materials are continuously searched for to replace biological polyesters. At present, some materials, such as biological phospholipid, chitosan, etc., have been tried to develop a long-acting sustained-release drug delivery system. However, the long-acting sustained-release drug delivery systems prepared from these materials have the defects of small drug loading, short drug delivery period and the like, and still have the phenomenon of drug burst release to a certain extent, so that the use of patients, especially patients with long-term drug dependence, still cannot be satisfied.
Disclosure of Invention
In order to overcome the defects of the current long-acting sustained-release drug delivery system, the invention provides the long-acting sustained-release drug delivery system suitable for subcutaneous drug delivery, which can avoid the defects of the currently reported sustained-release material (such as poor biocompatibility, small drug loading, sudden drug release phenomenon and the like).
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the long-acting sustained-release drug delivery system suitable for subcutaneous drug delivery is in a gel state and comprises porous microspheres for loading therapeutic drugs, and sodium alginate and calcium chloride which are mixed with the porous microspheres loaded with the therapeutic drugs and used as in-situ gel materials; the weight ratio of the porous microspheres to the sodium alginate to the calcium chloride is (1-90) to (10-100), and the porous microspheres contain phosphorus and/or calcium components, so that the therapeutic drug can be slowly released under the skin of a human body.
Preferably, when the porous microspheres contain a phosphorus component, the chemical component of the porous microspheres is any one or more of calcium hydrophosphate, tricalcium phosphate and hydroxyapatite.
Preferably, when the porous microspheres contain a calcium component, the chemical component of the porous microspheres is any one or more of calcium hydrogen phosphate, tricalcium phosphate, hydroxyapatite and calcium carbonate.
In the scheme, the average diameter of the porous microspheres is 0.1-3000 microns.
In the above scheme, the average pore diameter of the porous microspheres is 0.01-500 μm.
In the scheme, the porosity of the porous microspheres is 5-90%.
In the scheme, the weight ratio of the sodium alginate to the water in the sodium alginate aqueous solution is 0.1-5%.
In the scheme, the concentration of calcium chloride in the calcium chloride aqueous solution is 10-500 mmol/ml.
The preparation and use methods of the invention are as follows:
first, porous microsphere drug loading
First, the porous microspheres are soaked in a liquid containing a therapeutic drug and gently stirred so that the drug is sufficiently introduced into the pores of the porous microspheres. If the drug loading is insufficient, a vacuum may be applied to assist in the introduction of the drug into the porous microspheres. After the medicine is fully loaded in the porous microspheres (0.5-2 hours), separating the medicine-loaded porous microspheres from the liquid containing the medicine, drying (natural drying, freeze drying or drying), and then removing the liquid to obtain the medicine-loaded porous microspheres.
Second, subcutaneous administration
Subcutaneous administration can be achieved by two routes: subcutaneous injection or subcutaneous minimally invasive implantation.
(1) Subcutaneous injection
Before the long-acting sustained-release drug delivery system is injected, the porous microspheres loaded with the drug and the sodium alginate aqueous solution are mixed and loaded into an injector. At the same time, an aqueous calcium chloride solution was loaded into another syringe. After the sodium alginate mixed aqueous solution containing the porous microspheres (loaded with the therapeutic drugs) is injected to the subcutaneous part of the patient, the calcium chloride-loaded aqueous solution is injected into the subcutaneous mixed aqueous solution of the patient to carry out in-situ gelation, and the calcium alginate hydrogel containing the drug-loaded porous microspheres under the skin is obtained.
(2) Subcutaneous minimally invasive implantation
Before the long-acting sustained-release drug delivery system is implanted, the porous microspheres loaded with the drug are mixed with the sodium alginate aqueous solution. The obtained mixed solution is transferred into an aqueous solution containing calcium chloride to be cured in situ to form hydrogel with a specific shape (according to actual conditions, the hydrogel can be cured into a column shape or a sheet shape and the like). The obtained solid gel is implanted into the subcutaneous part of a patient through skin minimally invasive surgery.
Thirdly, taking out the drug delivery system and slowly releasing the drug again
And after the drug slow release reaches a preset release period, taking out the drug delivery system through skin minimally invasive surgery. If the patient needs to be administered again with sustained release, a new sustained release drug delivery system can be further injected or implanted at the removal site.
Compared with the prior art, the invention has the following beneficial effects:
(1) the invention takes the porous microspheres as carriers of the therapeutic drugs, the porous microspheres have porous structures and rich pores, the drug loading capacity of the therapeutic drugs can be improved, and the drug loading capacity can be adjusted at will by means of drug concentration, microsphere size, quantity and the like, so that the loading of one or more therapeutic drugs with ultra-high dose can be realized. Meanwhile, the porous microspheres contain phosphorus and/or calcium components, and the biological activity of the drugs, particularly protein/polypeptide drugs, can be maintained by utilizing the characteristic that the porous microspheres have rich calcium and/or phosphorus adsorption-desorption equilibrium sites on the surfaces, so that the slow release of a single therapeutic drug or the combined slow release of multiple therapeutic drugs in a patient body can be realized finally.
(2) When the invention is applied, because the calcium alginate and the loaded therapeutic drug can not generate chemical reaction or have adsorption, the drug can be released into the calcium alginate gel network through the porous microspheres firstly, and then released into the body of a patient from the calcium alginate gel, on one hand, the normal slow release of the drug can not be influenced, and on the other hand, because the drug delivery system of the invention is in a gel shape, the porous microspheres for loading the drug are fixed in the gel, the phenomenon of burst release of the drug can not occur in the whole drug release process.
(3) The invention uses sodium alginate and calcium chloride to complex as in-situ gel material, does not contain organic solvent, is not degraded, does not release heat in the gel curing process, can realize subcutaneous injection or implantation administration, and has equivalent concentration of calcium ions which can be complexed with the sodium alginate in human body, therefore, the material of the invention has no toxic or side effect after being injected or implanted into the subcutaneous (in vivo) of a patient. In addition, after the drug release is finished, the sustained-release drug delivery system can be taken out from the subcutaneous part through a minimally invasive surgery, and then a new sustained-release drug delivery system is injected/implanted again, so the operation is very simple, convenient and quick.
(4) The invention has reasonable design and good use effect, and compared with the existing long-acting sustained-release drug delivery system (such as Eligard, Atrigel, Atriorrb, biological phospholipid and the like), the cost is relatively economic, and the economic burden is reduced for patients, therefore, the invention is suitable for large-scale popularization and application in the aspect of subcutaneous drug delivery for disease treatment.
Drawings
FIG. 1 is a schematic view of the structure of porous microspheres used in example 1 of the present invention.
FIGS. 2 to 8 are respectively the in vitro cumulative release curve and the linear trend line graph of the subcutaneous long-acting sustained release drug delivery system composition of examples 8 to 14 of the present invention.
Detailed Description
The present invention will be further described with reference to the following description and examples, which include but are not limited to the following examples.
Examples 1-7 porous microsphere drug Loading
1g of the porous microspheres listed in Table 1 is soaked in 10mL of aqueous solution containing 5mg of recombinant human interferon α 1b, stirring and vacuumizing are carried out, so that the recombinant human interferon α 1b fully enters the pores of the microspheres, after the recombinant human interferon α 1b is fully loaded into the porous microspheres (for 2 hours), the porous microspheres loaded with drugs are separated from the drug-containing solution and dried or freeze-dried to remove water, and the porous microspheres loaded with recombinant human interferon α 1b are obtained.
TABLE 1
Examples 8 to 14 in vitro simulated drug sustained Release of the invention
The porous microspheres loaded with recombinant human interferon α 1b prepared in examples 1-7 were uniformly mixed with 2g of the aqueous solution of sodium alginate listed in Table 2, and then 2g of the aqueous solution of calcium chloride listed in Table 2 was added dropwise to the mixed solution to cure the mixture in situ into a cylindrical hydrogel.
The obtained hydrogel is subjected to in vitro drug release test, and the specific test method is as follows:
10g of the hydrogel are weighed into 200mL Erlenmeyer flasks (3 samples in parallel), 100mL of PBS buffer (containing 0.05% Tween 80, 0.05% sodium azide) at pH 7.4 is added, the mixture is placed in a thermostatic waterbath shaker at 37. + -. 0.5 ℃ and 100rpm, 100mL of the release solution is taken at predetermined time points (1 day, 2 days, and then samples are taken every 2 days), and the release test is continued in the thermostatic waterbath shaker after an equal amount of fresh medium has been added. Taking out liquid, detecting the drug release amount by adopting a high performance liquid chromatography, then making an accumulated release curve (containing a linear trend line), and calculating the daily release rate (sampling every 2 days, taking an average value), wherein the result is shown in fig. 2-8.
TABLE 2
As can be seen from the figures 2-8, the sustained-release preparation has no phenomenon of drug burst release and no obvious delayed release period for the release of the drug, can release in a trend close to zero order within 60 days, has small difference of drug release rate, shows excellent sustained-release effect, has no phenomenon of aggravation of early-stage release and slow later-stage release, avoids inconvenience caused by the fact that a patient still needs to take an oral ordinary preparation after injection for taking the drug, and obviously increases drug administration compliance and convenience.
EXAMPLE 15 animal subcutaneous injection administration test
New Zealand big-ear white rabbits with the weight of 2-3kg are taken, each group is divided into 6 rabbits (randomly grouped), the male rabbit and the female rabbit are half, each group is injected with the sodium alginate aqueous solution loaded with the recombinant human interferon α 1b porous microspheres with the proportion of examples 11-14 subcutaneously, and then is injected with the calcium chloride aqueous solution corresponding to examples 11-14, so that the sodium alginate aqueous solution is solidified into hydrogel in situ subcutaneously.
Then, 5mL of blood was taken from the rabbit ear vein at different time points, respectively. All collected blood samples were centrifuged at 8000rpm for 10min, the supernatants were removed and frozen at-70 ℃ and the plasma concentrations in all blood samples were determined by methods known in the art and averaged. The results are shown in Table 3.
| Time/day | Example 11 | Example 12 | Example 13 | Example 14 |
| 1 | 8.2 | 9.4 | 6.3 | 9.7 |
| 2 | 9.3 | 10.2 | 8.9 | 8.4 |
| 7 | 11.3 | 11.9 | 13.5 | 13.4 |
| 14 | 10.7 | 10.4 | 11.3 | 15.6 |
| 21 | 11.6 | 11.3 | 12.5 | 14.5 |
| 28 | 10.2 | 12.4 | 11.7 | 11.2 |
| 35 | 10.8 | 11.3 | 8.9 | 14.7 |
| 42 | 11.2 | 8.5 | 11.4 | 15.6 |
| 49 | 9.5 | 5.4 | 7.3 | 9.5 |
| 56 | 6.3 | 0 | 0 | 5.5 |
| 63 | 0 | - | - | 0 |
TABLE 3 concentration of drug after subcutaneous injection (ng/ml) in animals
As can be seen from table 3, the blood drug levels in the animals were generally stable.
EXAMPLE 16 animal subcutaneous implant dosing test
New Zealand big-ear white rabbits (2-3 kg in weight) are taken, 6 rabbits are taken in each group (randomly grouped), the male and female parts are in half, and each group is subcutaneously and minimally embedded with the cylindrical calcium alginate hydrogel prepared in the example 11-14. Then 5mL of blood was taken from the vein of the rabbit ear at different time points. All collected blood samples were centrifuged at 8000rpm for 10min, the supernatants were removed and frozen at-70 ℃ and the plasma concentrations in all blood samples were determined by methods known in the art and averaged. The results are shown in Table 4.
TABLE 4 concentration of drug after subcutaneous minimally invasive embedding administration (ng/ml) for animals
As can be seen from Table 4, the concentration of the subcutaneously entrapped long acting composition in animals was not significantly different from the concentration of the subcutaneously injected long acting composition, confirming that both modes of administration were feasible.
In conclusion, the invention fully utilizes the characteristics of the porous microspheres containing phosphorus and/or calcium components through reasonable design, and effectively combines the use of sodium alginate and calcium chloride, thereby well playing the role of long-acting and sustained-release administration when being used as a sustained-release administration system for treating diseases. The invention not only can realize the loading and slow release of the super-large dose of the medicine, but also can not generate the phenomenon of sudden release of the medicine, has relatively low use cost and has no toxic or side effect on patients when in use. Therefore, compared with the existing long-acting sustained-release drug delivery system, the invention has obvious technical progress, and has outstanding substantive characteristics and remarkable progress.
The above-mentioned embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, but all the insubstantial modifications or changes made within the spirit and scope of the main design of the present invention, which still solve the technical problems consistent with the present invention, should be included in the scope of the present invention.
Claims (10)
1. The long-acting sustained-release drug delivery system suitable for subcutaneous drug delivery is characterized in that the sustained-release drug delivery system is in a gel state and comprises porous microspheres for loading therapeutic drugs, and sodium alginate and calcium chloride which are mixed with the porous microspheres loaded with the therapeutic drugs and used as in-situ gel materials; the weight ratio of the porous microspheres to the sodium alginate to the calcium chloride is (1-90) to (10-100), and the porous microspheres contain phosphorus and/or calcium components, so that the therapeutic drug can be slowly released under the skin of a human body.
2. The long-acting sustained-release drug delivery system suitable for subcutaneous administration according to claim 1, wherein the porous microspheres comprise any one or more of calcium hydrogen phosphate, tricalcium phosphate and hydroxyapatite as a chemical component when containing a phosphorus component.
3. The long-acting sustained-release drug delivery system suitable for subcutaneous drug delivery according to claim 1, wherein the porous microspheres comprise a calcium component, and the chemical component is any one or more of calcium hydrogen phosphate, tricalcium phosphate, hydroxyapatite and calcium carbonate.
4. The long-acting sustained-release drug delivery system suitable for subcutaneous administration according to any one of claims 1 to 3, wherein the porous microspheres have an average diameter of 0.1 to 3000 μm.
5. The long acting sustained release delivery system suitable for subcutaneous administration according to claim 4, wherein the porous microspheres have a pore mean diameter of 0.01 to 500 microns.
6. The long-acting sustained-release drug delivery system suitable for subcutaneous administration according to claim 5, wherein the porous microspheres have a porosity of 5 to 90%.
7. The long-acting sustained-release delivery system suitable for subcutaneous delivery according to claim 1, 2, 3, 4, 5 or 6, wherein the weight ratio of sodium alginate to water in the aqueous solution of sodium alginate is 0.1-5%.
8. The long-acting sustained-release drug delivery system suitable for subcutaneous administration according to claim 7, wherein the concentration of calcium chloride in the aqueous solution of calcium chloride is 10 to 500 mmol/ml.
9. A method of preparing a long acting sustained release drug delivery system according to claims 1 to 8, comprising the steps of:
(1) soaking the porous microspheres in a liquid containing a therapeutic drug and slightly stirring to ensure that the drug fully enters the pores of the porous microspheres;
(2) after the medicine is fully loaded in the porous microspheres, separating the medicine-loaded porous microspheres from the liquid containing the medicine, drying, and then removing the liquid to obtain the medicine-loaded porous microspheres;
(3) mixing the drug-loaded porous microspheres with a sodium alginate aqueous solution, then mixing with a calcium chloride aqueous solution under the skin of a patient, and carrying out in-situ gelation to form a sustained-release drug delivery system.
10. A method of preparing a long acting sustained release drug delivery system according to claims 1 to 8, comprising the steps of:
(1) soaking the porous microspheres in a liquid containing a therapeutic drug and slightly stirring to ensure that the drug fully enters the pores of the porous microspheres;
(2) after the medicine is fully loaded in the porous microspheres, separating the medicine-loaded porous microspheres from the liquid containing the medicine, drying, and then removing the liquid to obtain the medicine-loaded porous microspheres;
(3) mixing the drug-loaded porous microspheres with a sodium alginate aqueous solution, and then curing in situ in a calcium chloride aqueous solution to form hydrogel in any shape, wherein the hydrogel is a sustained-release drug delivery system.
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| CN114652862A (en) * | 2020-12-23 | 2022-06-24 | 成都纽瑞特医疗科技股份有限公司 | Radioactive resin microsphere injection, preparation method and application |
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