CN118370728B - GLP-1RA drug-loaded nano-particle and preparation method thereof - Google Patents
GLP-1RA drug-loaded nano-particle and preparation method thereof Download PDFInfo
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Abstract
本发明提供了一种GLP‑1RA载药纳米颗粒和制剂及其制备方法，涉及医药技术领域。本发明先制备GLP‑1RA载药纳米颗粒，然后联合使用无机纳米材料载体介导技术和渗透促进技术，制备得到具有高口服生物利用度的GLP‑1RA制剂。本发明采用胃黏附的无机纳米颗粒作为GLP‑1RA载体，保护口服多肽药物免受胃肠道的降解；采用特定的表面改性剂增加纳米颗粒的载药量和药物回收率；使用特定种类的渗透促进剂改变胃壁屏障的物理和生化性质，增加口服多肽药物的胃壁渗透性，增加药物的溶解度和生物利用度。本发明所制备的GLP‑1RA制剂，可以显著提高主药和渗透促进剂的溶出速率，生物利用度显著提高。The present invention provides a GLP-1RA drug-loaded nanoparticle and preparation and a preparation method thereof, and relates to the field of medical technology. The present invention first prepares GLP-1RA drug-loaded nanoparticles, and then uses inorganic nanomaterial carrier-mediated technology and penetration-enhancing technology in combination to prepare a GLP-1RA preparation with high oral bioavailability. The present invention uses gastric-adherent inorganic nanoparticles as GLP-1RA carriers to protect oral polypeptide drugs from degradation in the gastrointestinal tract; uses specific surface modifiers to increase the drug loading and drug recovery rate of nanoparticles; uses specific types of penetration enhancers to change the physical and biochemical properties of the gastric wall barrier, increase the gastric wall permeability of oral polypeptide drugs, and increase the solubility and bioavailability of the drug. The GLP-1RA preparation prepared by the present invention can significantly improve the dissolution rate of the main drug and the penetration enhancer, and the bioavailability is significantly improved.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to GLP-1RA drug-loaded nano-particles and preparations and a preparation method thereof, and in particular relates to GLP-1RA drug-loaded nano-particles and preparations for enhancing oral bioavailability and a preparation method thereof.
Background
Glucagon-like peptide-1 receptor agonist (GLP-1 RA) is a polypeptide drug simulating glucagon-like peptide-1 (GLP-1) in human body, and GLP-1RA can stimulate insulin secretion, inhibit gastric emptying and increase satiety, thereby reducing blood sugar and weight, is mainly used for treating type 2 diabetes and obesity, and has good hypoglycemic effect and cardiovascular safety; in addition, GLP-1RA not only has the function of reducing blood sugar, but also has the function of protecting organs such as cardiovascular, kidney, nerve and the like.
One major problem with polypeptide drugs is that their oral administration is subject to various limitations, such as: polypeptide drugs are easily degraded by digestive enzymes in the gastric tract and are difficult to absorb through the intestinal wall. Therefore, polypeptide drugs are often administered by injection, which not only causes inconvenience and pain to the patient, but also affects drug compliance. In order to solve the above problems, researchers have been working on developing technology of oral polypeptide preparations, protecting polypeptide drugs from degradation of the gastrointestinal tract, increasing intestinal wall absorption of polypeptide drugs, and thus achieving oral administration.
Wherein, the invention patent with publication number MX2017004592A discloses a peptide or protein drug with specific molecular weight, copper salt/complex and/or zinc salt/complex and reducer combined oral medicine for treating and preventing diseases or symptoms; the medicine comprises a component absorption promoter, the absorption enhancer comprises 8-20C alkanoyl carnitine, salicylic acid derivatives, 3-methoxysalicylic acid, 5-methoxysalicylic acid, homovanillic acid, 8-20C alkanoic acid, citric acid, fatty acid acylated amino acid, 8-20C alkanoyl sarcosinate, alkyl saccharide, 8-10C alkyl polysaccharide, N-octyl-beta-D-glucopyranoside, N-dodecyl beta-D-maltoside, cyclodextrin, alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, methyl-beta-cyclodextrin, hydroxypropyl beta-cyclodextrin, sulfobutyl ether beta-cyclodextrin, N- [8- (2-hydroxybenzoyl) amino ] caprylic acid sodium, sulfur polymer, calcium chelate, ethylenediamine tetraacetic acid, ethylene glycol tetraacetic acid benzalkonium chloride, betaines, cetylpyridinium chloride, cetyltrimethylammonium bromide, 2-20 carbon alkanols, 8-20 carbon enols, 8-20 carbon alkenoic acids, dextran sulfate, diethylene glycol monoethyl ether, 1-dodecylazepan-2-one, ethyl octanoate, glyceryl monolaurate, lysophosphatidylcholine, menthol, 8-20 carbon alkylamines, 8-20 carbon alkenylamines, phosphatidylcholine, poloxamers, polyethylene glycol monolaurate, polyoxyethylene, polypropylene glycol monolaurate, polysorbate, deoxycholate, sodium glycocholate, sodium glycodeoxycholate, sodium lauryl sulfate, taurocholate, taurodeoxycholate, or a salt thereof.
In addition, the invention patent with publication number EP3359181A1 discloses an improved pharmaceutical formulation, which has higher bioavailability and safety of orally administered peptide drugs. The invention provides a pharmaceutical composition comprising a peptide drug having a molecular weight of 5kDa or less; a pharmaceutically acceptable copper salt complex and/or a pharmaceutically acceptable zinc salt/complex and/or a pharmaceutically acceptable iron salt/complex thereof; and a pharmaceutically acceptable complexing agent. The pharmaceutical composition further comprises an absorption enhancer selected from 8-20 carboalkanoyl carnitine, salicylic acid derivative compounds, 3-methoxysalicylic acid, 5-methoxysalicylic acid, homovanillic acid, 8-20 carboalkanoic acid, citric acid, tartaric acid and fatty acid acylated amino acids, and/or salts thereof.
At present, various preparation methods of oral polypeptide preparations are proposed, which mainly comprise the following categories:
The chemical modification method comprises the following steps: by changing the chemical structure of the polypeptide drug, the stability and the lipophilicity of the polypeptide drug are improved, so that the degradation resistance and the absorption capacity of the polypeptide drug are improved. The technology can effectively improve the bioavailability of the polypeptide drug; however, there are also disadvantages such as the possibility of affecting the bioactivity of the polypeptide drug, increasing the cost and complexity of synthesis, requiring additional safety evaluations, etc.
Vector-mediated method: by encapsulating the polypeptide drug in various carriers, it is protected from degradation by the gastrointestinal tract, while its absorption through the intestinal wall is facilitated by the specific properties of the carrier. The technology can effectively protect polypeptide drugs and simultaneously provide various absorption paths, such as transcellular, paracellular, M cell and the like; but it may affect the release and distribution of polypeptide drugs, increase the complexity and instability of the formulation, and also take into account the biocompatibility and toxicity of the carrier in use, etc.
Permeation enhancer method: the intestinal wall permeability of the polypeptide drug is increased by adding substances capable of changing the intestinal wall barrier, so that the absorption capacity of the polypeptide drug is improved. The technology can effectively increase the absorption of polypeptide drugs; however, there are some disadvantages, such as damage and irritation to the intestinal wall, and influence on the normal function of the intestinal tract, and the dosage and safety of the permeation enhancer should be considered during application.
Aiming at the technical problems, the invention combines the inorganic nano material carrier mediated technology and the permeation promotion technology to prepare the GLP-1RA preparation, thereby preparing and obtaining the glucagon-like peptide-1 pharmaceutical preparation with safety, stability and high oral bioavailability.
Disclosure of Invention
Aiming at the problems existing in the prior art, the invention provides GLP-1RA drug-loaded nano-particles, a preparation and a preparation method thereof, wherein an inorganic nano-material carrier mediation technology and a permeation promotion technology are used in combination, and gastric-adhesion inorganic nano-particles are used as GLP-1RA carriers, so that oral polypeptide drugs are effectively prevented from being degraded by gastrointestinal tracts, and various absorption ways are provided, and the gastric wall absorption capacity is improved; the specific surface modifier is adopted to increase the drug loading rate and the drug recovery rate of the nano-particles, increase the lipophilicity of the nano-particles and promote the penetration of the nano-particles through the stomach wall; the osmotic pressure promoter is combined, and the physical and biochemical properties of the stomach wall barrier are changed by using a specific type of osmotic promoter, so that the stomach wall permeability of the oral polypeptide drug is increased, the absorption capacity of the oral polypeptide drug is improved, and the solubility and bioavailability of the drug are increased. The GLP-1RA preparation medicine prepared by the invention has high dissolution rate of the main medicine and the penetration enhancer, and the bioavailability is obviously improved.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
firstly, the invention provides a preparation method of GLP-1RA drug-loaded nano-particles, which comprises the following steps:
(1) Dissolving and mixing GLP-1RA, a surface modifier 1 and metal salt to obtain solution A;
(2) Dissolving and mixing the surface modifier 2 and the medicinal component containing acid radical or hydroxyl ions to obtain solution B;
(3) Mixing the solution A and the solution B, regulating the pH value to form a precipitate, and obtaining GLP-1RA drug-loaded nano particles;
The surface modifier 1 is at least one selected from tween, span, poloxamer, sodium dodecyl sulfate, polyoxyethylated castor oil, bile acid and salts thereof, polyethylene glycol (PEG) and derivatives thereof, phospholipids, block copolymers Pluronic series, block copolymers P123, amphiphilic polypeptides, polyethylene oxide (PEO), polypropylene oxide (PPO), chitosan, hyaluronic acid, gum arabic, albumin, gelatin, polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), polycaprolactone (PCL), sodium alginate, dextran;
The surface modifier 2 is selected from bile acid and its derivatives, cholesterol and its derivatives, phosphatidylcholine (PC), phosphatidylethanolamine (PE), poloxamer F68, poloxamer F127, chitosan and its derivatives, polyglutamic acid (PGA), polylysine (PLL), polylactic acid (PLA), and Polycaprolactone (PCL).
Preferably, the dissolution mixing process occurs in a buffer saline solution, which is a biocompatible buffer saline solution; the buffer salt solution is at least one selected from phosphate buffer salt solution (PBS), hank's balanced salt solution (comprising components of sodium chloride, potassium chloride, phosphate, sodium bicarbonate and glucose), tris (Tris-hydroxymethyl-aminomethane hydrochloride) buffer, TAE buffer (comprising components of Tris-hydroxymethyl-aminomethane, acetic acid and ethylenediamine tetraacetic acid), TBE buffer (comprising components of Tris-hydroxymethyl-aminomethane, boric acid and ethylenediamine tetraacetic acid), MOPS (3- (N-morpholino) propanesulfonic acid) buffer, glycine buffer and HEPES (4-hydroxyethyl piperazine ethanesulfonic acid) buffer.
Preferably, the amphiphilic polypeptide is a peptide fragment consisting of a plurality of amino acids, including a polypeptide consisting of amphiphilic amino acids, or a polypeptide consisting of hydrophilic amino acids and hydrophobic amino acids; the amphiphilic amino acid is at least one selected from asparagine (Asn) and glutamine (Gln); the hydrophilic amino acid is at least one selected from aspartic acid (Asp), glutamic acid (Glu), lysine (Lys), arginine (Arg), histidine (His), serine (Ser), threonine (Thr) and tyrosine (Tyr); the hydrophobic amino acid is at least one selected from alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tryptophan (Trp), methionine (Met) and proline (Pro).
Preferably, the block copolymer Pluronic series is selected from at least one of Pluronic124, 188, 237, 338, 407.
Preferably, the medical ingredient containing acid radical or hydroxyl radical ion is at least one selected from calcium hydrophosphate, disodium hydrogen phosphate, tricalcium phosphate, sodium bicarbonate, calcium carbonate, sodium silicate, aluminum hydroxide, calcium sulfate and barium sulfate.
Preferably, the surface modifier 1 is selected from at least one of bile acid and its salt, PEG and its derivative, and phospholipid.
Further preferably, the surface modifier 1 is PEG and its derivatives.
Still more preferably, the surface modifier 1 is PEG; still more preferably, the PEG is at least one selected from PEG200, PEG300, PEG400, PEG600, PEG1000, PEG1450, PEG3350, PEG4000, PEG6000, PEG 8000.
Preferably, in step (1) -step (2), the dissolution mixing process occurs in a buffer salt solution, wherein the buffer salt solution is HEPES buffer solution, the concentration is 10-30mM, and the pH=7.0-8.5; further preferably, the concentration of HEPES buffer is 20mm, ph=8.0.
Preferably, in step (1), the metal salt is calcium chloride.
Preferably, in the step (2), the surface modifier 2 is at least one selected from glycocholic acid and its salt, deoxycholic acid and its salt, gentisic acid and its salt, chenodeoxycholic acid and its salt, taurocholate and its salt, glycocholic acid and its salt, taurodeoxycholic acid and its salt, tauroursodeoxycholic acid (Tauroursodeoxycholic Acid) and its salt, phosphatidylcholine, polylysine, polylactic acid, chitosan, polyglutamic acid, and polycaprolactone.
Further preferably, the surface modifier 2 is at least one selected from ursodeoxycholic acid, sodium chenodeoxycholic acid, glycocholic acid, sodium deoxycholate, gentisic acid, and sodium taurocholate.
Preferably, in the step (2), the acid group-containing or hydroxyl group-containing pharmaceutical ingredient is at least one selected from disodium hydrogen phosphate, calcium hydrogen phosphate, tricalcium phosphate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide.
Preferably, the step (2) specifically comprises: and (3) dissolving and mixing the surface modifier 2 and the medicinal components containing acid radicals or hydroxyl ions, and regulating the pH value to obtain the solution B.
Further preferably, in step (2), the pH is adjusted to 6.0 to 8.5; still more preferably, the pH is adjusted to 7.0-8.5; still more preferably, the pH is adjusted to 8.0.
Further preferably, after the precipitate is formed in the step (3), the method further comprises the steps of centrifuging and drying the precipitate to finally obtain GLP-1RA drug-loaded nano-particles; still more preferably, the centrifugation is specifically 7000-10000rpm for 8-15min; still more preferably, the centrifugation is specifically 8000rpm for 10min.
Still more preferably, the drying in step (3) is freeze drying.
Further preferably, the solution A and the solution B are mixed in the step (3), and shaking is required for 20-50min during mixing; still more preferably, the shaking is for 30min.
Preferably, in the step (3), the pH is adjusted to 6.0-8.5; further preferably, the pH is adjusted to 7.0-8.5; still more preferably, the pH is adjusted to 8.0.
Furthermore, the invention provides GLP-1RA drug-loaded nano-particles prepared by the preparation method, which comprise the following components in parts by weight: 2-4 parts of GLP-1RA, 15-27 parts of HEPES, 30-48 parts of metal salt, 0.3-0.8 part of pH regulator, 42-79 parts of surface modifier 1, 7.5-18.2 parts of surface modifier 2 and 13.5-20.7 parts of medical components containing acid radicals or hydroxyl ions.
Preferably, the GLP-1RA drug-loaded nano-particles comprise the following components in parts by weight: 2.5 to 3.5 parts of GLP-1RA, 20 to 23 parts of HEPES, 36 to 44 parts of metal salt, 0.5 to 0.7 part of pH regulator, 50 to 70 parts of surface modifier 1, 9 to 16 parts of surface modifier 2 and 15.5 to 18.7 parts of medical ingredient containing acid radicals or hydroxyl ions.
Further preferably, the GLP-1RA drug-loaded nanoparticle comprises the following components in parts by weight: 3 parts of GLP-1RA, 21.45 parts of HEPES, 39.45 parts of metal salt, 0.6 part of pH regulator, 60 parts of surface modifier 1, 12 parts of surface modifier 2 and 17.05 parts of medical ingredient containing acid radical or hydroxyl ion.
Preferably, the pH regulator is at least one selected from NaOH and KOH; when the pH regulator is used, water is used for preparation, and the final concentration is 0.1-0.3M.
Further preferably, the pH adjustor is NaOH, which in use is formulated as a NaOH solution at a concentration of 0.2M.
Then, the present invention provides a method for preparing a GLP-1RA formulation for improving oral bioavailability, comprising the steps of: preparing a preparation by using GLP-1RA drug-loaded nano particles and a penetration enhancer together to obtain a GLP-1RA preparation;
the penetration enhancer is at least one selected from medium chain fatty acid and its derivatives, nonionic surfactant, bile acid and its derivatives, C8 (octanoic acid), C10 (decanoic acid), sodium caprate, EDTA (ethylenediamine tetraacetic acid), acyl carnitine, and alkyl maltoside.
Preferably, the medium chain fatty acid includes, but is not limited to, at least one of sodium caprate, sodium laurate, ethyl laurate.
Preferably, the nonionic surfactant includes, but is not limited to, at least one of SNAC (sodium 8- (2-hydroxybenzoamide) octoate), 5-CNAC (sodium 5-chlorosalicylamide hexanoate), 4-CNAB (sodium 4-chlorosalicylamide butyrate).
Preferably, the bile acid and its derivative is selected from at least one of primary bile acid juice, secondary bile acid juice; further preferably, the cholic acid juice is selected from at least one of cholic acid, chenodeoxycholic acid, ursodeoxycholic acid, glycocholic acid, taurochenodeoxycholic acid, glycochenodeoxycholic acid, deoxycholic acid, lithocholic acid, glycodeoxycholic acid, taurocholic acid or salts thereof.
Preferably, the penetration enhancer is at least one selected from SNAC, 5-CNAC, 4-CNAB, ursodeoxycholic acid, chenodeoxycholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid.
Preferably, the preparation of the formulation is a conventional formulation preparation process including, but not limited to, powder blending, granulating, tabletting, coating, suspending, spray drying, hot melt extrusion steps.
Finally, the invention provides a GLP-1RA preparation prepared by the preparation method, which comprises the following components in parts by weight: 9-11.6 parts of GLP-1RA drug-loaded nano-particles and 56-80 parts of permeation enhancer.
Preferably, the GLP-1RA preparation comprises the following components in parts by weight: 10.51 parts of GLP-1RA drug-loaded nano-particles and 67.50 parts of permeation enhancer.
Preferably, fillers, binders and lubricants are also included in the GLP-1RA formulation.
Further preferred are microcrystalline cellulose, povidone and magnesium stearate also included in the GLP-1RA formulation.
Still more preferably, the GLP-1RA formulation comprises the following components in parts by weight: 9-11.6 parts of GLP-1RA drug-loaded nano-particles, 56-80 parts of permeation enhancer, 15-22 parts of filler, 1.2-2.5 parts of adhesive and 1.8-2.6 parts of lubricant.
Still more preferably, the GLP-1RA formulation comprises the following components in parts by weight: 10.51 parts of GLP-1RA drug-loaded nanoparticles, 67.50 parts of a permeation enhancer, 18 parts of a filler, 1.8 parts of a binder and 2.18 parts of a lubricant.
Compared with the prior art, the invention has the following beneficial effects:
1. The invention adopts inorganic nano particles as a carrier, has high drug loading capacity, good biocompatibility and stability, can effectively protect GLP-1RA from being degraded by gastrointestinal tract, and simultaneously provides a plurality of absorption ways: transcellular, paracellular and M-cell, enhancing the absorption capacity of GLP-1RA in the stomach wall; and the production process is simple, which is beneficial to industrialized production.
2. The invention adopts the penetration enhancer as a surface modification component, can increase the drug loading rate of the nano-particles, improve the recovery rate of the drug, and can also increase the lipophilicity of GLP-1RA drug loading nano-particles so as to promote the GLP-1RA drug loading nano-particles to be absorbed through the stomach wall.
3. The GLP-1RA drug-loaded nano-particles prepared by the invention have gastric mucosa adhesion capability, and can realize targeting of specific parts of the digestive tract; the nanoparticle has the advantages of simple preparation process, medicinal materials, high safety, simple product composition and good stability.
4. The GLP-1RA drug-loaded nano-particles are easy to dissolve and absorb in the gastrointestinal tract, have the characteristic of quick drug release, and can be modified by a preparation technical method, so that targeted and modified release is realized.
Detailed Description
The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the invention and are not intended to limit the invention in any way. The following is merely exemplary of the scope of the invention as it is claimed and many variations and modifications of the invention will be apparent to those skilled in the art in light of the disclosure, which should be considered as falling within the scope of the invention as claimed.
Where numerical ranges are provided in the examples, it is understood that unless otherwise stated herein, both endpoints of each numerical range and any number between the two endpoints are significant both in the numerical range. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The invention is further illustrated by means of the following specific examples.
The various chemical reagents used in the examples of the present invention were obtained by conventional commercial means unless otherwise specified. In the following examples and comparative examples, GLP-1RA was used as semaglutinin, purchased from Hubei's in-flight biopharmaceutical, lot number COO5AD230601; polyethylene glycol 6000, available from Jiangxi alpha Gao Ke pharmaceutical industry, lot number 20230102; SNAC (sodium 8- (2-hydroxybenzoamido) octoate) was purchased from the company, sumac pharmaceutical group, sumac biopharmaceutical limited, lot number 0920220901; microcrystalline cellulose was purchased from FMC under the lot number 2174359392 and model number PH102; povidone K90 is available from BASF under the lot number 78081424U0, model Kollidon 90F; the magnesium stearate is purchased from Anhui Shanhe pharmaceutical excipients Limited company, batch number 230824, model number SH-YM-M; ursodeoxycholic acid was purchased from the company Mikroot pharmaceutical Co., ltd, hunan, under the lot number T202306LED1.
The components have no obvious influence on the effect of products of different factories.
The "/" in the table represents that the corresponding data is not used, or that the corresponding content is not present.
Example 1
GLP-1RA drug-loaded nano-particles, as shown in table 1, comprise the following components in parts by weight:
TABLE 1
The preparation method of the GLP-1RA drug-loaded nano-particles (semaglutinin calcium phosphate particles) comprises the following steps:
(1) And (3) solution A: taking 3.0g of semaglutin, adding the semaglutin into 1500mL of 20mM HEPES buffer solution while stirring, continuously stirring until the semaglutin is dissolved, adding 39.42g of calcium chloride into the mixture while stirring, and stirring until the semaglutin is dissolved; then adding 30g PEG6000, and continuously stirring until the PEG6000 is completely dissolved; purified water was added to the solution to 3000mL and placed in a cold water bath.
(2) And (2) liquid B: 30g of PEG6000 was weighed, added to 600mL of 20mM HEPES buffer, 16.8g of disodium hydrogen phosphate was added, and after stirring until dissolution was complete, the pH was measured, adjusted to 8 with sodium hydroxide, and added to 3000mL using 20mM HEPES buffer.
(3) Slowly adding the solution B into the solution A while stirring, regulating the pH to 8, and placing the reaction solution on a shaking table after the addition is finished, and continuously shaking for 30min to form a precipitate.
(4) And (3) centrifuging: and then centrifuged at 8000rpm for 10min to obtain a precipitate and a supernatant.
(5) And (3) drying: and freeze-drying the collected precipitate to obtain the target semaglutin calcium phosphate particles.
A GLP-1RA formulation (tablet), as shown in table 2, comprising the components in parts by weight:
TABLE 2
The calcium phosphate particles of the semaglutin are calculated by semaglutin, and the unit dosage is 10.51 parts.
A method of preparing a GLP-1RA formulation comprising the steps of:
S1, uniformly mixing 80% of magnesium stearate, SNAC and 70% of microcrystalline cellulose in a mixer;
S2, uniformly mixing the calcium phosphate nano particles, 30% microcrystalline cellulose and povidone K90 in a mixer;
S3, total mixing: and (3) uniformly mixing the mixture obtained in the step (S1) and the step (S2) with the rest 20% magnesium stearate in a mixer, and tabletting (the tabletting pressure is 15-25 KN) to obtain the semaglutinin tablet.
The recovery amount and recovery rate of the semaglutin in the semaglutin calcium phosphate particles are calculated as follows:
the recovery amount (g) of semaglutin=semaglutin loading (mg/g) x total amount of semaglutin calcium phosphate particles;
Semaglutin recovery (%) = [ semaglutin recovery (mg)/semaglutin loading (mg) ], 100% = 80.4%.
The prepared semaglutin tablet is subjected to dissolution behavior detection, and the detection results are shown in table 3:
RSD refers to the relative standard deviation (RELATIVE STANDARD devimentations).
TABLE 3 Table 3
NJG 6248A 6248 sample was a market supervisor Meguerupeptide tablet, produced by NOVO Nordisk, dealer MSD Co., ltd., specification: 3mg.
Example 2
GLP-1RA drug-loaded nano-particles, as shown in table 4, comprise the following components in parts by weight:
TABLE 4 Table 4
The preparation method of the GLP-1RA drug-loaded nano-particles (semaglutinin calcium phosphate particles) comprises the following steps:
(1) And (3) solution A: taking 3.0g of semaglutin, adding the semaglutin into 1500mL of 20mM HEPES buffer solution while stirring, continuously stirring until the semaglutin is dissolved, adding 39.42g of calcium chloride into the mixture while stirring, and stirring until the semaglutin is dissolved; then 60g PEG6000 is added and continuously stirred until the mixture is completely dissolved; purified water was added to the solution to 3000mL and placed in a cold water bath.
(2) And (2) liquid B: 12.0g of ursodeoxycholic acid was weighed and dissolved in 225mL of absolute ethanol, neutralized with sodium hydroxide, then added to 1200mL of 20mM HEPES buffer, 17.05g of disodium hydrogen phosphate was added, after stirring until dissolution was complete, the pH was measured, adjusted to 8 with sodium hydroxide, and added to 3000mL using 20mM HEPES buffer.
(3) Slowly adding the solution B into the solution A while stirring, regulating the pH to 8, and placing the reaction solution on a shaking table after the addition is finished, and continuously shaking for 30min to form a precipitate.
(4) And (3) centrifuging: and then centrifuged at 8000rpm for 10min to obtain a precipitate and a supernatant.
(5) And (3) drying: and freeze-drying the collected precipitate to obtain the target semaglutin calcium phosphate particles.
A GLP-1RA formulation (tablet) comprising, as shown in table 5, the components in parts by weight:
TABLE 5
The calcium phosphate particles of the semaglutin are calculated by semaglutin, and the unit dosage is 10.51 parts.
A method of preparing a GLP-1RA formulation comprising the steps of:
S1, uniformly mixing 80% of magnesium stearate, SNAC and 70% of microcrystalline cellulose in a mixer;
S2, uniformly mixing the calcium phosphate nano particles, 30% microcrystalline cellulose and povidone K90 in a mixer;
S3, total mixing: and (3) uniformly mixing the mixture obtained in the step (S1) and the step (S2) with the rest 20% magnesium stearate in a mixer, and tabletting (the tabletting pressure is 15-25 KN) to obtain the semaglutinin tablet.
In the semaglutin tablet, the recovery amount and recovery rate of semaglutin were calculated as follows:
the recovery amount (g) of semaglutin=semaglutin loading (mg/g) x total amount of semaglutin calcium phosphate particles;
semaglutin recovery (%) = [ semaglutin recovery (mg)/semaglutin loading (mg) ]100% = 94.7%.
The prepared semaglutin tablet (example 2) was subjected to dissolution behavior detection.
The results of the dissolution test of semaglutin and SNAC in pH 1.2 medium are shown in table 6.
TABLE 6
NJG 6248A 6248 sample was a market supervisor Meguerupeptide tablet, produced by NOVO Nordisk, dealer MSD Co., ltd., specification: 3mg.
The results of the dissolution test of semaglutin and SNAC in pH 2.5 medium are shown in table 7.
TABLE 7
NJG 6248A 6248 sample was a market supervisor Meguerupeptide tablet, produced by NOVO Nordisk, dealer MSD Co., ltd., specification: 3mg.
The results of the dissolution test of semaglutin and SNAC in pH 6.8 medium are shown in table 8.
TABLE 8
NJG 6248A 6248 sample was a market supervisor Meguerupeptide tablet, produced by NOVO Nordisk, dealer MSD Co., ltd., specification: 3mg.
As can be seen from the dissolution results in tables 2 to 4, the dissolution rate of the stavudine preparation of the present invention was faster and the dissolution rate was higher in each dissolution medium than in the control preparation NJG and 6248.
Example 3
Unlike example 2, the GLP-1RA formulation was prepared differently, comprising the steps of:
s1, pretreatment: sodium 8- (2-hydroxybenzoamido) octoate was granulated, and SNAC was granulated with a 0.61mm screen at 1300 rpm.
S2, weighing: the components are weighed according to the formula amount.
S3, mixing:
Mixing the samples of step S1: mixing 80% sieved magnesium stearate with 2% SNAC, 20rpm for 2min, adding 4% SNAC, mixing at 20rpm for 2min, adding the rest SNAC and mixing at 20rpm for 20min; adding 30% microcrystalline cellulose into a mixer, and mixing at 20rpm for 10min to obtain a mixture S1;
mixing the samples of step S2: firstly, mixing the formula amount of the semaglutin drug-loaded particles with the same amount of microcrystalline cellulose at 20rpm for 2min; finally, adding the rest microcrystalline cellulose and povidone, and mixing for 10min at 20rpm to obtain a mixture S2.
S4, dry granulation:
Granulating the mixture S1: the feed screw speed is 35.0rpm, the roller speed is 6.0rpm, the pressure is 100bar, and the roller gap is 0.60mm, so that S1 particles are obtained;
granulating a mixture S2: feed screw speed 30.0rpm, roller speed 4.0rpm, pressure 110bar, roller gap 0.60mm; s2 particles are obtained.
S5, finishing:
The S1 particles were granulated using a 0.61mm screen at 1300rpm, and the resulting particles were collected, weighed and the yield was calculated.
The S2 particles were granulated using a 0.61mm screen at 1300rpm, and the resulting particles were collected, weighed and the yield was calculated.
S6, weighing:
calculating the amount of added magnesium stearate to be actually added based on the weight and yield of the S1 particles and the S2 particles; the magnesium stearate is weighed to obtain the target amount.
S7, total mixing:
The S1 particles and the S2 particles are mixed in a mixer at 20rpm for 25min, then magnesium stearate is added and mixed at 20rpm for 3min to obtain intermediate product powder.
S8, tabletting:
the above intermediate powder was compressed into tablets (semaglutin tablets) having a 14mg size and a 50-100N hardness using a rotary tablet press.
The prepared semaglutin tablet (example 3) was subjected to dissolution behavior detection.
The results of the dissolution test of semaglutin and SNAC in pH 1.2 medium are shown in table 9.
TABLE 9
NJG 6248A 6248 sample was a market supervisor Meguerupeptide tablet, produced by NOVO Nordisk, dealer MSD Co., ltd., specification: 3mg.
Example 4
Unlike example 2, ursodeoxycholic acid was replaced with sodium chenodeoxycholate. The remainder was the same as in example 1.
The prepared GLP-1RA preparation is subjected to dissolution behavior detection, and the detection results are shown in Table 10.
Table 10
Example 5
Unlike example 2, ursodeoxycholic acid was replaced with sodium taurocholate. The remainder was the same as in example 1.
The prepared GLP-1RA preparation is subjected to dissolution behavior detection, and the detection results are shown in Table 11.
TABLE 11
Comparative example 1
Unlike example 2, the kind of the surface modifier 2 is different, and the specific kind is shown in Table 12. The detection results of the recovery rate of the semaglutin in the prepared GLP-1RA preparation (semaglutin tablet) are shown in Table 12.
Table 12
The recovery amount (g) of semaglutin=semaglutin loading (mg/g) x total amount of semaglutin calcium phosphate particles;
the recovery rate (%) of semaglutin= [ semaglutin recovery amount (mg)/semaglutin loading amount (mg) ]×100%.
Comparative example 2
Unlike example 2, the GLP-1RA drug-loaded nanoparticle differs in parts by weight of the components. As shown in table 13:
TABLE 13
The prepared GLP-1RA preparation is subjected to dissolution behavior detection, and the detection result is shown in Table 14.
The recovery rate of the semaglutin is 65%.
TABLE 14
Comparative example 3
Unlike example 2, the permeation enhancer was replaced with sodium laurylalaninate for SNAC.
The prepared GLP-1RA preparation is subjected to dissolution behavior detection, and the detection results are shown in Table 15.
The recovery rate of the semaglutin is 62%.
TABLE 15
Comparative example 4
Unlike example 2, the preparation method of GLP-1RA drug-loaded nanoparticles is different, and is specifically shown in Table 16:
adding the semaglutin, PEG6000 and ursodeoxycholic acid ethanol solution into 20mM HEPES buffer solution, adding disodium hydrogen phosphate, stirring until the disodium hydrogen phosphate is completely dissolved, measuring pH, and regulating the pH to 8 by using sodium hydroxide; adding into calcium chloride solution under stirring, oscillating for precipitation, centrifuging, and drying.
The prepared GLP-1RA preparation is subjected to dissolution behavior detection, and the detection result is shown in Table 16.
The recovery rate of the semaglutin is 47%.
Table 16
Comparative example 5
Unlike example 2, the GLP-1RA formulation differs in parts by weight of the components, as shown in table 17:
TABLE 17
The prepared GLP-1RA preparation is subjected to dissolution behavior detection, and the detection result is shown in Table 18.
The recovery rate of the semaglutin is 70%.
TABLE 18
Bioavailability and safety detection
(1) Purpose of investigation
The semaglutin tablet (trade name: rybelsus) which is proved by NOVO NORDISK INC is used as a control preparation;
The human relative bioavailability of the two formulations was evaluated by single-center, randomized, open, single-dose, parallel-design clinical study using the semaglutinin tablets prepared in example 2 above as the test formulation.
Safety of the test and control formulations in healthy subjects in china was also observed.
(2) Research medicament
Test formulation (T): the semaglutin tablet of example 2, specification: 14mg.
Control formulation (R): semaglutin tablets (trade name: rybelsus), specification: 14mg,NOVO NORDISK INC is holding the evidence.
(3) Test design
Single-site, randomized, open, single-dose, parallel-trial design was employed. The subjects were divided into T, R groups on a randomized basis, and received either the test or control formulation in a fasting state. Word fasting test 6 healthy subjects were dosed at 14mg. Test blood collection time point: venous blood was collected at 20 time points for 0h (within 60 min) before dosing, 15min, 30min, 45min, 1h, 75min, 1.5h, 105min, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 48h, 72h after dosing.
(4) Administration mode
The subjects fasted overnight for at least 10 hours during the first period, and the next morning on an empty stomach were administered 120mL of warm water. Upon administration, the investigator instructs the subject not to chew the drug, but to swallow the drug in whole tablets or granules. After taking the medicine, the oral cavity, the medicine container, the cup and both hands are checked to ensure that the medicine and the water are taken.
Subjects were prohibited from drinking water (except 120mL of water given at the time of administration) 1h before to 1h after dosing, and fasted for 5h after dosing.
(5) Blood collection
Blood samples were collected at 0h before dosing, 15min, 30min, 45min, 1h, 75min, 1.5h, 105min, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h, 48h, 72h after dosing.
Sample collection was performed according to the sampling protocol and SOP of the clinical hospital, with each blood sample collected at the indicated theoretical time point, with the actual collection time of each blood sample recorded intact. See blood collection schedule for details. Before blood sample collection, a sufficient heparin sodium anticoagulation blood collection tube is prepared, a researcher uniformly numbers the heparin sodium anticoagulation blood collection tube according to a scheme and attaches a sample label, and meanwhile, a cryopreservation tube is uniformly numbered and attaches a special label. The vein blood is sampled by about 4mL, and the mixture is gently mixed upside down for 5-6 times. Before the whole blood sample is split, after the blood collection tube is gently inverted to ensure that blood cells are uniformly distributed, 1mL of whole blood is immediately removed to the detection tube, and the rest of whole blood is transferred to the backup tube. And (3) ice bath in the whole process.
All subjects blood samples were placed into an ultra-low temperature refrigerator within 2 hours after collection of the whole blood sample.
All blood samples were tested after the two-cycle test was completed.
(6) Pharmacokinetic parameter calculation
And calculating the pharmacokinetic parameters by adopting a non-parametric statistical model method.
(7) Test results
Results of the pharmacokinetic parameters of semaglutin are shown in table 19.
TABLE 19
Therefore, the GLP-1RA preparation prepared by the invention shows higher bioavailability than the commercially available preparation in the human pharmacokinetic study, which shows that the prescription process of the invention obviously improves the oral absorption of the semeglutide.
In summary, the preparation method and the prepared GLP-1RA preparation have the following technical effects:
1. The dissolution rate and the dissolution amount of GLP-1RA are improved, and compared with the common oral GLP-1RA preparation, the obtained inorganic nano particles have smaller particle size and rapid response, so that the dissolution rate and the drug dissolution amount are higher.
2. The drug loading rate and the drug recovery rate (more than 85%) are improved, and the loss in the preparation process is reduced by using the permeation enhancer as the surface modifier.
3. The technical scheme of combining the inorganic nano-carrier for the adhesion of the mucous membrane and the permeation promotion is adopted, so that the absorption of the medicine in the gastrointestinal tract is promoted; the mucosa-adhered inorganic nano particles can target gastric or intestinal mucosa, effectively protect the oral polypeptide medicament from being degraded by gastrointestinal tract, provide various absorption ways and improve the absorption capacity of gastric wall; the permeation enhancer can change physical and biochemical properties of intestinal wall barrier, increase intestinal wall permeability of oral polypeptide drug, improve absorption capacity, increase solubility of drug, and improve bioavailability.
4. The preparation method of the invention can realize effective delivery of the oral polypeptide drug, overcomes the inconvenience and pain of the traditional injection administration, and improves the compliance and the quality of life of patients.
5. The preparation method of the invention can protect the oral polypeptide drug from the degradation of gastrointestinal tract and the first pass effect of liver, improves the bioavailability and the drug effect of the oral polypeptide drug, and reduces the dosage and the toxic and side effects of the drug.
6. The preparation method can realize the controlled release and targeted treatment of the oral polypeptide drug, improves the pharmacokinetic and pharmacodynamic characteristics of the oral polypeptide drug, and enhances the treatment effect and safety of the oral polypeptide drug.
7. The preparation method adopts a simple, economical and feasible preparation method and raw materials, improves the convenience and economical efficiency of manufacturing and storing the oral polypeptide medicament, and has stronger industrialized application prospect.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
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