Astaxanthin composition, oral delivery system and application thereof

Abstract

The invention discloses an astaxanthin composition, an oral delivery system and application thereof, and relates to the technical field of drug delivery. The astaxanthin composition comprises the following raw materials: fatty acid, a foaming agent, weak organic acid and astaxanthin, fatty acid is selected from at least one of capric acid, caprylic acid and linoleic acid; the foaming agent is selected from at least one of sodium bicarbonate, potassium carbonate and potassium bitartrate; the weak organic acid is selected from at least one of citric acid, malic acid and tartaric acid. Through verification, the astaxanthin composition provided by the invention is coated by an enteric-coated material, and can relieve the thickening of vascular walls and improve angiosclerosis after being orally taken. Good application prospects are realized on prevention or treatment of vascular calcification and complications thereof.

Description

Technical Field

[0001] This invention relates to the field of drug delivery technology, and more specifically, to an astaxanthin composition, an oral delivery system, and its applications. Background Technology

[0002] Astaxanthin (AST) is a fat-soluble, red-orange carotenoid found in lobsters and used in aquaculture. It is widely distributed in microalgae, phytoplankton, yeast, and accumulates in zooplankton, crustaceans, and fish. Astaxanthin has attracted much attention due to its unique antioxidant activity, which even surpasses that of vitamin C, β-carotene, and α-tocopherol. However, astaxanthin is a lipophilic drug with poor oral bioavailability.

[0003] While some existing technologies report on astaxanthin delivery systems, most focus on freeze-drying delivery systems, which require stringent conditions such as liquid nitrogen flash freezing and low-temperature production.

[0004] In view of this, the present invention is proposed. Summary of the Invention

[0005] The purpose of this invention is to provide an astaxanthin composition, an oral delivery system, and its application to solve the above-mentioned technical problems.

[0006] This invention is implemented as follows: In a first aspect, the present invention provides an astaxanthin composition comprising the following raw materials: fatty acid, foaming agent, weak organic acid and astaxanthin; the fatty acid is selected from at least one of capric acid, caprylic acid and linoleic acid; the foaming agent is selected from at least one of sodium bicarbonate, potassium carbonate and potassium bitartrate; the weak organic acid is selected from at least one of citric acid, malic acid and tartaric acid. The mass ratio of fatty acids, foaming agents, weak organic acids and astaxanthin is 9:5:6:1-3.

[0007] In a second aspect, the present invention provides an oral delivery system comprising a capsule prepared from an enteric material, the capsule comprising oleic acid and the aforementioned astaxanthin composition.

[0008] Thirdly, the present invention provides the use of astaxanthin compositions or the above-described oral delivery systems in the preparation of medicaments for the prevention or treatment of vascular calcification and its complications.

[0009] Fourthly, the present invention provides a medicament comprising the astaxanthin composition described above or the oral delivery system described above.

[0010] The present invention has the following beneficial effects: This invention provides an astaxanthin composition that enables the transport and effective absorption of a lipophilic drug (astaxanthin) into the small intestine via an in-situ bubbling reaction; the drug ultimately accumulates in the bloodstream. Specifically, the composition comprises a fatty acid compound, an acid initiator (i.e., a weak organic acid), a bubbling agent, and astaxanthin. The fatty acid enhances the solubility of the lipophilic astaxanthin, thereby improving its oral bioavailability; furthermore, the fatty acid provided by this invention can be metabolized by most living cells in the human body and has the function of dispersing or encapsulating astaxanthin.

[0011] Weak organic acids react rapidly with foaming agents upon contact with water to generate carbon dioxide (CO2) bubbles. These bubbles increase the dispersion of astaxanthin in the small intestine. Once these bubbles burst at the water / air interface, astaxanthin is emulsified and sprayed onto the intestinal epithelial surface. The presence of surfactants such as bile salts in the intestinal fluid and epithelium helps stabilize the astaxanthin molecules, promoting its absorption in the intestine. The drug preferentially flows into the intestinal lymphatic capillaries, avoiding the first-pass effect of hepatic absorption and increasing its bioavailability.

[0012] Verification has shown that the astaxanthin composition provided by this invention, after being coated with an enteric-coated material, can reduce blood vessel wall thickening and improve arteriosclerosis when taken orally. It shows promising application prospects for the prevention or treatment of vascular calcification and its complications. Attached Figure Description

[0013] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the embodiments will be briefly introduced below. It should be understood that the following drawings only show some embodiments of the present invention and should not be regarded as a limitation on the scope. For those skilled in the art, other related drawings can be obtained based on these drawings without creative effort.

[0014] Figure 1 Flowchart for animal experiments; Figure 2 Image showing the results of an ultrasound experiment on the blood vessel wall of an orally administered enteric-coated astaxanthin capsule containing a foaming agent; Figure 3 Image showing the results of an ultrasound experiment on the blood vessel wall of an orally administered enteric-coated astaxanthin capsule containing a foaming agent; Figure 4 H&E staining, Alizarin red staining, and Vonkassa staining were used to study the effects of a new astaxanthin formulation on vascular calcification in CKD. Figure 5 The images show the pH results of systems containing citric acid and sodium bicarbonate in different ratios, as well as actual images of bubbles generated in test tubes. Detailed Implementation

[0015] Reference will now be made to detailed embodiments of the present invention, one or more of which are described below. Each example is provided for explanation and not for limitation of the invention. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the invention without departing from its scope or spirit. For example, features described or illustrated as part of one embodiment may be used in another embodiment to produce further embodiments.

[0016] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0017] Definition of noun As used in this article, the term "prevention" means reducing the risk of disease in an individual or group, or mitigating the severity or slowing the progression of disease, through a series of proactive interventions. Disease prevention is a proactive health management concept that aims to avoid or mitigate the harm of disease through "intervention," and its value far exceeds that of treatment after the onset of disease.

[0018] As used herein, the term "treatment" refers to a series of medical actions that involve intervention through medical means, techniques, or methods to address an existing disease, with the aim of eliminating the cause, alleviating symptoms, controlling disease progression, promoting tissue repair, restoring function, or reducing pain. Specifically, in this application, "treatment" refers to administering the drug of this application after vascular calcification, which can improve vascular sclerosis caused by calcification and reduce the thickening of the vascular wall.

[0019] In a first aspect, the present invention provides an astaxanthin composition comprising the following raw materials: fatty acid, foaming agent, weak organic acid and astaxanthin; the fatty acid is selected from at least one of capric acid, caprylic acid and linoleic acid; the foaming agent is selected from at least one of sodium bicarbonate, potassium carbonate and potassium bitartrate; the weak organic acid is selected from at least one of citric acid, malic acid and tartaric acid. The mass ratio of fatty acids, foaming agents, weak organic acids and astaxanthin is 9:5:6:1-3.

[0020] The composition provided by this invention enables the transport and effective absorption of a lipophilic drug (astaxanthin) into the small intestine, a process achieved through an in-situ foaming reaction; the drug ultimately accumulates in the blood vessels. Specifically, the composition contains a fatty acid compound, an acid initiator (i.e., a weak organic acid), a foaming agent, and astaxanthin. The fatty acid enhances the solubility of the lipophilic astaxanthin, thereby improving its oral bioavailability; furthermore, the fatty acid provided by this invention can be metabolized by most living cells in the human body and has the function of dispersing or encapsulating astaxanthin.

[0021] Weak organic acids react rapidly with foaming agents upon contact with water to generate carbon dioxide (CO2) bubbles. These bubbles increase the dispersion of astaxanthin in the small intestine. Once these bubbles burst at the water / air interface, astaxanthin is emulsified and sprayed onto the intestinal epithelial surface. The presence of surfactants such as bile salts in the intestinal fluid and epithelium helps stabilize the astaxanthin molecules, promoting its absorption in the intestine. The drug preferentially flows into the intestinal lymphatic capillaries, avoiding the first-pass effect of hepatic absorption and increasing its bioavailability.

[0022] Verification has shown that the astaxanthin composition provided by this invention, after being coated with an enteric-coated material, can reduce blood vessel wall thickening and improve arteriosclerosis when taken orally. This invention provides an effective solution for the prevention or treatment of vascular calcification and its complications.

[0023] Adding a weak organic acid allows for a gentle reaction with the foaming agent, resulting in more uniform gas release and providing some buffering and stabilizing functions.

[0024] The mass ratio of fatty acids, foaming agents, weak organic acids and astaxanthin is, for example, 9:5:6:1, 9:5:6:2 or 9:5:6:3.

[0025] In a preferred embodiment of the present invention, the astaxanthin composition comprises raw materials in the following mass ratio: decanoic acid, sodium bicarbonate, citric acid, and astaxanthin in a mass ratio of 9:5:6:3. With decanoic acid, sodium bicarbonate, and citric acid in a 9:5:6 mass ratio, the astaxanthin composition exhibits a system pH above 5 at 37°C, and the weak organic acid reacts rapidly with the foaming agent upon contact with water, releasing a large amount of bubbles.

[0026] When the amount of astaxanthin added was 1 mg, 2 mg, and 3 mg, the encapsulation efficiency was at a high level. However, when the amount of astaxanthin added was greater than or equal to 4 mg, the encapsulation efficiency decreased significantly. Considering both the encapsulation efficiency and the total amount of drug, the optimal astaxanthin composition ratio was determined to be 6:5:9:3.

[0027] In a second aspect, the present invention provides an oral delivery system comprising a capsule prepared from an enteric material, the capsule comprising oleic acid and the aforementioned astaxanthin composition.

[0028] In a preferred embodiment of the present invention, the mixing ratio of the oleic acid and astaxanthin composition is adjusted as needed. Oleic acid serves a coating function.

[0029] Thirdly, the present invention provides the use of astaxanthin compositions or the above-described oral delivery systems in the preparation of medicaments for the prevention or treatment of vascular calcification and its complications.

[0030] After administration of the astaxanthin composition provided by the present invention or the oral delivery system described above, in animal models of vascular calcification, the thickening of the vascular wall was reduced, vascular sclerosis was improved, and calcification foci were reduced after drug intervention. Therefore, the astaxanthin composition provided by the present invention or the oral delivery system described above has good prospects for clinical application.

[0031] In a preferred embodiment of the present invention, vascular calcification is selected from intimal calcification or medial calcification of blood vessels.

[0032] In a preferred embodiment of the present invention, vascular calcification is vascular calcification induced by a high-phosphorus diet.

[0033] In a preferred embodiment of the present invention, vascular calcification is selected from aortic vascular calcification and / or coronary vascular calcification.

[0034] In a preferred embodiment of the present invention, the complications of vascular calcification are selected from cardiovascular complications, cerebrovascular complications, peripheral vascular complications, or kidney-related complications. In a preferred embodiment of the present invention, cardiovascular complications are selected from coronary heart disease and myocardial infarction, valvular heart disease, refractory hypertension, or heart failure. Cerebrovascular complications are selected from stroke; Peripheral vascular complications are selected from peripheral artery disease; kidney-related complications are selected from chronic kidney disease.

[0035] Fourthly, the present invention provides a medicament comprising the astaxanthin composition described above or the oral delivery system described above; In a preferred embodiment of the present invention, the drug also includes pharmaceutically acceptable excipients.

[0036] In a preferred embodiment of the present invention, the excipients include, but are not limited to, conventional pharmaceutical excipients, carriers, or diluents.

[0037] Drugs also include pharmaceutically acceptable carriers, such as water, saline, sugars, polysaccharides, buffers, excipients, biodegradable polymers, liposomes, stabilizers, and other substances.

[0038] Pharmaceutically acceptable excipients include, but are not limited to, fillers, lubricants, disintegrants, binders, and flow aids.

[0039] In a preferred embodiment of the present invention, the pharmaceutically acceptable excipients include, but are not limited to, one or more of the following: polyvinylpyrrolidone and its derivatives, polyvinyl alcohol and its derivatives, methylcellulose and its derivatives, ethylcellulose and its derivatives, hydroxypropylcellulose and its derivatives, hydroxypropyl methylcellulose, starch and its derivatives, polyethylene glycol and its derivatives, lactose, lactose-starch complex, lactose-cellulose complex, sucrose, mannitol, mannitol-starch complex, trehalose, sorbitol, dextrin, microcrystalline cellulose, acrylic resin, povidone, copovidone, calcium hydrogen phosphate, calcium stearate, sodium stearoyl fumarate, silicon dioxide, titanium dioxide, talc, indigo, low-substituted hydroxypropyl cellulose, croscarmellose sodium cellulose, croscarmellose, magnesium stearate, sodium stearate fumarate, talc, and stearic acid, or a combination thereof.

[0040] In a preferred embodiment of the present invention, the dosage form of the drug is tablet, pill, powder, suspension, gel, emulsion, granule, capsule, injection, or injection.

[0041] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0042] Example 1 This embodiment provides an astaxanthin composition and an oral delivery system, wherein the astaxanthin composition comprises: 9 mg decanoic acid (analytical grade), 5 mg sodium bicarbonate (analytical grade), 6 mg citric acid (analytical grade), and 3 mg astaxanthin powder.

[0043] The oral delivery system comprises the astaxanthin composition described above. The raw materials of the astaxanthin composition are mixed at room temperature, coated with oleic acid, and then loaded into enteric-coated capsules.

[0044] After oral administration of enteric-coated capsules, as they dissolve in the small intestine, the citric acid and sodium bicarbonate immediately generate carbon dioxide gas bubbles upon contact with the aqueous fluid in the intestine. These bubbles increase the dispersion of astaxanthin in the small intestine. Once these bubbles burst at the water / air interface, astaxanthin is emulsified and sprayed onto the intestinal epithelial surface, promoting its absorption in the intestine and increasing its bioavailability.

[0045] Example 2 This embodiment provides an astaxanthin composition and an oral delivery system, wherein the astaxanthin composition comprises: 9 mg caprylic acid, 5 mg sodium bicarbonate, 6 mg citric acid and 3 mg astaxanthin powder.

[0046] The oral delivery system comprises: the above-mentioned astaxanthin composition, wherein the raw materials of the above-mentioned astaxanthin composition are mixed and then coated with oleic acid and loaded into enteric-coated capsules.

[0047] Example 3 This embodiment provides an astaxanthin composition and an oral delivery system, wherein the astaxanthin composition comprises: 9 mg linoleic acid, 5 mg sodium bicarbonate, 6 mg citric acid and 3 mg astaxanthin powder.

[0048] The oral delivery system comprises: the above-mentioned astaxanthin composition, wherein the raw materials of the above-mentioned astaxanthin composition are mixed and then coated with oleic acid and loaded into enteric-coated capsules.

[0049] Example 4 This embodiment provides an astaxanthin composition and an oral delivery system, wherein the astaxanthin composition comprises: 9 mg linoleic acid, 5 mg potassium hydrogen tartrate, 6 mg malic acid and 3 mg astaxanthin powder.

[0050] The oral delivery system comprises: the above-mentioned astaxanthin composition, wherein the raw materials of the above-mentioned astaxanthin composition are mixed and then coated with oleic acid and loaded into enteric-coated capsules.

[0051] Experimental Example 1 This experiment screened the formulation of an oral delivery system. Capric acid, citric acid, and sodium bicarbonate were selected and combined to test their foaming effect and pH in intestinal fluid.

[0052] To simulate the environment inside the human small intestine, the reaction solution was small intestinal fluid containing 5 mg / mL bile salt extract (3 mL, pH 6.4, preheated to 37°C).

[0053] In the oral delivery system, the dosage of sodium bicarbonate as the foaming agent is fixed at 5 mg, the dosage of decanoic acid is 9 mg, and the dosage of citric acid is added at 0, 2, 4, 6, and 8 mg, respectively, corresponding to acid-base weight ratios of 0:5, 2:5, 4:5, 6:5, and 8:5. Decanoic acid, as the core lipid-soluble carrier component of the delivery system, plays a key role in improving the solubility and intestinal absorption efficiency of lipid-soluble drugs (astaxanthin).

[0054] The specific experimental steps are as follows: Take five test tubes and weigh 9 mg of capric acid into each test tube. Add 3 mL of small intestinal fluid to each test tube and preheat to 37°C to dissolve the capric acid. Take another five test tubes and label them test tubes 1, 2, 3, 4, and 5. Weigh the corresponding amounts of citric acid and sodium bicarbonate into the corresponding test tubes according to the acid-base weight ratio described above. Then, add the small intestinal fluid containing capric acid to test tubes 1, 2, 3, 4, and 5 respectively, and record the generation of CO2 bubbles. After the bubble generation stops, mix the resulting solution and measure its pH value.

[0055] Figure 5 The results showed that the 6:5 and 8:5 ratios of citric acid and sodium bicarbonate produced more CO2 bubbles. This is because the pH in the human small intestine fluctuates between 5 and 7, while the pH is less than 5 with the 8:5 ratio. To simulate the environment of the human small intestine, the pH of the system after the reaction should be maintained above 5. Therefore, a 6:5 mass ratio of citric acid to sodium bicarbonate was chosen as the optimal acid-base ratio. This means the better formulation for the oral delivery system is 9 mg of decanoic acid, 5 mg of sodium bicarbonate, and 6 mg of citric acid.

[0056] Experimental Example 2 This experimental case studies involved animal experiments on vascular calcification in chronic kidney disease to evaluate the effectiveness of treatment.

[0057] To evaluate the treatment efficacy, this experimental case used a chronic kidney disease vascular calcification model induced by 5 / 6 nephrectomy combined with a 1.5% high-phosphorus diet. Astaxanthin (AST) and the astaxanthin material preparation (ASTb) prepared in Example 1 were administered orally (by gavage, every other day). Vascular calcification is a complication of chronic kidney disease with a high mortality rate and a strong tendency to induce cardiovascular disease.

[0058] Astaxanthin was purchased from Beijing Solarbio Pharmaceutical Co., Ltd. (product number: A9241-1g).

[0059] The specific animal experimental methods are as follows: (1) Experimental animals and grouping: Male wild-type Wistar rats aged 8-10 weeks and weighing 250-350g were purchased from Chengdu Dashuo and randomly divided into the following groups: sham operation group (Sham), CKD vascular calcification group (CAL), new astaxanthin preparation (10 mg / kg) + CKD vascular calcification group (CAL+ASTb10mg), new astaxanthin preparation (20 mg / kg) + CKD vascular calcification group (CAL+ASTb20mg), astaxanthin (10 mg / kg) + CKD vascular calcification group (CAL+AST10mg), astaxanthin (20 mg / kg) + CKD vascular calcification group (CAL+AST20mg), new astaxanthin preparation alone (20mg / kg) (ASTb20mg), and astaxanthin preparation alone (20mg / kg) + sham group (Asx20mg).

[0060] (2) Modeling: High-phosphorus feed containing 1.5% phosphate was purchased from Jiangsu Xietong Biotechnology. Olive oil was purchased from Beijing Solarbio Co., Ltd. (item number: 08320). Astaxanthin was dissolved in olive oil to prepare a working solution. All experimental animals underwent modeling surgery one week after feeding. Rats in the CAL group underwent 5 / 6 nephrectomy, specifically as follows: first, 2 / 3 of the left kidney was removed, and one week after the surgery, the contralateral nephrectomy was performed. One week after the 5 / 6 nephrectomy, rats in the CAL group were fed a high-phosphorus diet continuously. Rats in the Sham group continued to be fed a normal diet.

[0061] (3) Administration: After 5 / 6 nephrectomy, the model group was fed a high-phosphorus diet of 1.5% for 12 weeks. At the same time, the administration group was administered the oral delivery capsules prepared in Example 1 to rats by gavage (once every other day) for 12 weeks according to the grouping scheme.

[0062] (4) Data Collection: All rats were collected at the same time, and their blood vessels were subjected to ultrasound and histopathological staining. Ultrasound, alizarin red staining, silver nitrate staining, and H&E staining were used to assess the effects. Statistical Methods: All experimental data were processed using Graphpad Prism 10.0. Data from two groups were analyzed using t-tests, and data from three or more groups were analyzed using one-way ANOVA. * indicates P < 0.01. ** indicates P < 0.05, indicating a statistically significant difference.

[0063] Animal experiment flowchart (refer to) Figure 1 As shown.

[0064] Figure 2 The results showed that vascular calcification (CAL) induced by 5 / 6 nephrectomy combined with a high-phosphorus diet typically involved thickening and sclerosis of the abdominal aorta. After drug intervention, ultrasound revealed a reduction in vascular wall thickening and improvement in sclerosis. Therefore, oral administration of enteric-coated astaxanthin capsules containing effervescent agents effectively improved vascular wall thickening caused by calcification.

[0065] Figure 3 The results showed that vascular calcification induced by 5 / 6 nephrectomy combined with a high-phosphorus diet was typically accompanied by thickening and sclerosis of the abdominal aorta. After drug intervention, ultrasound revealed a reduction in vascular wall thickening and improvement in vascular sclerosis. Therefore, oral administration of enteric-coated astaxanthin capsules containing effervescent agents effectively improved vascular sclerosis caused by calcification.

[0066] Alizarin red and Vonkassa staining are good methods for detecting vascular calcification. H&E staining is used for observing vascular morphology. In the 5 / 6 nephrectomy combined with a high-phosphorus diet-induced vascular calcification group (CAL group), positive Alizarin red and Vonkassa staining were observed, reflecting the formation of calcification foci. After drug intervention, the number of calcification foci decreased. Figure 4 ).

[0067] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. An astaxanthin composition, characterized in that, It comprises the following raw materials: fatty acids, foaming agents, weak organic acids, and astaxanthin; wherein the fatty acids are selected from at least one of capric acid, caprylic acid, and linoleic acid; wherein the foaming agent is selected from at least one of sodium bicarbonate, potassium carbonate, and potassium hydrogen tartrate; and wherein the weak organic acid is selected from at least one of citric acid, malic acid, and tartaric acid. The mass ratio of the fatty acid, foaming agent, weak organic acid and astaxanthin is 9:5:6:1-3.

2. The astaxanthin composition according to claim 1, characterized in that, The astaxanthin composition comprises raw materials in the following mass ratio: decanoic acid, sodium bicarbonate, citric acid and astaxanthin in a mass ratio of 9:5:6:

3.

3. An oral delivery system, characterized in that, It includes capsules made from enteric-coated materials, the capsules containing oleic acid and the astaxanthin composition according to any one of claims 1-2.

4. The use of the astaxanthin composition according to any one of claims 1-2 or the oral delivery system according to claim 3 in the preparation of a medicament for the prevention or treatment of vascular calcification and its complications.

5. The application according to claim 4, characterized in that, The vascular calcification is selected from intimal calcification or medial calcification of blood vessels.

6. The application according to claim 4, characterized in that, The vascular calcification mentioned is vascular calcification induced by a high-phosphorus diet.

7. The application according to claim 4, characterized in that, The selected vascular calcifications are aortic vascular calcifications and / or coronary vascular calcifications.

8. The application according to claim 4, characterized in that, The complications of vascular calcification are selected from cardiovascular complications, cerebrovascular complications, peripheral vascular complications, or kidney-related complications.

9. The application according to claim 8, characterized in that, The cardiovascular complications mentioned are selected from coronary heart disease and myocardial infarction, valvular heart disease, refractory hypertension, or heart failure; The cerebrovascular complications mentioned are selected from stroke; The peripheral vascular complications are selected from peripheral artery disease; the kidney-related complications are chronic kidney disease. Preferably, the complications of vascular calcification are selected from arteriosclerosis and / or thickening of the vessel wall caused by vascular calcification.

10. A drug, characterized in that, It includes the astaxanthin composition according to any one of claims 1-2 or the oral delivery system according to claim 3; Preferably, the drug further includes pharmaceutically acceptable excipients.

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