CN115025036A - Application of caffeine overlong sustained-release preparation in preparation of medicine for treating retinopathy of prematurity and preparation method - Google Patents
Application of caffeine overlong sustained-release preparation in preparation of medicine for treating retinopathy of prematurity and preparation method Download PDFInfo
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- CN115025036A CN115025036A CN202210627680.4A CN202210627680A CN115025036A CN 115025036 A CN115025036 A CN 115025036A CN 202210627680 A CN202210627680 A CN 202210627680A CN 115025036 A CN115025036 A CN 115025036A
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- 229960001948 caffeine Drugs 0.000 title claims abstract description 59
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- 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
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Abstract
An application of the super-long slow-release caffeine preparation in preparing the medicine for treating retinopathy of prematurity and its preparing process, wherein the oily medium with good biocompatibility and solidifying agent are used to prepare the injectable preparation, which is used as the caffeine delivering carrier, and the slow dissolving of hydrophilic medicine in oily medium and the slow exchange of oil-water interface are used to realize the super-long slow-release of caffeine. The ultra-long sustained-release preparation provided by the invention can be used for intravitreal injection administration, so that the caffeine administration frequency can be obviously reduced, and the preparation can be better used for treating retinopathy of prematurity.
Description
Technical Field
The invention relates to the technical field of pharmacy, in particular to application of a caffeine overlong sustained-release preparation in preparing a medicine for treating retinopathy of prematurity and a preparation method thereof.
Background
Retinopathy of prematurity (ROP) is an eye disease causing blindness in children, caused by retinal vascular dysplasia in premature infants. Statistically, about 5-10 million new ROP patients are added in every year around the world, and the ROP patient proportion is in an increasing trend along with medical progress and the survival rate of premature infants. It is expected that under the background of encouraging multiparous childbirth in China, the increase of ROP patients will be more obvious, which can seriously affect the family happiness of the newborn and cause heavy economic and social burdens.
Laser photocoagulation is the traditional method of clinical treatment for ROP, but has very limited efficacy and is more at risk of causing a reduction in the patient's visual field. VEGF antibodies (ranibizumab, combaici-cept, aflibercept and the like) are successfully used for eyeground neovascular diseases such as age-related macular degeneration (AMD), Diabetic Retinopathy (DR) and the like in ophthalmology, and researches show that the VEGF antibodies injected in a vitreous cavity have a certain treatment effect on ROP. It is noted, however, that the challenges of using VEGF antibodies for ROP far exceed those of adult diseases such as AMD, DR: the physiological blood vessels of the adult are well developed, and the VEGF antibody only interferes with the nascent pathological blood vessels; the eyes of premature infants are not mature, and the VEGF antibody interferes with pathological neovascularization and can prevent normal development of physiological blood vessels. Thus, treatment of ROP with existing VEGF antibodies often results in permanent retinal vascular density reduction in the newborn, which in turn causes permanent visual impairment to the patient. Caffeine is used clinically to treat apnea in premature infants and studies have shown that ROP is also alleviated in patients with apnea using caffeine.
Intravitreal injection is the most direct and effective route of administration for the treatment of retinal diseases, and can reduce systemic exposure and make the drug accumulate at the focal site as much as possible. This mode of administration is somewhat traumatic and therefore clinical use must minimize the frequency of administration, i.e. preferably a sustained release formulation. Caffeine belongs to hydrophilic drugs, the solubility of caffeine reaches 21.6mg/mL, and the problem caused by excessive hydrophilicity is that caffeine enters a human body and is rapidly dissolved and metabolized by body fluid, so frequent administration is required. Traditional drug sustained release systems are often only effective for hydrophobic drugs, and the sustained release of hydrophilic drugs is a worldwide problem. For coffee, a sustained release period of 2-16 hours has been reported for the most part. It is currently known that the use of MOF materials by spanish scientists to deliver caffeine (ACS appl. mater. interfaces 2012,4,9, 5016-. In order to meet the clinical requirement of slow release of caffeine (the slow release period reaches about 30 days), an ultra-long slow release preparation is urgently needed to better treat retinopathy of prematurity by injecting caffeine in a vitreous cavity.
Disclosure of Invention
In order to solve the defects and shortcomings of the prior art, the invention provides an application of a caffeine ultra-long sustained-release preparation in preparation of a medicine for treating retinopathy of prematurity and a preparation method thereof.
The technical solution adopted by the invention is as follows: the application of the overlength sustained-release preparation of the caffeine in preparing the medicine for treating retinopathy of prematurity is characterized in that the overlength sustained-release preparation of the caffeine is obtained by encapsulating the caffeine in an injectable preparation, and the injectable preparation consists of an oily medium and a curing agent, wherein the solubility of the caffeine in the oily medium is low.
The oily medium comprises one or more of high oleic acid sunflower oil, olive oil, soybean oil, rapeseed oil, palm oil, linseed oil, safflower seed oil and sesame oil.
The curing agent comprises one or more of fructus Momordicae oil, gamma-oryzanol, monoglyceride, beta-sitosterol, stearic acid, stearyl alcohol, beeswax, sunflower wax, and ethyl cellulose.
The medicine for treating retinopathy of prematurity is a medicine for intravitreal injection.
The curing agent concentration is less than 50% (wt%).
The amount of caffeine in the caffeine ultra-long sustained-release preparation is greater than the solubility of the oil medium to caffeine.
The final concentration of the caffeine in the caffeine ultralong sustained-release preparation is higher than the dissolving capacity of a mixed system.
The effective treatment concentration of the caffeine released in vivo by the caffeine ultralong sustained-release preparation is 0.4-9.7 mug/mL.
A preparation method of a caffeine ultra-long sustained release preparation comprises the following steps: heating the oily medium, adding the curing agent and the caffeine, uniformly mixing and cooling to obtain the caffeine ultra-long sustained-release preparation.
The invention has the beneficial effects that: the invention provides an application of a caffeine overlength sustained release preparation in preparing a medicine for treating retinopathy of prematurity and a preparation method thereof. The ultra-long sustained-release preparation provided by the invention can be used for intravitreal injection administration, so that the caffeine administration frequency can be obviously reduced, and the preparation can be better used for treating retinopathy of prematurity.
Drawings
Fig. 1 is a graph for evaluating the in vivo safety of the injectable preparation of the present invention.
Fig. 2 shows the in vitro release behavior of the caffeine ultra-long sustained release preparation, in which a is a real-time release profile and b is a cumulative release profile.
Fig. 3 is a schematic diagram of a rabbit eye intravitreal injection of a caffeine ultralong sustained release preparation.
Fig. 4 is a fundus photographic image of the ultralong sustained-release formulation of caffeine injected in the vitreous chamber.
Detailed Description
The present invention is further described below in conjunction with the following embodiments and the accompanying drawings, it being understood that the drawings and the following embodiments are illustrative of the invention only and are not limiting thereof.
EXAMPLE 1 preparation of injectable formulations
Taking a certain volume of soybean oil, and adding 10% of beewax; transferring the mixture to 80 ℃ water bath or oil bath, and uniformly stirring by using a magnetic stirrer; sucking the uniformly mixed mixture solution by using an injector; cooling to obtain injectable preparation.
Example 2 in vivo safety evaluation of injectable formulations
Taking the injectable preparation obtained in example 1; performing intravitreal injection (the volume is 25-50 μ l) for rabbit eyes; animals were sacrificed 5 months after implantation of the injectable formulation in rabbit eyes; separating the injection eye; fixing; dehydrating; embedding paraffin; making paraffin sections; row H & E staining. As can be seen from FIG. 1, when the injectable preparation is implanted into rabbit eyes for 5 months, the structures of the central retina and the peripheral retina are kept normal without inflammatory cell infiltration, which indicates that the injectable preparation has good biocompatibility.
EXAMPLE 3 preparation of an ultralong sustained-Release formulation of caffeine
Taking a certain volume of soybean oil, and adding 10% (w/v%) beeswax; transferring the mixture to 80 ℃ water bath or oil bath, and uniformly stirring by using a magnetic stirrer; adding caffeine to make the final concentration higher than the dissolving capacity of the mixed system to form a uniform suspension (5-10%, w/v%); sucking the uniformly mixed mixture solution by using an injector; cooling to obtain the final product.
EXAMPLE 4 in vitro Release study of an ultralong sustained Release formulation of caffeine
A caffeine ultra-long sustained-release preparation was prepared according to the method described in example 3; 50 mu L of the caffeine overlength sustained-release preparation is taken and placed in 5mL of PBS; carrying out shaking table incubation at 37 ℃ and 100rpm for in vitro release; all release media (5mL PBS) were collected every 24h and 5mL fresh PBS was added until the end of the experiment; detecting the light absorption value of the sample at 229nm of each sampling point, and quantifying by a standard curve; and drawing a real-time release curve and an accumulated release curve. The effective treatment concentration of the caffeine is 0.4-9.7 mug/mL, and as can be seen from figure 2a, the caffeine ultra-long sustained release preparation can release the caffeine above the effective treatment concentration for 30 days; as can be seen in FIG. 2b, the extended sustained release formulation of caffeine extended the time required to release 78% of the caffeine to 35 days, which was 4 times longer than the maximum time (8 days) reported in the prior art.
EXAMPLE 5 Rabbit eye intravitreal injection of a lengthy sustained-release formulation of caffeine
Injecting sodium pentobarbital (2%) and mepiquat chloride intramuscularly to perform general anesthesia on animals; the anesthetized animals are transferred to an operating microscope operating table; dripping compound tropicamide eye drops into the injection-planned eye to mydriasis, and carrying out local anesthesia by using proparacaine hydrochloride eye drops; the caffeine ultra-long sustained-release preparation obtained in example 3 is injected into a vitreous chamber (injection volume: 25-50 μ L), and the needle head is prevented from moving during the injection process; after the injection of the eye, levofloxacin eye ointment is used for nursing to prevent infection. As can be seen from FIG. 3, the prolonged sustained-release preparation of caffeine obtained in example 3 can be successfully injected into the vitreous chamber; fundus camera observation (fig. 4) shows that the caffeine ultra-long sustained-release preparation after intravitreal injection floats above the vitreous cavity and thus does not affect the line of sight.
The skilled person should understand that: although the invention has been described in terms of the above specific embodiments, the inventive concept is not limited thereto and any modification applying the inventive concept is intended to be included within the scope of the patent claims.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and adaptations to those skilled in the art without departing from the principles of the present invention should also be considered as within the scope of the present invention.
Claims (9)
1. The application of the caffeine overlength sustained-release preparation in preparing the medicine for treating retinopathy of prematurity is characterized in that the caffeine overlength sustained-release preparation is obtained by encapsulating caffeine in an injectable preparation, and the injectable preparation is composed of an oily medium and a curing agent, wherein the solubility of the caffeine in the oily medium is low.
2. The use according to claim 1, wherein the oily medium comprises one or more of high oleic sunflower oil, olive oil, soybean oil, rapeseed oil, palm oil, linseed oil, safflower seed oil, sesame oil.
3. The use of claim 1, wherein the curing agent comprises one or more of fructus Momordicae oil, gamma-oryzanol, monoglyceride, beta-sitosterol, stearic acid, stearyl alcohol, beeswax, sunflower wax, and ethyl cellulose.
4. The use of claim 1, wherein the medicament for the treatment of retinopathy of prematurity is a medicament administered by intravitreal injection.
5. Use according to claim 1, wherein the curing agent concentration is less than 50% by weight.
6. The use according to claim 1, wherein the amount of caffeine in the extended release formulation is an amount greater than the solubility of the oily medium for caffeine.
7. The use according to claim 6, wherein the final concentration of caffeine in the extended release formulation is higher than the dissolution capacity of the combined system.
8. The use according to claim 7, wherein the therapeutically effective concentration of caffeine in the sustained release formulation is 0.4 to 9.7 μ g/mL in vivo.
9. A method for preparing an ultra-long sustained-release preparation of caffeine according to claim 1, which comprises the steps of: heating the oily medium, adding curing agent and caffeine, mixing, and cooling to obtain the final product.
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