CN107823178B - Niflumic acid colon targeted preparation for treating irritable bowel syndrome and preparation method thereof - Google Patents
Niflumic acid colon targeted preparation for treating irritable bowel syndrome and preparation method thereof Download PDFInfo
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- CN107823178B CN107823178B CN201711110770.1A CN201711110770A CN107823178B CN 107823178 B CN107823178 B CN 107823178B CN 201711110770 A CN201711110770 A CN 201711110770A CN 107823178 B CN107823178 B CN 107823178B
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- niflumic acid
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
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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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A—HUMAN NECESSITIES
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- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A—HUMAN NECESSITIES
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- General Health & Medical Sciences (AREA)
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- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a colon-targeted preparation of niflumic acid for treating irritable bowel syndrome and a preparation method thereof. The preparation is orally administered, and the medicine is concentrated in colon for release, so as to improve the adhesion rate of the medicine to colon focus part, and further improve the medicine concentration in colon part. Reduces the side effect of the medicine on the gastrointestinal tract and simultaneously fully plays the therapeutic effect of the medicine.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and relates to a niflumic acid colon-targeted preparation and a preparation method thereof. More specifically, the invention relates to a micro-pill which can target to a colon part to release niflumic acid and stay for a long time at a colon inflammation part and a preparation method thereof.
Background
Irritable Bowel Syndrome (IBS) is a common functional bowel disorder characterized by chronic abdominal pain or abdominal discomfort with altered bowel habits, with the primary site of dysfunction being in the colon. It is widely believed that chronic visceral hyperalgesia is a major cause of abdominal pain and intestinal motility abnormalities in IBS patients and may involve two mechanisms of sensitization of the peripheral colon and afferent nerves and sensitization of the spinal cord and above the central sensitization (Aguas m., et al, 2011; tanghami et al, 2009). The prevalence rate in European and American countries is up to 15%, and the prevalence rate in the world is on the rise. At present, IBS clinical treatment mainly comprises medicines, but most medicines only relieve symptoms and cannot completely cure the symptoms, so that the development of novel effective therapeutic medicines is urgently needed.
Chronic pain is a complex physiological and psychological activity that is processed by different parts of the brain together to produce functions that include sensory recognition, emotional motivation, and cognitive assessment. Chronic persistent pain affects the function of the hippocampus, resulting in various brain dysfunction diseases such as anxiety, depression, etc. Studies have shown that pain is not only sensation, but also memory, and that the hippocampus is a key site of memory. Long-term potentiation is also considered as a biological basis of the neural synaptic plasticity that is closely related to the memory of pain, as one of the research models for learning and memorizing synaptic plasticity. NMDA receptor blocker AP-7 and the like are reported to have inhibitory effect on IBS visceral pain sensitization, however, such non-subtype specific receptor blocker often has serious systemic toxic and side effect such as dyskinesia and the like when playing analgesic effect. Therefore, the great attention is paid at home and abroad to the therapeutic value of the subtype specific receptor blocker capable of directly inhibiting the peripheral or central sensitization, and the search of safe and effective therapeutic drugs is an important research and development direction.
Niflumic acid (Niflumic acid) is a nonsteroidal anti-inflammatory analgesic, and is clinically used for treating body pain such as rheumatic pain. Recent research finds that niflumic acid is a specific blocker of hyperpolarization activated cyclic nucleotide gated cation channel subtype 2 (HCN 2), and can selectively act on the outer region of HCN 2S 4 voltage sensitive region, so as to change the gating effect of pacing channel (Cheng L, et al, 2009); HCN2 channels have been reported to play an important role in somatic inflammatory and neuropathic pain (Papp i., et al., 2012; Emery EC, et al.,2012), however whether niflumic acid has a therapeutic effect on IBS visceral pain remains to be confirmed. Previous studies found that HCN2 protein was significantly enhanced in expression in the visceral pain-related center of IBS rats (liu ciosite, 2009); and the abdominal cavity of IBS young mouse is injected with niflumic acid, which can inhibit the visceral pain sensitization behavior in a dose-dependent manner and improve the visceral pain threshold (Luda, 2010); further studies have also found that niflumic acid can also significantly inhibit the synaptic long-term potentiation in the hippocampus of IBS rats (blessing et al, 2012). The results of these studies consistently indicate that HCN2 may be involved in the development of chronic visceral hyperalgesia in IBS, suggesting that niflumic acid may have a novel role in the treatment of visceral pain in IBS.
The oral colon targeted drug delivery system is a novel targeted drug delivery system which is used for delivering drugs to the ileum and releasing the drugs after returning to the cecum without releasing the drugs at the front ends of the stomach, the duodenum, the jejunum and the ileum after oral administration through different medicament technologies so as to play a local or systemic therapeutic role. The system can prevent the medicine from the action of gastrointestinal fluid, accurately convey the medicine to the colon part and slowly release the medicine, not only can directly release the medicine at the pathological change part, increase the local medicine concentration and improve the treatment effect of local large intestine diseases such as constipation, irritable bowel syndrome, ulcerative colitis, hemorrhagic colitis, Crohn's disease, colon cancer and the like, but also can play the long-acting role through the slow release of the medicine in the colon.
It is known that niflumic acid has serious toxic and side effects in the gastrointestinal tract like other non-steroidal anti-inflammatory drugs. Compared with enteric-soluble drugs which are mainly absorbed in the small intestine, colon-targeted drug delivery is that a drug is crosslinked with a carrier with a targeting effect, so that the drug is directionally released in the colon, thereby continuously increasing the concentration of the drug in the colon and fully playing the drug effect (Vadlamudi H.C., et al., 2012). Therefore, the niflumic acid is prepared into a colon-targeted preparation, so that the drug is prevented from being decomposed and damaged in the gastrointestinal tract, and the bioavailability of the drug is increased; but also can reduce the toxic and side effect of the medicine on the gastrointestinal tract, improve the local medicine concentration of the colon, inhibit the peripheral sensitization of the colon part and further play the therapeutic role.
In recent years, it has been reported that reducing the particle size is an effective means for improving colon targeting, and firstly, due to the presence of the eepr (epithelial enhanced permeability and latency) effect of inflammatory intestinal epithelial cells (Schmidt C, et al, 2013; collanot E M, et al, 2012), nanoscale particles can be preferentially taken up by a large number of immune cells in an inflammatory region; secondly, the reduction in particle size also avoids rapid excretion of the drug out of the body due to frequent diarrhea in patients with colonic inflammation (Beloqui a, et al, 2013). Furthermore, nanoparticles can also be transported by adsorption through the gaps or pores of the epithelial villus tips by porosity (pichia M V, et al, 2012). Therefore, the subject group adopts a two-step method, the niflumic acid is firstly encapsulated in the high polymer material to form the nano micelle, and then the nano micelle is encapsulated in the micro-pill by adopting an orifice-solidification method, so that the targeting of the niflumic acid at the colon part is improved, and the damage of the gastrointestinal environment to the niflumic acid nano micelle is reduced.
Patent document 200119464.X discloses a metronidazole colon-specific enteric-coated tablet preparation, which is coated on a tablet of nitroimidazole drugs; the patent document with the patent number of 200710029476.8 discloses a colon-targeted drug delivery preparation of cardiac muscle protein polypeptide and a preparation method thereof, the preparation is prepared by coating drug-containing pellets prepared from drug materials containing the cardiac muscle protein polypeptide component by adopting colon-targeted coating liquid or directly filling the drug-containing pellets into a colon-targeted capsule shell; the patent document 200710029478.7 discloses a colon-targeted preparation of liver protein polypeptide and its preparation method, which is prepared by coating drug-containing pellets made of drug containing liver protein polypeptide component with colon-targeted coating liquid or directly filling into colon-targeted capsule shell. The content reported in the above documents is fundamentally different from the object and method of the present invention.
At present, no colon-targeted preparation containing niflumic acid is seen in the domestic market, and no research report of the pharmaceutical preparation is seen, so that the development of the drug has important clinical significance and wide market prospect.
Disclosure of Invention
The invention aims to provide a colon targeted niflumic acid preparation for treating irritable bowel syndrome and a preparation method thereof. The colon-targeted preparation of niflumic acid can release the drug in the colon and fully play the therapeutic role of the drug.
According to the problems to be solved, a colon targeting preparation containing niflumic acid is designed, which is characterized in that niflumic acid is firstly encapsulated in a high polymer material to form nano micelles, and then the nano micelles are further encapsulated in a pellet by adopting an orifice-solidification method, and the colon targeting preparation is characterized in that:
the feed amount of the niflumic acid and the high polymer material is 1: 20-1: 1, dissolving a high polymer material in an organic solvent to prepare a high polymer solution, wherein the mass volume percentage concentration of the high polymer solution is 2-20%;
wherein the high polymer material is one or more of pluronic F127, polylactic-co-glycolic acid (PLGA) and polyethylene glycol 1000 vitamin E succinate.
The nano micelle is required to be frozen and dried to form freeze-dried powder for storage.
The micro-pill is prepared by mixing one or more than two of low-ester pectin, sodium alginate, chitosan and ethyl cellulose.
The diameter of the prepared drug-containing micro-pill is 0.5-1.5 mm, wherein the preferred diameter is 0.8-1.2 mm.
According to the second problem to be solved, the preparation method of the colon targeting preparation containing niflumic acid is designed, and comprises the following steps:
1) putting the niflumic acid and the carrier material in a formula amount into a container, adding methanol into the container to dissolve the niflumic acid and the carrier material in the methanol, removing the methanol to form a thin film on the inner wall of the container by the mixture of the niflumic acid and the carrier material, adding PBS buffer solution (pH = 7.4) into the container, hydrating the thin film formed on the inner wall of the container, oscillating and hydrating the thin film by ultrasonic waves (240W and 40 kHz) at 37 ℃ until the thin film is dissolved, sequentially and respectively filtering by polycarbonate films with the pore diameters of 0.2 mu m and 0.1 mu m, repeating the steps for 3 times, and freeze-drying to obtain the niflumic acid nano micelle.
2) Dissolving a pellet high polymer material with a formula amount in water to prepare a solution with a certain concentration, uniformly suspending a niflumic acid-containing nano micelle with the formula amount in the high polymer solution to form a suspension, dripping the suspension into a calcium chloride aqueous solution in a droplet shape, solidifying, filtering and drying to obtain a drug-loaded pellet core;
3) and (3) taking the drug-loaded pill core, immersing the drug-loaded pill core in a polyethyleneimine water solution, and carrying out soaking, filtering and drying to obtain the niflumic acid colon-targeted preparation.
The material amount of the nano micelle containing niflumic acid and the micro-pill high polymer material is 1: 20-1: 1; the mass volume percentage concentration of the polymer solution prepared by dissolving the polymer material in water is 5-15%.
The preferable material amount of the niflumic acid nano micelle and the high polymer material is 1: 10; the mass volume percentage concentration of the polymer solution is preferably 8%.
The application of the colon targeted preparation of niflumic acid in preparing the medicines for treating local large intestine diseases such as irritable bowel syndrome, ulcerative colitis, hemorrhagic colitis, Crohn's disease, colon cancer and the like is disclosed.
One of the characteristics of the preparation method of the invention is as follows: the organic solvent used in the process of preparing the nano micelle is methanol, and can simultaneously dissolve the niflumic acid and the high polymer material, thereby ensuring the uniformity and accuracy of the drug content in the nano micelle.
The second characteristic of the preparation method of the invention is that: the two-step method is adopted to prepare the niflumic acid colon-targeted preparation, and the niflumic acid is prepared into the nano micelle, so that the problem that the niflumic acid is difficult to dissolve in water is solved, the absorption is promoted, and the in vivo bioavailability is improved. In addition, the nano micelle can ensure that the niflumic acid exists in the colon part in a nano-scale size, is favorable for improving the targeting property of the colon, enables the medicine to be specifically adhered to the tissues of the colon inflammation, and prolongs the retention time of the medicine in the focus area.
Considering that under the action of a large amount of water and enzyme substances in the gastrointestinal tract, the niflumic acid nano-micelle can generate unstable phenomena such as structural destruction or surface charge change of the nano-micelle. Based on the above, the nano-micelle is wrapped in the pellet in the second step to play a role in protecting the stomach and the small intestine, and the nano-micelle is biodegraded at the colon part to release the nano-micelle to be phagocytized by cells, so that the therapeutic effect is played. Through comparative research, designers surprisingly find that the preparation prepared by adopting the two-step method has obvious colon-targeted drug release performance and biological adhesiveness.
The invention has the beneficial effects that:
1) the preparation of the invention releases the drug at the colon part, can ensure that the drug concentration at the target area is higher than that of other tissues, and can also enter the blood circulation through the colon, thereby effectively avoiding the side effect of the drug on the gastrointestinal tract and the damage of gastric acid or enzyme on the nano micelle and fully playing the therapeutic effect of the drug.
2) The preparation has obvious treatment effect on local large intestine diseases such as irritable bowel syndrome, ulcerative colitis, hemorrhagic colitis, Crohn's disease, colon cancer and the like.
Drawings
Fig. 1A is a graph depicting the particle size and morphology distribution of niflumic acid nanomicelles.
FIG. 1B is a scanning image of transmission electron microscope depicting the particle size and morphology of Niflumic acid nanomicelles.
Fig. 2 is an electron microscope scan depicting the appearance of niflumic acid colon targeted pellets, where a is drug-containing pellets (x 150); in the figure, B is the pellet surface (. times.1000).
Fig. 3 is a graph depicting the swelling-erosion rate of a niflumic acid colon targeting formulation in artificial gastrointestinal fluids.
Fig. 4 is a graph depicting drug dissolution profiles of niflumic acid colon targeted formulations in different artificial digestive fluids, wherein a is the release profile of niflumic acid colon targeted pellets; in the figure, B is the release curve of the niflumic acid nano-micelle.
Fig. 5 is a graph depicting the in vitro adhesion of niflumic acid nanomicelles.
Detailed Description
The invention will be further elucidated with reference to specific embodiments. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers.
Example 1
Precisely weighing niflumic acid and D-alpha-vitamin E polyethylene glycol 1000 succinate (TPGS 1000) respectively according to a drug loading ratio of 1:10 (W/W), placing the materials in an eggplant-shaped bottle, adding a proper amount of methanol, dissolving the materials by ultrasonic oscillation, removing the methanol by rotary evaporation at 40 ℃, adding 50mL of PBS buffer solution (pH = 7.4) when a layer of uniform film is formed at the bottom and the inner wall of the eggplant-shaped bottle, hydrating the materials by ultrasonic oscillation (240W and 40 kHz) at 37 ℃ until the film is dissolved, sequentially filtering the materials by polycarbonate films with the pore diameters of 0.2 mu m and 0.1 mu m respectively, repeating the steps for 3 times, and freeze-drying to obtain nano-micelle freeze-dried powder for later use.
Feeding according to the mass ratio of the nano micelle freeze-dried powder to the low-ester pectin of 1: 10. Spreading low ester pectin in purified water, dissolving to obtain 8% solution, adding nanometer micelle lyophilized powder, stirring, and adding CaCl 10% by mass and volume with No. 6 syringe needle2Curing the mixture in the solution for 30min, filtering, drying at 60 ℃, soaking the pellets in a Polyethyleneimine (PEI) solution with the mass volume percentage concentration of 1.0%, crosslinking for 6h, filtering, washing with purified water, and drying at 60 ℃ to obtain the colon targeting preparation.
Example 2
Precisely weighing niflumic acid and D-alpha-vitamin E polyethylene glycol 1000 succinate (TPGS 1000) according to a drug loading ratio of 1: 15(W/W), respectively, placing the materials in an eggplant-shaped bottle, adding a proper amount of methanol, dissolving the materials by ultrasonic oscillation, removing the methanol by rotary evaporation at 40 ℃, adding 50mL of PBS buffer solution (pH = 7.4) when a layer of uniform film is formed at the bottom and the inner wall of the eggplant-shaped bottle, hydrating the materials by ultrasonic oscillation (240W and 40 kHz) at 37 ℃ until the film is dissolved, sequentially filtering the materials by polycarbonate films with the pore diameters of 0.2 mu m and 0.1 mu m respectively, repeating the steps for 3 times, and freeze-drying to obtain nano-micelle freeze-dried powder for later use.
And feeding according to the mass ratio of the nano micelle freeze-dried powder to the low-ester pectin of 1: 8. Dispersing low-ester pectin in purified water, and dissolvingDecomposing into 6% mass volume percentage concentration solution, adding nano micelle lyophilized powder, stirring and suspending uniformly, and then dripping the mixed solution into slowly stirred CaCl 8% mass volume percentage concentration with No. 6 syringe needle2Curing the mixture in the solution for 30min, filtering, drying at 60 ℃, soaking the pellets in a Polyethyleneimine (PEI) solution with the mass volume percentage concentration of 1.0%, crosslinking for 6h, filtering, washing with purified water, and drying at 60 ℃ to obtain the colon targeting preparation.
Example 3
Precisely weighing niflumic acid and pluronic F127 according to a drug loading ratio of 1:10 (W/W), respectively placing the niflumic acid and the pluronic F127 into an eggplant-shaped bottle, adding a proper amount of methanol, dissolving the mixture by ultrasonic oscillation, removing the methanol by rotary evaporation at 40 ℃, adding 50mL of PBS buffer solution (pH = 7.4) when a layer of uniform film is formed at the bottom and the inner wall of the eggplant-shaped bottle, hydrating the mixture by ultrasonic oscillation (240W and 40 kHz) at 37 ℃ until the film is dissolved, sequentially filtering the mixture by polycarbonate films with the pore diameters of 0.2 mu m and 0.1 mu m respectively, repeating the steps for 3 times, and freeze-drying to obtain nano-micelle freeze-dried powder for later use.
And feeding according to the mass ratio of the nano micelle freeze-dried powder to the sodium alginate of 1: 8. Dispersing sodium alginate into purified water, dissolving to obtain solution with mass volume percentage concentration of 8%, adding nanometer micelle lyophilized powder, stirring, suspending, and dripping into CaCl with mass volume percentage concentration of 10% with No. 6 syringe needle2Curing the mixture in the solution for 30min, filtering, drying at 60 ℃, soaking the pellets in a Polyethyleneimine (PEI) solution with the mass volume percentage concentration of 1.0%, crosslinking for 6h, filtering, washing with purified water, and drying at 60 ℃ to obtain the colon targeting preparation.
Example 4
Precisely weighing 1g of niflumic acid, 9g of pluronic F1271 g and D-alpha-vitamin E polyethylene glycol 1000 succinate, placing the mixture into an eggplant-shaped bottle, adding 50mL of methanol, dissolving the mixture by ultrasonic oscillation, rotationally evaporating the mixture at 40 ℃ to remove the methanol until a layer of uniform film is formed at the bottom and the inner wall of the eggplant-shaped bottle, adding 50mL of PBS (pH = 7.4) and ultrasonic (240W and 40 kHz) at 37 ℃, oscillating and hydrating the mixture until the film is dissolved, sequentially and respectively filtering the mixture by polycarbonate films with the pore diameters of 0.2 mu m and 0.1 mu m, repeating the steps for 3 times, and freeze-drying the mixture for later use.
And feeding according to the mass ratio of the nano micelle freeze-dried powder to the low-ester pectin of 1: 8. Dispersing sodium alginate into purified water, dissolving to obtain solution with mass volume percentage concentration of 8%, adding nanometer micelle lyophilized powder, stirring, suspending, and dripping into CaCl with mass volume percentage concentration of 10% with No. 6 syringe needle2Curing the mixture in the solution for 30min, filtering, drying at 60 ℃, soaking the pellets in a Polyethyleneimine (PEI) solution with the mass volume percentage concentration of 1.0%, crosslinking for 6h, filtering, washing with purified water, and drying at 60 ℃ to obtain the colon targeting preparation.
Example 5
Preparing the drug-containing pellets by the method for preparing the drug-containing pellets in the embodiment, and filling the drug-containing pellets into capsule shells, wherein the filling specification is that each capsule contains 10-50 mg of niflumic acid, thus obtaining the capsule of the colon-targeted preparation.
Example 6
Taking a proper amount of the niflumic acid nano micelle obtained in the example 1, diluting the niflumic acid nano micelle by 10 times with purified water, uniformly mixing, and filtering by a microporous filter membrane of 0.22 mu m. The particle size and Zeta potential of the micelles were determined using a laser particle sizer. For each sample, 20 cycle times were measured, and the measurement temperature was set to 25 ℃. The experimental result shows that the average particle size of the niflumic acid nano micelle is (25.8 +/-0.6) nm, the Zeta potential is (-18.73 +/-0.23) mV, the polydispersity is 0.25, and the dispersity is good. As shown in fig. 1A, the nano-micelle has a small particle size and a narrow distribution.
Taking a proper amount of niflumic acid nano micelle, diluting with purified water, filtering by a 0.22-micron microporous filter membrane, floating a copper net coated with a carbon film on the nano micelle solution, taking out the copper net after 1-2 min, and sucking excess liquid from the edge of the copper net by using filter paper. And (3) floating the copper net with the captured nano micelle particles on 1% uranyl acetate dye liquor for about 1 min, taking out, and absorbing the redundant liquid by using filter paper in the same way. After standing overnight at room temperature, the air-dried copper mesh was placed in a transmission electron microscope and the external morphology of the nanomicelle was observed at an accelerating voltage of 160 kV. As shown in FIG. 1B, the nano-micelles are spherical, have round appearance and uniform particle size of about 20-30 nm, and have the particle size consistent with the result measured by a laser particle sizer.
Example 7
100 pellets obtained in example 1 were randomly collected, placed on a slide in a batch manner, and subjected to magnification imaging using a Motic digital microscope, followed by measurement of particle size one by one (scale corrected) using Motic image plus 2.0 image analysis software, and an average value was calculated using Excel 2003 software. After fitting of the lognormal distribution, D90, D50 and D10 are obtained. The span SD = (D90-D10)/D50 is calculated. The average particle size of the pellets is calculated to be 1.33 +/-0.14 mm, and the span is 0.26.
Spraying gold powder on the dried pellets, adhering the pellets on a sample table by using conductive adhesive, and observing the physical and morphological characteristics of the pellets by using a scanning electron microscope. The results are shown in FIG. 2, where the pellet was relatively round and had a rough surface texture, forming a hydrophobic layer of PEI.
Example 8
Weighing a proper amount of the sample obtained in example 1, suspending the sample in a test tube filled with artificial gastric juice (pH =1.2, preheated to 37 ℃ +/-0.2 ℃), and placing the test tube in a constant temperature water bath oscillation box (37 ℃ +/-0.2 ℃) for oscillation (100 r.min < -1 >) for 2 h; then, the medium was replaced with an artificial small intestine solution (prepared according to the "chinese pharmacopoeia" 2015 edition, pH = 6.8) and an artificial colon solution containing 2% pectinase (prepared according to the "chinese pharmacopoeia" 2015 edition, pH =6 adjusted with hydrochloric acid), and the mixture was shaken for 3 h. Taking out the pellets from the test tube every 1h, sucking off excessive water on the surfaces of the pellets by using filter paper, weighing, and calculating the erosion rate of the pellets. The result is shown in fig. 3, the process of water absorption and expansion of the pellet in the artificial gastric juice is slow, the pellet swells to the maximum degree in the artificial intestinal juice for 3 hours, but the appearance of the pellet is kept complete, and no obvious corrosion phenomenon occurs; in the artificial colon liquid containing pectinase, the erosion rate is gradually reduced, and the micro-pill has an erosion phenomenon, which prompts that the niflumic acid nano-micelle starts to release from the micro-pill.
Example 9
Weighing an appropriate amount of the sample obtained in example 1, suspending the sample in a test tube filled with artificial gastric juice (pH =1.2, preheated to 37 ℃ +/-0.2 ℃), and placing the test tube in a constant temperature water bath oscillation box (37 ℃ +/-0.2 ℃) for oscillation (100 rpm) for 2 h; then, the medium was replaced with an artificial small intestine solution (pH = 6.8) and an artificial colon solution (pH = 6) containing pectinase at a mass-volume percentage concentration of 2%, and the mixture was shaken for 3 hours. Sampling is carried out periodically during the period, and in-vitro dissolution experiments are carried out. The results are shown in FIG. 4A. As shown in the figure, the niflumic acid colon-targeted pellet slowly releases the drug in 2h of artificial gastric juice and 3h of artificial intestinal juice, and the cumulative release amount is lower than 30%; in the colonic fluid containing pectinase, the release is accelerated after the pellets swell, and the release is complete after 2 hours, which shows that the pellets have colon targeting effect.
The niflumic acid nanomicelle with the known content in example 1 was mixed with 2 mL of PBS solution (pH = 7.4) and put into a dialysis bag which had been treated in advance, and the dialysis bag was put into 100 mL of artificial colon fluid (not containing pectinase, prepared according to chinese pharmacopoeia 2015 edition, pH = 7.4) and oscillated in a constant temperature water bath at (37.0 ± 0.2) ° c (100 r · min)-1) 1 mL of the release medium was sampled periodically and supplemented with the same amount of release medium. The rest were processed as above to plot the release profile, the result is shown in fig. 4B. As shown in the figure, the niflumic acid nano micelle only releases about 15% of the drug in the first 2h in an accumulated manner, then the release is accelerated, the release reaches about 90% in 8h, and the release is complete in 12 h.
Barium sulfate is used for replacing a medicament to prepare a colon-targeted preparation, five times of in-vivo tracking experiments are carried out, and X-ray examination shows that the results of shooting and recording show that: after the preparation is taken, the disintegration part of three barium sulfate tracer capsules taken by three persons is the tail part of ileum, and three capsules taken by two persons are totally disintegrated in ileocecal part without disintegration in transverse colon.
Example 10
Taking 10mg of the niflumic acid nano micelle in example 1 and placing the nano micelle in a container containing 0.1 mg-1Eosinophil cationic protein and transferrin in PBS solution, shaking in water bath at 37 deg.C (100 r.min)-1) Respectively sampling at 30, 60, 90 and 180min, and processing at 10000 r.min-1Centrifuging for 30min, collecting appropriate amount of supernatant, treating with methanol, detecting by HPLC sample injection, and calculating adhesion rate. The result is shown in FIG. 5, the adhesion rate of the niflumic acid nano micelle gradually increases with time, the highest value reaches 94.5%, and the result shows that the micelle and the nano micelle are adhered togetherThe cationic protein has good adhesion effect.
Example 11
A newborn SD rat is selected, 60 mmHg colorectal dilatation stimulation is given once every day within 8-14 days after birth, a chronic visceral pain model is established, and a control rat does not perform colorectal dilatation and is the same as a model rat under other conditions. Experimental groups were performed as follows: a control group, a control blank group, a control niflumic acid group, a model blank control group, a model niflumic acid preparation low dose group, a model niflumic acid preparation medium dose group and a model niflumic acid preparation high dose group. Rats were given gastrointestinal administration starting on day 28 and following 14 consecutive days of administration of the niflumic acid targeting formulation, sensitivity to intestinal pain was assessed by discharging the abdominal oblique muscles; furthermore, the change of field potential LTP (long-term potential) in the CAl region of the hippocampus of the young mouse with chronic visceral pain is observed by adopting an in vitro brain slice field potential recording method.
The results show that the extraabdominal oblique muscle discharge of the model young mouse is obviously enhanced, and the extraabdominal oblique muscle discharge amplitude is obviously reduced under the CRD pressure of 40 mmHg and 60 mmHg when the low-dose, medium-dose and high-dose groups of the niflumic acid targeting preparation are given compared with the model group of rats; recording field potential LTP in the cai region of the hippocampus ex vivo showed that the peak value of model pups was significantly increased (P <0.05) compared to normal pups, and the peak value of field potential LTP in hippocampus of model pups was significantly decreased by the niflumic acid preparation. The colon-targeted preparation of niflumic acid is proved to have the functions of treating pain caused by visceral hypersensitivity and inhibiting visceral hyperalgesia of a model mouse.
Claims (5)
1. A colon-targeted niflumic acid preparation for treating irritable bowel syndrome is prepared by a two-step method, namely, coating niflumic acid in a high polymer material to form niflumic acid nano micelles, coating the niflumic acid nano micelles in a pellet high polymer material by an orifice-solidification method to obtain a drug-loaded pellet core, soaking the drug-loaded pellet core in a polyethyleneimine aqueous solution, soaking, filtering and drying to obtain the colon-targeted niflumic acid preparation, and is characterized in that:
1) the niflumic acid nano micelle is prepared by the following method: according to the weight ratio of the input amount of the niflumic acid to the input amount of the high polymer material as 1: 20-1: 1, putting niflumic acid and a high polymer material into a container, adding a proper amount of methanol into the container to dissolve the niflumic acid and the high polymer material into the methanol, wherein the mass volume percentage concentration of a high polymer solution prepared by dissolving the high polymer material into the methanol is 2-20%; the method comprises the following steps of removing methanol to enable a mixture of niflumic acid and a high polymer material to form a film on the inner wall of a container, wherein the high polymer material is one or two of pluronic F127 and polyethylene glycol 1000 vitamin E succinate; adding PBS buffer solution with pH =7.4 into the container, hydrating the film formed on the inner wall of the container, oscillating and hydrating the film at 37 ℃ by ultrasonic waves until the film is dissolved, sequentially and respectively filtering the film by polycarbonate films with the pore diameters of 0.2 mu m and 0.1 mu m, repeating the steps for 3 times, and freeze-drying the film to form freeze-dried powder, namely the niflumic acid nano micelle;
2) the drug-loaded pill core is prepared by the following method: dissolving a pellet high polymer material with a formula amount in water to prepare a high polymer solution with a certain concentration, and uniformly suspending the niflumic acid nano micelle prepared in the step 1) of the formula amount in the high polymer solution to form a suspension, wherein the pellet high polymer material is formed by mixing one or more than two of low-ester pectin, sodium alginate, chitosan and ethyl cellulose; dripping the suspension into calcium chloride aqueous solution in a drop shape, solidifying, filtering and drying to obtain the drug-loaded pill core.
2. The colon targeted formulation of niflumic acid for treating irritable bowel syndrome according to claim 1, wherein: the diameter of the drug-loaded pill core is 0.5-1.5 mm.
3. The method for preparing a colon targeted niflumic acid preparation for treating irritable bowel syndrome according to claim 1 or 2, comprising the steps of:
1) according to the weight ratio of the input amount of the niflumic acid to the input amount of the high polymer material as 1: 20-1: 1, putting niflumic acid and a high polymer material into a container, adding a proper amount of methanol into the container to dissolve the niflumic acid and the high polymer material into the methanol, wherein the mass volume percentage concentration of a high polymer solution prepared by dissolving the high polymer material into the methanol is 2-20%; the method comprises the following steps of removing methanol to enable a mixture of niflumic acid and a high polymer material to form a film on the inner wall of a container, wherein the high polymer material is one or two of pluronic F127 and polyethylene glycol 1000 vitamin E succinate; adding PBS buffer solution with pH =7.4 into the container, hydrating the film formed on the inner wall of the container, oscillating and hydrating the film at 37 ℃ by ultrasonic waves until the film is dissolved, sequentially and respectively filtering the film by polycarbonate films with the pore diameters of 0.2 mu m and 0.1 mu m, repeating the steps for 3 times, and freeze-drying the film to form freeze-dried powder, namely the niflumic acid nano micelle;
2) dissolving a pellet high polymer material with a formula amount in water to prepare a high polymer solution with a certain concentration, and uniformly suspending the niflumic acid nano micelle prepared in the step 1) of the formula amount in the high polymer solution to form a suspension, wherein the pellet high polymer material is formed by mixing one or more than two of low-ester pectin, sodium alginate, chitosan and ethyl cellulose; dripping the suspension into calcium chloride aqueous solution in a drop shape, solidifying, filtering and drying to obtain a drug-loaded pill core;
3) and (3) taking the drug-loaded pill core, immersing the drug-loaded pill core in a polyethyleneimine water solution, and carrying out soaking, filtering and drying to obtain the niflumic acid colon-targeted preparation.
4. The method for preparing a colon targeted niflumic acid preparation for treating irritable bowel syndrome according to claim 3, wherein: the material feeding amount of the niflumic acid nano micelle and the micro-pill high polymer material is 1: 20-1: 1; the mass volume percentage concentration of the polymer solution prepared by dissolving the pellet polymer material in water is 5-15%.
5. The method for preparing a colon targeted niflumic acid preparation for treating irritable bowel syndrome according to claim 4, wherein: the material feeding amount of the niflumic acid nano micelle and the micro-pill high polymer material is 1: 10; the mass volume percentage concentration of the polymer solution is 8%.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102764426A (en) * | 2012-07-30 | 2012-11-07 | 福建卫生职业技术学院 | Scorpion venom protein polypeptide colon-targeted preparation and preparation method thereof |
| CN103070866A (en) * | 2012-11-27 | 2013-05-01 | 福建医科大学 | Application of niflumic acid in preparation of inhibition medicines for preparing chronic visceralgia |
| EP2977043A2 (en) * | 2003-08-25 | 2016-01-27 | Foamix Pharmaceuticals Ltd. | Penetrating pharmaceutical foam |
| CN105722993A (en) * | 2011-12-01 | 2016-06-29 | 俄亥俄州国家创新基金会 | Materials and methods related to NSAID chemoprevention in colorectal cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2977043A2 (en) * | 2003-08-25 | 2016-01-27 | Foamix Pharmaceuticals Ltd. | Penetrating pharmaceutical foam |
| CN105722993A (en) * | 2011-12-01 | 2016-06-29 | 俄亥俄州国家创新基金会 | Materials and methods related to NSAID chemoprevention in colorectal cancer |
| CN102764426A (en) * | 2012-07-30 | 2012-11-07 | 福建卫生职业技术学院 | Scorpion venom protein polypeptide colon-targeted preparation and preparation method thereof |
| CN103070866A (en) * | 2012-11-27 | 2013-05-01 | 福建医科大学 | Application of niflumic acid in preparation of inhibition medicines for preparing chronic visceralgia |
Non-Patent Citations (1)
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| Regulatory volume increase after secretory volume decrease in colonic epithelial cells under muscarinic stimulation;Ken-ichi Manabe等;《Pflügers Archiv - European Journal of Physiology》;20041231;第448卷(第6期);第596-604页 * |
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