CN114177133A - Drug sustained-release carrier, sustained-release drug composition and application thereof - Google Patents

Abstract

The invention provides a drug sustained-release carrier, a sustained-release drug composition and application thereof, wherein the drug sustained-release carrier comprises gel loaded with a first drug and electrostatic spinning loaded with a second drug; the sustained-release pharmaceutical composition comprises a first drug, a second drug and a drug sustained-release carrier, wherein the first drug is selected from local anesthetics, and the second drug is selected from anti-inflammatory analgesics.

Description

Drug sustained-release carrier, sustained-release drug composition and application thereof

Technical Field

The invention belongs to the field of medicines, and relates to a drug sustained-release carrier, a sustained-release drug composition and application thereof.

Background

Pain is an unpleasant sensation produced when the body is subjected to an external noxious stimulus, often mixed with other sensations, with a strong emotional response, which is a complex subjective sensation (Gordon D B, De Leon-casola O A, Wu C L, et al. research Gaps in Practice Guidelines for the use of acid Positive Pain Management in additives: fields From a Review of the experience for the use of an American fashion Clinical Practice Guidelines [ J ] Journal of a Panel, 2016,17(2): 158-. Clinically, pain is usually accompanied by symptoms of tissue damage, hyperalgesia and inflammation, and patients not only suffer from great mental problems, but also cause dysfunction of the body's immune system to induce complications, and even endanger the life of the patients.

Pain can be classified into acute pain and chronic pain in terms of the length of the disease course. Acute pain, which is a short duration of pain, mostly due to an external stimulus or injury to the body, is a more spontaneous warning signal from the body, and is reflected in a transient pain manifestation beyond the physiological tolerance. However, in clinic, many patients or doctors do not pay attention to the generation of acute pain, and often miss the best treatment opportunity to cause a series of complications, even develop chronic pain, namely, the phenomenon that the pain persists after the healing period of the wound part. Chronic pain can usually last for more than one to six months, with recurrent episodes of loss of appetite, sleep disturbance, mental depression, etc., with severe consequences for quality of life (Roger C, Turner J A, Devine E B, et al. the efficacy and costs of long-term ocular therapy for a viral disease: a systemic review for a national institutes of health care to depression of the disease [ J ]. Annals of Internal Medicine 2015 (162): 276-. In addition, because the mechanism of chronic pain is complex, the focus of source disease is extremely difficult to determine, and for chronic pain such as neuropathic pain, advanced cancer pain and the like, the chronic pain is often difficult to cure clinically, and even the existing pain treatment control is not good.

For post-operative acute pain management, the clinically desirable duration of analgesia is several days or even a week to achieve adequate analgesia in the post-operative acute phase. However, the duration of single use of the existing analgesic drugs is only 12 hours at most, and the clinical requirement is difficult to achieve. Thus, analgesia is typically prolonged by frequent repeat dosing, catheterization of a continuous pump, self-controlled analgesia (PCA), or neuro-destructive surgery. However, excessive administration times not only bring great inconvenience to patients, especially patients with needle fear, but also lead to drug accumulation, and cause adverse reactions such as cardiovascular toxicity, central system toxicity and the like. In addition, catheter implantation or self-controlled analgesia pumps require expensive equipment and continuous monitoring, and prolonged catheter retention can also be prone to a series of complications such as catheter occlusion, catheter breakage, infection, etc. Therefore, in order to solve the current clinical use condition and requirement of analgesics, the development of a sustained release preparation with a long-lasting analgesic effect is a problem to be solved.

Sustained release formulations are an important direction in the research and development of the pharmaceutical industry at home and abroad, and achieve the aims of reducing the administration frequency and dosage, maintaining the Drug concentration constant in vivo and prolonging the treatment effect by delaying the release rate of the Drug (Samir M, Burke P A, Robert L. converting the concentrations of drugs in administration biological drugs: formation and delivery strategies [ J ]. Nature Reviews Drug Discovery,2014,13(9):655 672.). The traditional sustained-release analgesic preparation is usually only carried with one analgesic drug, and the sustained-release duration is limited, so that the analgesic effect is difficult to further improve. Meanwhile, in consideration of the phenomenon of change of pain generation mechanism, if a sustained-release analgesic preparation carrying two analgesic drugs with different mechanisms at the same time can be developed, and drugs (such as local anesthetic for inhibiting pain stimulation transmission in early stage and NSAIDs for inhibiting peripheral and central inflammatory reactions in middle stage) with corresponding analgesic mechanisms can be released in compliance with the change of the pain generation mechanism, the long-acting analgesia can be realized, and simultaneously the multi-mode analgesic principle can be further satisfied, and the analgesic efficacy can be improved.

Disclosure of Invention

In order to make up for the deficiencies of the prior art and the application effects, the invention aims to provide a sustained-release pharmaceutical composition and a system of multiple active ingredients.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect of the invention there is provided a drug delivery vehicle/system comprising a gel loaded with a first drug, and electrospun loaded with a second drug.

Further, the gel is a temperature sensitive gel.

Furthermore, the temperature-sensitive gel is prepared by dissolving the copolymer in a buffer solution.

Further, the copolymer is selected from one or more of polyethylene oxide (PEO), pectin, CHT-PEGDMA-MAA (chitosan-polyethylene glycol dimethacrylate-methacrylic acid) copolymer particles, polyethylene glycol dimethacrylate (PEGDMA), hydroxypropyl methylcellulose (HPMC), gellan gum, gelatin, polymethacrylic acid-co-ethyl acrylate (Eudragit), chitosan, Polydimethylsiloxane (PDMS), xanthan gum, poloxamer 407, polyacrylic acid (PAA), alginate, poly N-isopropylacrylamide, polyphosphazene, polylactic acid PLA, polylactic acid-glycolic acid copolymer PLGA, PLA derivatives.

Further, the copolymer is selected from PLGA, PLA derivatives.

Further, the PLGA and PLA derivatives comprise PEG-PLGA, PEG-PLA, PEI-PLGA, PEI-PLA and PLGA-PEG-PLGA.

Further, the PLGA and PLA derivatives are PLGA-PEG-PLGA.

Further, the buffer is a phosphate buffer.

Further, the electrospinning is prepared from a polymer.

Further, the polymer is selected from one or more of polyethylene oxide (PEO), pectin, CHT-PEGDMA-MAA (chitosan-polyethylene glycol dimethacrylate-methacrylic acid) copolymer particles, polyethylene glycol dimethacrylate (PEGDMA), hydroxypropyl methylcellulose (HPMC), gellan gum, gelatin, polymethacrylic acid-co-ethyl acrylate, chitosan, Polydimethylsiloxane (PDMS), xanthan gum, poloxamer 407, polyacrylic acid (PAA), alginate, poly N-isopropylacrylamide, polyphosphazene, polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), PLGA, and PLA derivatives.

Further, the polymer is PLGA.

In a second aspect, the present invention provides a sustained release pharmaceutical composition comprising a first drug, a second drug and a sustained release carrier/system according to the first aspect of the present invention.

Further, the first medicament is a local anesthetic.

Further, the local anesthetic is selected from amide anesthetics.

Further, the amide anesthetic is selected from lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pyrrolocaine, articaine and/or prilocaine.

Further, the amide anesthetic is bupivacaine.

Further, the bupivacaine is bupivacaine hydrochloride.

Further, the weight volume ratio of the first medicament to the gel solution is 0.5-1.5%.

Further, the weight to volume ratio of the first drug to the gel solution was 1%.

Further, the second medicament is an anti-inflammatory analgesic.

Further, the anti-inflammatory analgesic is selected from non-steroidal anti-inflammatory drugs.

Further, the non-steroidal anti-inflammatory drug is selected from aspirin, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamic acid, meclofenamate sodium, flufenamic acid, tolmetin, ketorolac, diclofenac sodium, ibuprofen, naproxen sodium, fenoprofen, ketoprofen, flurbiprofen, oxaprozin oxamate, piroxicam, meloxicam, ampiroxicam, droxicam, lornoxicam, cinnoxicam, sudoxicam, and/or tenoxicam.

Further, the non-steroidal anti-inflammatory drug is acetaminophen.

Further, the mass ratio of the second drug to the PLGA is 50%.

In a third aspect, the present invention provides a process for preparing a sustained-release pharmaceutical composition according to the second aspect of the present invention, which comprises mixing the second drug-loaded gel solution with the second drug-loaded gel solution by electrospinning.

Further, the preparation method further comprises the step of stirring at low temperature to form a suspension.

Further, the preparation method further comprises stirring at 37 ℃ to form a gel.

Further, the mass-to-volume ratio of the electrospun fiber to the gel solution was 4%.

Further, the preparation method of the first drug-loaded gel comprises the following steps:

1) dissolving a first drug in a buffer;

2) the copolymer is dissolved in a buffer containing the drug at low temperature.

Further, the copolymer in 2) is dissolved in a buffer solution according to a mass volume ratio of 15-25%.

Further, the copolymer in 2) is dissolved in the buffer solution according to the mass volume ratio of 18-22%.

Further, 2) the copolymer was dissolved in a buffer at a mass volume ratio of 20%.

Further, the ambient temperature for 2) dissolution is 22-24 ℃.

Further, the preparation method of the second drug-loaded electrospinning comprises the following steps:

dissolving a second medicament in a polymer solution for preparing electrostatic spinning to prepare a spinning solution;

the electrostatic spinning of the loaded drug is prepared by adopting the electrostatic spinning technology.

Further, hexafluoroisopropanol was used to dissolve the polymer.

Further, the mass-volume ratio of the polymer to the hexafluoroisopropanol is 20-40: 100.

Further, the mass-to-volume ratio of the polymer to the hexafluoroisopropanol is 25-35: 100.

Further, the mass volume ratio of the polymer to hexafluoroisopropanol was 30: 100.

Further, electrostatic spinning parameter setting: the injection speed is 0.05mm/min, the rotating speed of the receiver is adjusted to 10-200r/min, the electric field is kept at about 1kV/cm, the environmental temperature is 20-30 ℃, and the humidity is 30-40%.

A fourth aspect of the invention provides the use of any one of:

1) the use of a sustained release carrier/system according to the first aspect of the invention in the preparation of a sustained release medicament of a plurality of active ingredients;

2) the use of a pharmaceutical sustained release composition according to the second aspect of the invention in the manufacture of a medicament for the treatment of a disease;

3) the use of the process according to the third aspect of the invention for the preparation of a slow-release medicament of a plurality of active ingredients.

Further, the disease is selected from pain and inflammation.

Further, the pain is selected from acute pain and chronic pain.

Further, the pain is selected from chronic pain.

Further, the pain is postoperative chronic pain.

Further, the medicament also comprises a pharmaceutically acceptable carrier.

Further, the dosage form of the medicament comprises oral preparation, transdermal preparation, implant preparation, mucosa patch and injection.

A fifth aspect of the invention provides a pharmaceutical formulation comprising a sustained release pharmaceutical composition according to the second aspect of the invention.

Further, the pharmaceutical preparation further comprises a pharmaceutically acceptable carrier.

Further, the pharmaceutical preparation includes oral preparations, transdermal preparations, implants, mucosal patches, injections.

The invention has the advantages and beneficial effects that:

the drug sustained-release carrier can load different active ingredients, realize the sufficient release of the first drug, relieve the early small loss of the second drug in electrostatic spinning, and simultaneously realize the sufficient release of the second drug by utilizing the characteristics of long-term and later-term release of electrostatic spinning.

The sustained-release pharmaceutical composition can realize the sufficient release of different active ingredients and the sufficient degradation of a sustained-release carrier, and the release of different active ingredients has no mutual influence.

The analgesic sustained-release pharmaceutical composition disclosed by the invention is simultaneously loaded with two analgesic drugs with different mechanisms, so that the long-acting analgesic effect can be realized, the multi-mode analgesic principle can be further met, and the analgesic efficacy is improved.

Drawings

FIG. 1 is an electron micrograph of electrospinning.

FIG. 2 is an infrared spectrum of a drug, wherein 2A is an infrared spectrum of bupivacaine hydrochloride, 2B is an infrared spectrum of PLGA-PEG-PLGA, 2C is an infrared spectrum of PLGA-PEG-PLGA loaded with bupivacaine hydrochloride, 2D is an infrared spectrum of acetaminophen, 2E is an infrared spectrum of PLGA electrospinning, and 2F is an infrared spectrum of PLGA electrospinning loaded with acetaminophen;

FIG. 3 is a graph showing the results of in vitro sustained release of a drug.

Figure 4 is a graph of the mechanical pain threshold results for each group.

Detailed Description

Through extensive and intensive research, the invention firstly constructs a drug sustained-release system carrying different active ingredients, the sustained-release system can realize the full and sequential release of the different active ingredients, and the sustained-release carrier can be fully degraded, is safe and has no toxicity.

In the present invention, the term "pharmaceutically acceptable" carrier refers to a substance that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit to risk ratio, and effective for its intended use.

The term "treatment" generally refers to the route by which a beneficial or desired clinical result is obtained. For example, "treating" in various aspects refers to ameliorating, reversing, alleviating, inhibiting the progression of a disease/disorder or condition in a subject, or preventing one or more symptoms of the disease/disorder or condition in a subject.

The term "therapeutically effective amount" refers to an amount sufficient to achieve a desired result when administered to a subject (including a mammal, e.g., a human). An effective amount of a compound described herein may vary depending on factors such as the disease state, age, sex, and weight of the subject. As will be appreciated by those skilled in the art, the dosage or treatment regimen may be adjusted to provide the optimal therapeutic response.

The term "active ingredient", "active agent" or "active substance" refers to any compound having biological, chemical or physiological use, including, but not limited to: an active pharmaceutical ingredient; a drug; a naturally occurring compound; a nucleic acid compound; a peptide compound; a biological agent; nutraceutical, agricultural or nutraceutical ingredients or synthetic drugs, including addictive substances, such as opioid agonists or narcotic analgesics; hypnotic drugs; an antipsychotic agent; stimulants and antidepressants. In a particular embodiment of the invention the active ingredient is an active pharmaceutical ingredient.

The term "phosphate buffer" refers to any buffer solution containing disodium phosphate and sodium chloride. Some such buffer solutions contain potassium cations in addition to or in place of sodium cations. In any event, those skilled in the art are well aware of compatible inorganic and organic compounds (either commercially available or prepared in standard fashion in the laboratory) that can be added to these solutions, since minor modifications/additions (such as the addition of relatively small amounts of Ca) can be made as needed, as long as the ability of the solution to maintain a reasonably constant pH is not altered²⁺、Fe³⁺And/or ethylenediaminetetraacetic acid (ETDA)).

According to the present invention, the medicaments described herein are administered in the form of sustained release formulations. Other expressions such as "delayed release", "controlled release", "modified release", "delayed release" or "formulation" as understood herein have the same meaning as "sustained release formulation". Such preparations are in principle in any form which can be envisaged by the person skilled in the art, as long as sustained release is ensured, including pharmaceutical forms for oral (solid, semisolid, liquid), dermal (skin patch), sublingual, parenteral (injection), ocular (eye drops, gels or ointments) or rectal (suppository) administration.

The pharmaceutical formulations described herein can be tablets, pills, caplets, capsules, granules containing powder or granules, powders, granules, spheres, beads, pellets, liquid solutions or suspensions, emulsions, or capsules filled therewith, patches, the like, and combinations thereof.

In the present invention, "sustained-release pharmaceutical composition" and "sustained-release drug" are used interchangeably.

Local anesthetic/local anesthetic

The terms "local anesthetic," "local anesthetic," or "local anesthetic" are used interchangeably herein and encompass one or more groups of substances that cause hypoesthesia or loss of sensation in a defined area of an individual via reduction of nerve terminal excitation or inhibition of peripheral nerve conduction processes. In some embodiments, the local anesthetic is an amide anesthetic. Typical amide anesthetic structures comprise a lipophilic portion and a hydrophilic portion bonded by an amide (-NHCO-). Suitable amide anesthetics include, but are not limited to, lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pyrrolocaine, articaine, prilocaine. In the present invention, the aforementioned amide-based anesthetic is present as an active ingredient, and generally includes at least one of a base thereof, a pharmaceutically acceptable prodrug thereof, a pharmaceutically acceptable derivative thereof, a pharmaceutically acceptable complex thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymorph thereof, a pharmaceutically acceptable hydrate thereof, a pharmaceutically acceptable solvate thereof, an enantiomer thereof, and a racemate thereof. For example, bupivacaine according to the present invention includes, but is not limited to, bupivacaine, a base thereof, a pharmaceutically acceptable prodrug thereof, a pharmaceutically acceptable derivative thereof, a pharmaceutically acceptable complex thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymorph thereof, a pharmaceutically acceptable hydrate thereof, and a pharmaceutically acceptable solvate thereof.

As an alternative embodiment, the local anesthetic is bupivacaine.

In a preferred embodiment, the local anesthetic is bupivacaine hydrochloride.

Antiphlogistic and analgesic medicine

In an embodiment of the present application, the anti-inflammatory analgesic drug is loaded in electrospinning. In a preferred embodiment, the anti-inflammatory analgesic is selected from the group consisting of non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs of the present application include, but are not limited to, aspirin, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamic acid, meclofenamate sodium, flufenamic acid, tolmetin, ketorolac, diclofenac sodium, propionic acid derivatives, such as ibuprofen, naproxen sodium, fenoprofen, ketoprofen, flurbiprofen, and oxaprozin, and enolic acids, such as piroxicam, meloxicam, and other oxicams, such as ampiroxicam, droxicam, pivoxicam, lornoxicam, cinoxicam, sudoxicam, and tenoxicam. In particular, the NSAIDs in the formulations of the present application may comprise acetaminophen.

Electrostatic spinning

Electrospinning is an efficient fiber preparation process that can be used to assemble fibrous polymer films containing fiber diameters in the nanometer to micrometer range. Electrostatic processes use high voltage electric fields to inject an electric current of a certain polarity into a polymer solution/melt, accelerating the solution/melt towards a collecting surface of opposite polarity, thereby forming solid fibers. The electrospun (formed) fibrous matrix has a three-dimensional pore structure with a relatively large surface area. Good fiber formation requires optimization of solution parameters and electrospinning configuration. The controlled parameters during electrospinning affect the release pattern of the drug from the membrane matrix. In this way, the electrospun membrane matrix can be tailored to achieve a desired drug release profile. Polymers for electrospinning, such as polyaniline, polyacetylene, polypyrrole, etc., and active substance(s), solvent, and adjuvants, are mixed in the form of a solution, suspension, emulsion, or melt, and a voltage of from about 1-20kV may be applied to the polymer solution, suspension, emulsion, or melt form. The active substance can be incorporated by direct dissolution, suspension or in the form of an emulsion. Suitable solvents for preparing the electrospinning solution include water and organic and inorganic solvents. Typical adjuvants are plasticizers, surfactants and/or defoamers. Catalysts may also be used, including but not limited to acids such as hydrochloric acid, acetic acid, and formic acid.

Composition and pharmaceutically acceptable carrier

In the present invention, the composition may be in a form suitable for administration by injection, in a form suitable for oral ingestion (e.g., capsules, tablets, caplets, elixirs), in the form of an ointment, cream or lotion suitable for topical administration, in a delivery form suitable for use as eye drops, in an aerosol form suitable for administration by inhalation (e.g., by intranasal inhalation or oral inhalation), in a form suitable for parenteral administration, i.e., subcutaneous, intramuscular or intravenous injection.

For administration as an injectable solution or suspension, non-toxic parenterally acceptable diluents or carriers can include ringer's solution, isotonic saline, phosphate buffered saline, ethanol and 1, 2 propylene glycol.

Some examples of suitable carriers, diluents, excipients and adjuvants for oral use include peanut oil, liquid paraffin, sodium carboxymethylcellulose, methylcellulose, sodium alginate, gum acacia, gum tragacanth, dextrose, sucrose, sorbitol, mannitol, gelatin and lecithin. In addition, these oral dosage forms may contain suitable flavoring and coloring agents. When used in the form of a capsule, the capsule may be coated with a compound that delays disintegration, such as glyceryl monostearate or glyceryl distearate.

Adjuvants typically include lubricants, emulsifiers, thickeners, preservatives, bactericides, and buffers.

Solid dosage forms for oral administration may contain binders, sweeteners, diluents, flavoring agents, coating agents, preservatives, lubricants and/or time delay agents (timedelayagent) acceptable in human and veterinary practice. Suitable binders include acacia, gelatin, corn starch, gum tragacanth, sodium alginate, carboxymethylcellulose or polyethylene glycol. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable diluents include lactose, sorbitol, mannitol, dextrose, kaolin, cellulose, calcium carbonate, calcium silicate or dicalcium phosphate. Suitable flavoring agents include peppermint oil, oil of wintergreen, cherry, citrus or raspberry flavors. Suitable coating agents include polymers or copolymers of acrylic and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delays include glyceryl monostearate or glyceryl distearate.

Liquid dosage forms for oral administration may contain, in addition to the above-mentioned drugs, a liquid carrier. Suitable liquid carriers include water, oils such as olive oil, peanut oil (arachis oil), sesame oil, sunflower oil, safflower oil, peanut oil (arachis oil), coconut oil, liquid paraffin, ethylene glycol, propylene glycol, polyethylene glycol, ethanol, propanol, isopropanol, glycerol, fatty alcohols, triglycerides or mixtures thereof.

Suspensions for oral administration may further include dispersing and/or suspending agents. Suitable suspending agents include sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium alginate or acetyl alcohol. Suitable dispersing agents include lecithin, polyoxyethylene esters of fatty acids such as stearic acid, polyoxyethylene sorbitol mono-or di-oleate, -stearate or-laurate, polyoxyethylene sorbitan mono-or di-oleate, -stearate or-laurate and the like.

Emulsions for oral administration may further comprise one or more emulsifiers. Suitable emulsifying agents include the dispersing agents exemplified above or natural gums such as guar gum, gum arabic or gum tragacanth.

Current features of post-operative analgesia include wound infiltration with local anesthetics, combined with systemic administration of NSAIDs and opioids. Opioids have considerable drawbacks, including the time and resources required to monitor and treat the side effects associated with opioids. Clinical practice therefore expects a reduction in the use of postoperative opioids to reduce the incidence and severity of their side effects, such as respiratory depression, nausea, vomiting, constipation, lethargy, pruritis and urinary retention. Embodiments of the present application provide extended release formulations of local anesthetics and NSAIDs to the wound site, thereby reducing or even avoiding systemic opioids.

In any embodiment, the pharmaceutical formulations of the present application may be administered by bolus injection, such as subcutaneous bolus injection, intra-articular bolus injection, intramuscular bolus injection, intradermal bolus injection, and the like. In any embodiment, administration can be by infusion, such as subcutaneous infusion, intra-articular infusion, intramuscular infusion, intradermal infusion, and the like. In any embodiment, administration may be direct wound penetration by local injection into the wound margin, or instillation into the incision, or a combination thereof. The pharmaceutical formulation may also be administered by other routes of administration to treat local inflammation or pain, including but not limited to topical, ocular, intraocular, nasal, and otic delivery.

In certain embodiments, the pharmaceutical formulation optionally includes a pharmaceutically acceptable carrier. Effective injectable compositions containing these compounds may be in the form of suspensions or solutions. In the preparation of suitable formulations, it will be appreciated that in general the water solubility of the acid addition salts is greater than that of the free bases. Similarly, bases are more soluble in dilute acids or acidic solutions than neutral or basic solutions.

In solution form, the compound is dissolved in a physiologically acceptable medium. Such media include suitable solvents, isotonic agents, for example, sucrose or saline, preservatives, for example benzyl alcohol, and buffers, as desired. For example, useful solvents include water and aqueous alcohols, glycols, and carbonates, such as diethyl carbonate.

Injectable suspension compositions require a liquid suspending vehicle with or without adjuvant as the medium. The suspending vehicle may be, for example, an aqueous solution of sodium chloride, sucrose, polyvinylpyrrolidone, polyethylene glycol or a combination of the foregoing.

Suitable physiologically acceptable adjuvants are required to keep the compound suspended in the suspension composition. Adjuvants may be selected from thickening agents such as carboxymethylcellulose, polyvinylpyrrolidone, gelatin and alginates. Many surfactants can also be used as suspending agents. Lecithin, alkylphenol polyethylene oxide adducts, naphthalene sulfonates, alkylbenzene sulfonates, and polyoxyethylene sorbitan esters are useful suspending agents.

Many substances which influence the hydrophilicity, density and surface tension of the liquid suspending vehicle may help in the preparation of injectable suspensions in each case. For example, silicone antifoam, sorbitol and sugar may be useful suspending agents.

As used herein, unless otherwise specified, the "rate of release", "release rate", or "dissolution rate" of a drug refers to the amount of drug released from a dosage form per unit time, e.g., milligrams of drug released per hour (mg/hr), or the percentage of the total drug dose released per hour. The drug release rate of a dosage form is typically measured as the in vitro release rate of the drug, i.e., the amount of drug released from the dosage form per unit time as measured under appropriate conditions and in a suitable fluid. The release rates referred to herein are determined by placing the dosage form to be tested in an appropriate dissolution cell (dissolvantbath) and measuring the medium therein. Aliquots of the medium collected at predetermined time intervals are injected into a chromatographic system equipped with a suitable detector to quantify the amount of drug released during the test interval.

In the present invention, a drug-treated subject is intended to include any member of the animal kingdom, typically a mammal. The term "mammal" refers to any animal classified as a mammal, including humans, other higher primates, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cows, horses, sheep, pigs, goats, rabbits, and the like. As a preferred embodiment, the subject is a human.

The present invention is further illustrated below with reference to specific examples, which are provided only for the purpose of illustration and are not meant to limit the scope of the present invention.

The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.

Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.

EXAMPLE 1 preparation of a Complex sequential sustained Release System

1. Experimental Material

PLGA1654-PEG1500-PLGA 1654: X-PLS35, 10g, Hangzhou

PLGA: lactide Glycolide 65:35, Mw 40,000-75,000, P2066, USA

2. Preparation of temperature-sensitive gel

Adding 1% w/v bupivacaine hydrochloride into Phosphate Buffer Solution (PBS), stirring at low temperature for dissolving, dissolving PLGA-PEG-PLGA copolymer in 20% mass-volume ratio in PBS containing bupivacaine hydrochloride, standing for dissolving, and maintaining ambient temperature at 22-24 deg.C.

3. Preparation of PLGA Electrostatic spinning

Hexafluoroisopropanol was used at 30: a mass to volume ratio of 100 dissolves PLGA. Acetaminophen was added to the resulting solution so that the mass ratio of acetaminophen to PLGA was 50%. The solution obtained was filled into a syringe with a syringe needle about 10cm from the receiver. The electrostatic spinning parameters are set to be the injection speed of 0.05mm/min, the rotating speed of the receiver is adjusted to 200r/min, the needle is connected with the anode, the receiver is connected with the cathode, and the electric field is kept at about 1 kV/cm.

4. Preparation of composite sequential sustained release system/programmed sustained release

Mixing the obtained electrostatic spinning with 4% mass volume ratio in gel solution, stirring at low temperature for 24h to form homogeneous suspension, and stirring at 37 deg.C for 30min to form gel.

EXAMPLE 2 procedure testing of the Material characteristics of the sustained Release analgesic Carrier

1. Electron microscopy imaging

And (3) freeze-drying and cutting the electrostatic spinning with a certain size by using liquid nitrogen, and coating a gold conducting film on a sample by evaporation. And observing under certain voltage and magnification.

2. FTIR experiments

Weighing a certain amount of PLGA-PEG-PLGA, bupivacaine hydrochloride powder and acetaminophen powder. The test conditions were 40kV, 150mA, starting angle 5 °, ending angle 60 °, increasing at intervals of 0.02 °, and the results were expressed in 2 θ.

3. In vitro release experiment of sustained release system

Putting a certain mass of drug-loaded temperature-sensitive gel, electrostatic spinning and a gel/electrostatic spinning mixture into a dialysis bag. 1ml of PBS was filled into the dialysis bag and suspended in a centrifuge tube containing 15ml of PBS to ensure that the dialysis bag was immersed in the PBS in the centrifuge tube. The centrifuge tube was rotated at a constant speed at 37 ℃ and 60 rpm. At the specified time point, 200. mu.l PBS in the centrifuge tube was placed in an EP tube and stored in a-20 ℃ freezer. Centrifuge tubes were filled with 200. mu.l fresh PBS. The concentrations of bupivacaine hydrochloride and acetaminophen in samples at various times were measured using high performance liquid chromatography.

4. Results

The electron microscopy results showed that the electrospinning was disordered and about 2 μm in diameter (FIG. 1).

The results of FTIR experiments showed that no chemical reaction was found between the carrier and the drug, no chemical bond of each substance itself was destroyed, and no new chemical bond was formed (fig. 2).

In vitro sustained release results are shown in table 1 and fig. 3, and the release speed of the carried drug is reduced regardless of the temperature-sensitive gel coated outside or the electrostatic spinning coated outside. Avoiding early burst release of the drug while achieving longer release times. Meanwhile, the release rate of the temperature-sensitive gel coated outside is higher than that of the coated electrostatic spinning, and the sequential release of the medicines can be realized.

TABLE 1 in vitro sustained Release results

EXAMPLE 3 Experimental study of analgesic potency of the controlled Release analgesic Carrier System

1. Establishment of rat Sciatic Nerve compression Chronic pain model (Chronic constraint of the scientific Nerve, CCI)

Pentobarbital sodium is injected intraperitoneally at 60mg/kg, and after anesthesia, the right thigh hair is shaved off by an electric shaver. Then, the rat is placed on a heat preservation blanket in a prone position, a temperature probe is lightly placed from the anus, and the body temperature in the operation is set to be 37-38 ℃. The sciatic nerve was visualized by incising the skin of the rat about 1cm along the lateral side of the femur, blunt dissection of the subcutaneous tissue with bent forceps, and blunt dissection along the muscle texture of the biceps femoris muscle after reaching the muscle layer. 7mm sciatic nerves were dissociated with curved forceps, and 4-0 sutures were applied four times in order from proximal to distal. The degree of ligation is preferably such that the lower limb undergoes slight muscle contraction or movement. After ligation, the skin was sutured and sterilized.

2. Behavioral experiments on the rat CCI model

The experiment is divided into four groups, namely a CCI model group, a temperature-sensitive gel group loaded with bupivacaine hydrochloride, an electrostatic spinning group loaded with acetaminophen and a program slow-release group, wherein 6 rats in each group obtain a mechanical pain threshold base line value (0d) of the rats at 3d before operation, and the mechanical pain threshold values of the rats are tested at 1, 3, 7, 14, 21, 28 and 35d after operation. On the day of testing, rats were individually placed in a porous steel wire cage in a quiet environment for 15 min. An electronic von Frey test needle is used for vertically stimulating the skin of a 2cm area around the operation part of the rat, and the value on the recorder is recorded when the evasive reflex appears. Each rat was tested 3 times, with a 30s interval between each test. Rats with significantly reduced values of Post-operative 21d are considered to have Post-operative Chronic Pain (CPSP).

3. Detection of rat CCI model myeloglial markers Iba-1 and GFAP

After 35d postoperative rats are taken and subjected to pentobarbital sodium abdominal anesthesia, the operative spinal cords of T3-T5 segment rats are taken and subjected to immunofluorescence staining of Iba-1 and GFAP.

4. Results

The behavioral results are shown in fig. 4 and table 2, and the programmed sustained release can further prolong the action time of the drug and improve the analgesic effect on the basis of single drug sustained release.

TABLE 2 mechanical pain threshold

Point in time	CCI	Temperature-sensitive gel	Electrostatic spinning	Programmed sustained release
					0	15.8839	15.5186	15.9263	15.5813
1	10.9222	11.8240	16.5744*	14.83*
					3	6.3381	12.4919*	9.7558*	12.0389*
7	6.5383	9.1823	11.2296*	11.8922*
					14	8.8247	11.5945	10.7283	13.7828*
21	10.6081	11.1708	11.2028	13.4372
					28	12.3592	13.9153	12.1172	13.7065
35	14.3194	15.5673	13.7065	14.3767

Significant difference between each group and CCI group in mechanical pain threshold at corresponding time points

Immunofluorescent staining results are shown in tables 3 and 4, with significant differences between Iba1 and GFAP between groups, programmed slow-release group < temperature-sensitive gel group < electrospinning group < CCI group.

TABLE 3Iba1 levels

TABLE 4GFAP levels

Example 4 procedure safety experiments with sustained-release analgesic systems

1. Muscle toxicity test

The carrier material without medicine is put around the quadriceps femoris of the rat in large dose, any part or obvious lesion part of the quadriceps femoris of the rat in the experimental group and the normal rat is taken at 1, 7 and 21d after operation, fixed in 10 percent formaldehyde solution, dehydrated, embedded, sliced and subjected to H & E staining. The muscle samples were observed under 10X 20 microscope for obvious lesions (nuclear shift, lymphocyte and macrophage accumulation, etc.).

2. Neurotoxicity test

Placing a large amount of slow-release carrier around sciatic nerve of a rat, taking any part or obvious lesion part of sciatic nerve of rats in experimental groups and normal rats at 1, 7 and 21d after operation, respectively, fixing the parts or the obvious lesion part in 10% formaldehyde solution, dehydrating the obtained sample, carrying out resin embedding, carrying out semi-thin slicing, and then staining with toluidine blue. The nerve samples were observed under 10X 20 microscope for obvious lesions (demyelination, axonal loss, inflammatory cell infiltration, etc.).

3. Systematic toxicity test

Any part or obvious lesion parts of hearts, livers, spleens, lungs, kidneys and brains of rats in experimental groups and normal rats are taken at 1, 7 and 21d after operation respectively, fixed in 10% formaldehyde solution, dehydrated, embedded, sliced and subjected to H & E staining. The organ tissues were observed under 10X 10 times microscope for changes such as edema and necrosis.

4. Results

The results show that toxicity experiments show that muscle samples and nerve samples of the electrostatic spinning group, the gel group and the program slow-release group have no obvious pathological changes; the changes of edema, necrosis and the like of the heart, the liver, the spleen, the lung, the kidney and the brain of the experimental group of rats and the normal rats do not occur, which indicates that the carrier material has higher safety.

The above description of the embodiments is only intended to illustrate the method of the invention and its core idea. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications will also fall into the protection scope of the claims of the present invention.

Claims (10)

1. A drug delivery vehicle/system comprising a gel loaded with a first drug and an electrospun fiber loaded with a second drug.

2. The sustained release carrier/system of claim 1, wherein the gel is a temperature sensitive gel;

preferably, the temperature-sensitive gel is prepared by dissolving the copolymer in a buffer solution;

preferably, the copolymer is selected from one or more of polyethylene oxide (PEO), pectin, CHT-PEGDMA-MAA (chitosan-polyethylene glycol dimethacrylate-methacrylic acid) copolymer particles, polyethylene glycol dimethacrylate (PEGDMA), hydroxypropyl methylcellulose (HPMC), gellan gum, gelatin, poly (methacrylic acid) -co-ethyl ethacrylate (Eudragit), chitosan, Polydimethylsiloxane (PDMS), xanthan gum, poloxamer 407, polyacrylic acid (PAA), alginate, poly (N-isopropylacrylamide), polyphosphazene, polylactic acid PLA, polylactic-glycolic acid copolymer PLGA, PLA derivatives;

preferably, the copolymer is selected from PLGA, PLA derivatives;

preferably, the PLGA, PLA derivatives comprise PEG-PLGA, PEG-PLA, PEI-PLGA, PEI-PLA, PLGA-PEG-PLGA;

preferably, the PLGA, PLA derivative is PLGA-PEG-PLGA;

preferably, the buffer is a phosphate buffer.

3. The slow release carrier/system of claim 1, wherein the electrospun is made of a polymer;

preferably, the polymer is selected from one or more of polyethylene oxide (PEO), pectin, CHT-PEGDMA-MAA (chitosan-polyethylene glycol dimethacrylate-methacrylic acid) copolymer particles, polyethylene glycol dimethacrylate (PEGDMA), hydroxypropyl methylcellulose (HPMC), gellan gum, gelatin, polymethacrylic acid-co-ethylacrylate, chitosan, Polydimethylsiloxane (PDMS), xanthan gum, poloxamer 407, polyacrylic acid (PAA), alginate, poly N-isopropylacrylamide, polyphosphazene, polylactic acid (PLA), polylactic acid-glycolic acid copolymer (PLGA), PLGA and PLA derivatives;

preferably, the polymer is PLGA.

4. A modified release pharmaceutical composition comprising a first drug, a second drug and a modified release carrier/system according to any one of claims 1-3.

5. The extended release pharmaceutical composition of claim 4, wherein the first drug is a local anesthetic;

preferably, the local anesthetic is selected from amide anesthetics;

preferably, the amide-based anesthetic is selected from lidocaine, bupivacaine, levobupivacaine, ropivacaine, mepivacaine, pyrrolocaine, articaine and/or prilocaine;

preferably, the amide anesthetic is bupivacaine;

preferably, the amide anesthetic is bupivacaine hydrochloride;

preferably, the weight to volume ratio of the first drug to the gel solution is 0.5-1.5%;

preferably, the weight to volume ratio of the first drug to the gel solution is 1%.

6. The extended release pharmaceutical composition of claim 4, wherein the second drug is an anti-inflammatory analgesic;

preferably, the anti-inflammatory analgesic is selected from non-steroidal anti-inflammatory drugs;

preferably, the non-steroidal anti-inflammatory drug is selected from aspirin, acetaminophen, indomethacin, sulindac, etodolac, mefenamic acid, meclofenamic acid, meclofenamate sodium, flufenamic acid, tolmetin, ketorolac, diclofenac sodium, ibuprofen, naproxen sodium, fenoprofen, ketoprofen, flurbiprofen, oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, lornoxicam, cinnoxicam, sudoxicam, and/or tenoxicam;

preferably, the non-steroidal anti-inflammatory drug is acetaminophen;

preferably, the mass ratio of the second drug to the PLGA is 50%.

7. A process for the preparation of a sustained release pharmaceutical composition according to any one of claims 4 to 6, which comprises electrospinning a solution loaded with a second drug into a solution of a gel loaded with a first drug;

preferably, the preparation method further comprises low-temperature stirring to form a suspension;

preferably, the preparation method further comprises stirring at 37 ℃ to form a gel;

preferably, the mass volume ratio of the electrospinning to the gel solution is 4%.

8. The method of claim 7, wherein the first drug loaded gel is prepared by a method comprising:

1) dissolving a first drug in a buffer;

2) dissolving the copolymer in a buffer solution containing the drug at a low temperature;

preferably, the copolymer in 2) is dissolved in the buffer solution according to the mass volume ratio of 15-25%;

preferably, the copolymer is dissolved in the buffer solution according to the mass volume ratio of 18-22%;

preferably, the copolymer is dissolved in a buffer at a mass to volume ratio of 20%;

preferably, the ambient temperature of dissolution in 2) is 22-24 ℃.

9. The method of claim 7, wherein the second drug-loaded electrospinning is performed by:

dissolving a second drug in a solution for preparing an electrostatic spinning polymer to prepare a spinning solution;

preparing electrostatic spinning loaded with a medicament by adopting an electrostatic spinning technology;

preferably, hexafluoroisopropanol is used to dissolve the polymer;

preferably, the mass volume ratio of the polymer to the hexafluoroisopropanol is 20-40: 100;

preferably, the mass-to-volume ratio of polymer to hexafluoroisopropanol is 25-35: 100;

preferably, the mass volume ratio of the polymer to the hexafluoroisopropanol is 30: 100;

preferably, the electrospinning parameters set: the injection speed is 0.05mm/min, the rotating speed of the receiver is adjusted to 10-200r/min, the electric field is kept at about 1kV/cm, the environmental temperature is 20-30 ℃, and the humidity is 30-40%.

10. Use according to any one of the following:

1) use of a sustained release carrier/system according to any one of claims 1-3 for the manufacture of a sustained release medicament of a plurality of active ingredients;

2) use of a pharmaceutical sustained release composition according to any one of claims 4 to 6 in the manufacture of a medicament for the treatment of a disease;

3) use of the preparation method according to any one of claims 7 to 9 for the preparation of a slow-release medicament of a plurality of active ingredients;

preferably, the disease is selected from pain and inflammation;

preferably, the pain is selected from acute pain, chronic pain;

preferably, the pain is selected from chronic pain;

preferably, the pain is postoperative chronic pain;

preferably, the medicament further comprises the pharmaceutical formulation further comprises a pharmaceutically acceptable carrier;

preferably, the dosage form of the drug comprises oral agent, transdermal agent, implant, mucosa patch and injection.

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