CN113262302A

CN113262302A - Injectable long-acting semisolid gel preparation

Info

Publication number: CN113262302A
Application number: CN202010506479.1A
Authority: CN
Inventors: 沈惠荣
Original assignee: Huzhou Huizhong Jishi Biotechnology Co ltd
Current assignee: Huzhou Huizhong Jishi Biotechnology Co ltd
Priority date: 2020-02-17
Filing date: 2020-06-05
Publication date: 2021-08-17
Anticipated expiration: 2040-06-05
Also published as: CN113262302B

Abstract

An injectable long-acting semi-solid gel formulation is disclosed comprising a mixture comprising a triglyceride of ricinoleic acid and a gelling agent, and an active ingredient comprising loteprednol etabonate, latanoprost, celecoxib, triamcinolone acetonide or betamethasone. The pharmaceutical composition of the invention is a bioerodible semisolid carrier gel preparation, which has the advantage of sustained release of the drug without obvious burst release.

Description

Injectable long-acting semisolid gel preparation

Technical Field

The invention provides an injectable long-acting semisolid gel preparation, wherein the pharmaceutical composition comprises loteprednol etabonate, latanoprost, celecoxib, triamcinolone acetonide and/or betamethasone in a semisolid lipid carrier, and the semisolid lipid carrier comprises triglyceride of ricinoleic acid and a gelling agent.

Background

Controlled release formulations for topical administration may be used specifically for the treatment of inflammation and pain caused by disease or tissue damage. Drug delivery vehicles are generally composed of a polymeric carrier matrix through which the drug is degraded and diffused for controlled release. The active ingredient is usually embedded or encapsulated in microspheres or microparticles and can be applied in the form of an implant by injection or infusion into the surgical cavity.

Researchers have done a great deal of research to synthesize hydrolysis-resistant lactic acid-castor oil copolymers for sustained release formulations of bupivacaine. Sokolsky-Papkov in 2009; pharma Res, 3: 7-10 and 2010, J Pharma Sci, 99: 2732-38, a single injection of the formulation is reported to result in a motor block for 64 hours and a sensory block for 96 hours. However, there is a significant burst of this formulation, resulting in systemic toxicity. Increasing bupivacaine concentration to 15% showed less burst release than 10% bupivacaine.

Larsen at 2008;drug Develop industry Pharm, 34: 297-304 discloses the results of measuring the release rate of bupivacaine from various oils. Larsen discloses the application of in vitro tests under non-sink conditions (rotating dialysis membrane devices) to simulate drug release following intra-articular injection into the joint cavity. Larsen showed bupivacaine in fractionated coconut oil (with C)₈And C₁₀A mixture of saturated fatty acids) released 80% in less than two hours.

Castor oil has been used as a commercial pharmaceutical product

A solvent for testosterone dodecanoate injection for testosterone replacement therapy by intramuscular (gluteal muscle) administration. O' Hanlon, 2013, Lancet, special issue 1(S14), the U.S. Food and Drug Administration (FDA) found that care had to be taken to avoid intravascular injections because of

Inadvertent entry into the vascular system may lead to vascular occlusion and pulmonary oil microembolism POME short-term consequences, primarily manifested as cough, but sometimes with other associated symptoms. Mechanical obstruction of the pulmonary vasculature from POME can cause acute transient pulmonary hypertension, leading to a variety of symptoms, ranging from mild cough to circulatory failure.

While the above systems are of value, they are complicated and expensive to manufacture. In addition, these products have a large amount of drug released (also called "burst") in the initial period after injection, and the kinetics of drug release are also poor and the reproducibility is poor. There remains a need for a more effective sustained release medium to effectively release drugs locally and to extend the drug release time by one week or more.

Disclosure of Invention

One aspect of the present invention provides a pharmaceutical composition comprising:

(A) a glyceride mixture comprising:

(i) ricinoleic acid triglyceride; and

(ii) glycerides having a melting point between 37 ℃ and 100 ℃ as gelling agent;

wherein the ratio of (i) to (ii) is 50:1 to 2:1 (w/w); and

(B) a therapeutically effective amount of an active ingredient selected from loteprednol etabonate, latanoprost, celecoxib, triamcinolone acetonide and betamethasone or a pharmaceutically acceptable salt thereof.

In one or more embodiments, the active ingredient is present in an amount of 0.01 to 60% by weight, based on the total weight of the pharmaceutical composition.

In one or more embodiments, the glycerides having a melting point between 37 ℃ and 100 ℃ are selected from the following glycerides: (a) c₁₂To C₁₈A mixture of fatty acid triglycerides; (b) c₈To C₁₈A mixture of triglycerides; (c) mixtures of hydrogenated coconut glycerides; and (d) C₁₀To C₁₈A mixture of fatty acid triglycerides.

In one or more embodiments, the C₁₂To C₁₈The mixture of fatty acid triglycerides is SUP DM or SUP CM.

In one or more embodiments, the C₈To C₁₈The mixture of triglycerides is G43/01.

In one or more embodiments, the mixture of hydrogenated cocoglycerides is WIT E85 or WIT E76.

In one or more embodiments, the C₁₀To C₁₈The mixture of fatty acid triglycerides is SUP D.

In one or more embodiments, the active ingredient further comprises one or more of a corticosteroid, an analgesic or an anti-inflammatory agent.

In one or more embodiments, the pharmaceutical composition is a semi-solid gel.

In one or more embodiments, the pharmaceutical composition is biocompatible, bioerodible, and homogeneous.

In one or more embodiments, the semi-solid gel has a viscosity of 50 to 700cPS at 30 ℃.

In one or more embodiments, less than 80% of the active ingredient is released from the semi-solid gel in less than one week when tested in vitro at 37 ℃.

In one or more embodiments, the corticosteroid is a glucocorticoid.

In one or more embodiments, the anti-inflammatory agent is a non-steroidal anti-inflammatory agent (NSAID) selected from the group consisting of ketoprofen, naproxen, meloxicam, COX-1 inhibitors, and COX-2 inhibitors.

In one or more embodiments, the weight ratio of the ricinoleic acid triglyceride to the glyceride having a melting point between 37 ℃ and 75 ℃ is 8: 1 to 2.5: 1, preferably 6: 1 to 3: 1 (w/w).

In one or more embodiments, 80% of the active ingredient is released from the semi-solid gel within 1 to 16 weeks when tested in vitro at 37 ℃.

In one or more embodiments, the semi-solid gel has a viscosity of 200 to 400cPs at 30 ℃.

In one or more embodiments, the pharmaceutical composition releases the active ingredient for at least one week when tested in vitro at 37 ℃.

In one or more embodiments, the pharmaceutical composition releases the active ingredient for more than 4 weeks when tested in vitro at 37 ℃.

In one or more embodiments, the glyceride mixture has an aqueous solubility of less than 1mg/ml, preferably at or less than 0.1mg/ml, in a physiological pH buffer at 37 ℃.

In one or more embodiments, the ricinoleic acid triglyceride comprises castor oil, the glyceride having a melting point between 37 ℃ and 75 ℃ comprises SUP DM or SUP CM; wherein, the weight ratio of the castor oil to the SUP DM or the SUP CM is 6: 1 to 3: 1 (w: w) and the aqueous solubility of the glyceride mixture is less than 1mg/ml, preferably less than 0.1mg/ml, in a physiological PH buffer at 37 ℃. Preferably, the pharmaceutical composition releases the active ingredient for at least more than one week, preferably at least more than two weeks, when tested in vitro at 37 ℃.

In another aspect of the invention, there is provided a pharmaceutical formulation comprising:

(A) a glyceride mixture comprising:

(i) ricinoleic acid triglyceride; and

(ii) a glyceride selected from: (a) c₁₂To C₁₈Mixture of triglycerides (SUP DM or SUP CM), (b) C₈To C₁₈A mixture of triglycerides (G43/01), (c) a mixture of hydrogenated cocoglycerides (WIT E85 or WIT E76); and (d) C₁₀To C₁₈Mixture of triglycerides (SUP D); or other solid glycerides having a melting point between 37 ℃ and 75 ℃;

wherein the ratio (i) to (ii) is from 50:1 to 2:1 (w/w); and

(B) selecting an active ingredient selected from loteprednol etabonate, latanoprost, celecoxib, triamcinolone acetonide and betamethasone or a pharmaceutically acceptable salt thereof, and a corticosteroid, an analgesic or an anti-inflammatory agent which may be a second choice;

wherein the active ingredient is dissolved in the glyceride mixture at a concentration of 0.01 to 60% by weight; and wherein the pharmaceutical composition is a biocompatible, bioerodible, and homogeneous semi-solid gel; and wherein the pharmaceutical composition consists of a semi-solid gel having a viscosity of 50 to 700cPs at 30 ℃. Wherein less than 80% of the active ingredient is released from the depot of the semi-solid gel within one week when tested in vitro at 37 ℃.

In one or more embodiments, the glyceride mixture comprises C₁₂To C₁₈Mixture of triglycerides (SUP DM or SUP CM).

In one or more embodiments, the glyceride mixture comprises a ratio of ricinoleic acid triglycerides to gelling agent at a relative concentration of 8: 1 to 2.5: 1 (w: w).

In one or more embodiments, less than 50% of the active ingredient is released from the reservoir of the semi-solid gel within one week when tested in vitro at 37 ℃.

In one or more embodiments, less than 60% of the active ingredient is released from the depot of the semi-solid gel within one week when tested in vitro at 37 ℃.

In one or more embodiments, the pharmaceutical composition releases the active ingredient for at least two weeks when tested in vitro at 37 ℃.

In one or more embodiments, the pharmaceutical composition releases the active ingredient for at least one month when tested in vitro at 37 ℃.

In one or more embodiments, the glyceride mixture has a viscosity of 200 to 400cPs (30 ℃) at 37 ℃.

In one or more embodiments, the glyceride mixture has an aqueous solubility of less than 1mg/ml in a physiological pH buffer at 37 ℃.

In one or more embodiments, the ricinoleic acid triglyceride is castor oil.

In one or more embodiments, the glyceride mixture comprises castor oil in a relative concentration of 6: 1 to 3: 1 (w: w): (SUP DM or SUP CM).

In one or more embodiments, the pharmaceutical formulation comprises a therapeutically effective amount of celecoxib, triamcinolone acetonide or betamethasone for the treatment of pain and inflammation. In a preferred embodiment, the pharmaceutical compositions of the present invention containing celecoxib can be used to treat various types of symptoms of arthritic pain, including osteoarthritis and Familial Adenomatous Polyposis (FAP), to reduce colon precancerous polyps. In a preferred embodiment, the pharmaceutical composition of the present invention containing triamcinolone acetonide can be used for treating various inflammatory conditions of the body such as allergic rhinitis and acute exacerbation of multiple sclerosis. In a preferred embodiment, osteoarthritis, as well as chronic inflammation and pain associated with knee osteoarthritis, can be treated using the pharmaceutical compositions of the present invention comprising betamethasone.

In one or more embodiments, the pharmaceutical formulation comprises loteprednol etabonate or latanoprost in a therapeutically effective amount for treating an ophthalmic disease. In preferred embodiments, the ophthalmic diseases include ocular inflammation and pain, such as allergy-induced ocular inflammation, chronic keratitis (e.g., adenovirus or Thygeson's keratitis), vernal keratoconjunctivitis and episcleritis, and glaucoma or ocular hypertension, among others. In one or more embodiments, the pharmaceutical formulation comprises loteprednol etabonate in a therapeutically effective amount for the treatment of tonsillitis.

In one or more embodiments, the pharmaceutical formulation comprises a second class of glucocorticoid, analgesic, or anti-inflammatory agent.

In one or more embodiments, the pharmaceutical formulation is preservative-free.

In one or more embodiments, the drug is composed of castor oil, C₁₂To C₁₈A mixture of triglycerides (SUP DM or SUP CM) and a therapeutically effective amount of an active ingredient selected from loteprednol etabonate, latanoprost, celecoxib, triamcinolone acetonide and betamethasone. Wherein the pharmaceutical composition is a biocompatible, bioerodible and homogeneous semi-solid gel, wherein the semi-solid gel has a viscosity of 50 to 700cPs at 30 ℃ and less than 80% of the active ingredient is released from a depot of the semi-solid gel within one week when tested in vitro at 37 ℃.

In one or more embodiments, the glyceride mixture comprises a mixture of glycerides having a relative concentration of 6: 1 to 3: 1 (w: w) castor oil: a gelling agent.

In one or more embodiments, the glyceride mixture has a viscosity of 285cPs to 347cPs at 30 ℃.

In one or more embodiments, less than 50% of the active ingredient is released from the reservoir of the semi-solid gel within one month when tested in vitro at 37 ℃.

Drawings

Figure 1 shows the release of loteprednol etabonate (LOTE) from a castor oil gel formulation gelled by SUP DM.

Figure 2 shows the release of Latanoprost (LATA) from a castor oil gel formulation gelled by SUP DM or SUP CM.

Figure 3 shows the release of Celecoxib (CEL) from castor oil gel formulations gelled by SUP DM or SUP CM.

Figure 4 shows the release of Triamcinolone Acetonide (TA) from a castor oil gel formulation gelled by SUP DM or SUP CM.

Figure 5 shows the release of betamethasone valerate (BETV) from castor oil gel formulations gelled by SUP DM or SUP CM.

All of the above releases were tested in PBS at 37 ℃ and pH 7.4.

Detailed Description

The entire contents of PCT/US2018/064325 are incorporated herein by reference.

Technical advantages of bioerodible semi-solid carriers

The formulations described herein provide a long-term release of the drug to achieve a therapeutically effective concentration locally and rapidly for at least one week. The benefit of a long release time is that a rapid pain relief can be achieved and a higher level of active drug can be maintained at the site of pain for a long period of time, thereby providing a longer therapeutic effect for at least one week.

Benefits of bioerodible semi-solid carrier technology

The pharmaceutical composition described herein is a bioerodible semisolid carrier gel formulation that provides the benefits of sustained drug release without significant burst release. In vitro drug release and animal model studies have shown that injections based on our bioerodible semisolid carrier technology have a smaller burst release than injections produced by the existing controlled release technology on the market.

The semi-solid carrier technology described herein preferably has a drug loading concentration of 1-20% by weight, which is much higher than other controlled release technologies.

The semi-solid gel formulations described herein have a relatively low viscosity and can therefore be injected through a 21 to 25 gauge needle. Furthermore, due to the high drug loading of the semisolid gel formulations described in the present invention, less volume of drug needs to be injected. The small injection volume and low viscosity make injection more convenient and less painful. The viscosity of the semisolid preparation of polyorthoester at 30 ℃ is several thousand mpa.s, which is difficult to inject with a 21-gauge needle.

The formulations of the present invention comprise glycerides and natural fatty acids. These compounds are readily degraded by lipase to glycerol and free fatty acids. These compounds are non-toxic and have good biocompatibility in vivo. The formulations described herein are biodegradable, bioerodible, and fully resorbable. In animal experiments, no adverse effect of the semisolid formulation on wound healing was observed at 2 weeks after administration. The site of administration is pink, the sciatic nerve is normal, and there is no inflammation, necrosis, ulceration or infection.

Compared with microspheres and other high-molecular drug controlled-release injections, the semisolid gel preparation technology disclosed by the invention is easy to produce and low in cost. At relatively low elevated temperatures, the active ingredient is mixed very easily with the semi-solid gel carrier component without the need for solvents. Because of the use of solid glycerides (gelling agents) with relatively low melting points (less than 50 ℃), product production can be carried out at about 60 ℃.

In addition, the formulations described herein can be applied directly where desired. Because the formulation can provide sustained drug release (days to a month), the duration of the pharmacological effect is increased, which can reduce the frequency of administration. The formulation produces fewer side effects (due to topical administration) than systemic administration, which is readily acceptable to patients.

Definition of

All technical and scientific terms used herein are used according to their conventional definitions as they are commonly used and commonly understood by those skilled in the art of drug delivery. The terminology used in the present invention is as follows.

Abbreviations described herein include: abbreviations: betamethasone, BET; betamethasone valerate, BETV; celecoxib, CEL; ketoprofen, KETO; methylprednisolone, MP; triamcinolone acetonide, TA; meloxicam, MELO; loteprednol etabonate, LOTE; latanoprost, LATA; castor oil, CO.

As used herein, "active agent" includes loteprednol etabonate (methyl-17 α - [ (ethoxycarbonyl) oxy ] -11 β -hydroxy-3-oxoandrosta-1, 4-diene-17 β -carboxylate or), latanoprost (isopropyl- (Z) -7(1R, 2R, 3R, 5S) 3.5-dihydroxy-2- (3R) -3-hydroxy-5-phenylpentyl) 5-pentanoic acid cyclopentyl ester)), celecoxib (4- [5- (4-methylphenyl) -3- (trifluoromethyl) pyrazol-1-yl ] benzenesulfonamide), triamcinolone acetonide (9-fluoro-11 β, 21-dihydroxy-16 α,17[ (l-methylethylidene) bis (oxy) ] -pregna-1, 4-diene-3, 20-dione) and betamethasone ((8S, 9R, 10S, 11S, 13S, 14S, 16S, 17R) -9-fluoro-11, 17-dihydroxy-17- (2-hydroxyacetyl) -10, 13, 16-trimethyl-6, 7,8,9,10,11,12,13,14,15,16, 17-dodecatrihydro-3H-cyclopenta [ a ] phenanthren-3-one) or a pharmaceutically acceptable salt thereof. The active agent of the present invention may also include a second corticosteroid, an analgesic or an anti-inflammatory agent. For example, the second corticosteroid can be a glucocorticoid; the anti-inflammatory agent is a non-steroidal anti-inflammatory agent (NSAID) selected from the group consisting of ketoprofen, naproxen, meloxicam, COX-1 inhibitors and COX-2 inhibitors.

The term "semi-solid" is characterized as a substance that is flowable under moderate pressure. More specifically, the semi-solid material has a viscosity of 50 to 700cPs (mPa.s), preferably 200 to 400cPs, at 30 ℃.

The term "bioerodible" refers to a material that gradually decomposes, dissolves, hydrolyzes, and/or erodes in situ. In general, the "bioerodible" semi-solid gels of the invention are hydrolyzable materials, and bioerodible primarily by in situ lipolysis or hydrolysis.

The semi-solid lipid, solvent or other agent of the present invention must be "biocompatible"; i.e. it does not cause irritation and necrosis in the environment of use. The environment of use is a fluid environment and may include subcutaneous, subconjunctival, intramuscular, intravascular (high/low flow), intramyocardial, adventitial, intratumoral, or intracerebral portions, wound sites, tight joint spaces or body cavities of humans or animals.

Castor oil and gelling agent

Castor oil injectable grade (USP-NF41-362S) is the preferred triglyceride component of the semi-solid formulations described herein. Castor oil is a triglyceride in which about 90% of the fatty acid chains are ricinoleic acid ester. Oleic acid and linoleate are other important ingredients.

Castor oil is a liquid with a viscosity of about 700cPs at 25 c. Although it is a relatively viscous vegetable oil, when a drop of castor oil is added to water or PBS at 37 ℃, it immediately spreads and dissipates on the surface of the aqueous solution, eventually forming a small droplet. Therefore, castor oil is not suitable for use as a sustained release agent. Liquid castor oil for injectable dosage forms is sold as "ultra refined castor oil" which meets the USP monograph USP-NF41-362S standard, supplied by Croda inc.

However, once castor oil is converted to hydrogenated castor oil (castor wax), a hard, high melting point (85 to 88 ℃) wax, which has been used as an extended release agent in oral and topical pharmaceutical formulations by hydrogenation of castor oil using a catalyst. In oral formulations, hydrogenated castor oil has been used to prepare sustained release tablets and as a capsule lubricant formulation. In topical formulations, it has been used to provide firmness to creams and lotions.

It has surprisingly been found that when a solid gelling agent is selected comprising C₁₂-C₁₈Triglycerides (SUP DM or SUP CM), C₈-C₁₈Mixture of triglycerides (G43/01), mixture of hydrogenated coconut oil glycerides (WIT E85 and WIT E76), C₁₀-C₁₈Triglyceride mixture (SUP D) and or other solid glycerides with a melting point between 37 ℃ and 75 ℃; when added to castor oil, the liquid castor oil (700cPs) becomes a soft, semi-solid gel.

For example, when SUP DM is 5 wt%, gelation is very slow at room temperature (flowable at 37 ℃ body temperature). When SUP DM is equal to or higher than 10 wt%, gelation occurs at room temperature. With increasing amount of SUP DM, less time is required to start gelling. At the 20 wt% level, the semi-solid gel formed was still a soft gel and could be injected with a 21 gauge needle. When the amount of SUP DM increased to 30 wt%, the formed semi-solid gel became a relatively hard gel and was difficult to inject with a 21 gauge needle.

The castor oil gels of the present invention are characterized in that they have the property of changing from a fluid at room temperature to a gel at room temperature and remain as a gel in a certain form when the semi-solid gel is placed in water at 37 ℃.

Furthermore, the slow release of castor oil into water, probably due to the cohesion between castor oil and gelling agent and the relatively hydrophobic semi-solid gel structure, results herein show the kinetics of active drug release from formulations comprising CO. The stable gel formulation ensures that the formulation maintains a depot of a certain morphology once injected into the human body to control the gradual release of the active drug and prevents the rapid release of castor oil into the blood of animals or humans which can lead to vascular occlusion and potential Pulmonary Oil Microembolism (POME). Furthermore, because the viscosity of the soft semi-solid gel formulation formed is low (about 350cP at 30 ℃), it can be easily injected with a 21-gauge needle or used for topical delivery.

The gelling agent is a material which is acceptable in pharmacy and has good compatibility with castor oil. Since castor oil is a mixture of triglycerides, the solid or semi-solid glycerides described herein are well compatible with castor oil to form a semi-solid gel.

More specifically, suitable gelling agents may be solid triglycerides of mixed esters, solid partial glycerides of fatty acids, mixtures of triglycerides, diglycerides or monoglycerides, and other castor oil compatible gelling agents, such as the sterol ester lanolin. Since these gelling agents are similar in structure to castor oil, they are expected to be compatible. Physically, these substances may be in the form of solid or semi-solid lipids, at room temperature, and should also have a low solubility, less than 1mg/mL, preferably less than 0.1mg/mL, of water in a physiological pH buffer at 37 ℃. If the gelling agent is too hydrophilic and water soluble it will cause a burst of active drug, especially when the active drug is relatively soluble, which may cause undesirable side effects. If the gelling agent is significantly less soluble than the main semisolid lipid, the residence time of the active drug and the main semisolid lipid in the body will be significantly longer when it is completely dissolved and absorbed by the body.

The solid or semi-solid lipids described herein are well compatible with castor oil and can form a semi-solid gel delivery vehicle with castor oil for active drugs, including solid triglycerides of mixed esters, solid partial glycerides of fatty acids, mixtures of triglycerides, diglycerides or monoglycerides, and other compatible castor oil gelling agents (e.g., sterol ester lanolin) having a melting point below 100 ℃, preferably between 37 ℃ and 75 ℃, more preferably between 37 ℃ and 50 ℃. When the melting point becomes too high, especially at higher concentrations (>20 wt%), it will cause hardening of the semi-solid gel and affect the injectability of the semi-solid gel formulation.

The solid triglycerides of the present invention that can be added to castor oil to form a semi-solid gel include SUP DM, C₁₂To C₁₈A mixture of triglycerides having a melting point of 42.5 ℃ to 46 ℃;

D(SUP D)，C₁₂to C₁₈A mixture of triglycerides having a melting point of 42 ℃ to 45 ℃;

CM(SUP CM)，C₁₂to C₁₈A mixture of triglycerides having a melting point of 37.8 ℃ to 39.8 ℃;

378(S378)，C₁₀to C₁₈Triglycerides of fatty acids having a melting point of 39 ℃ to 42 ℃; and hydrogenated castor oil having a melting point of 85 ℃ to 88 ℃.

Solid partial glycerides of fatty acids that can be added to castor oil to form a semi-solid gel according to the present invention include C₁₂To C₁₈A GELUCIRE 43/01(G43/01) glyceride of a fatty acid having a melting point of 42 ℃ to 45 ℃; GELEOL^TMGlyceryl monostearate, having a melting point of from 54 ℃ to 64 ℃; GELUCIRE 39/01(G39/01) C₁₂To C₁₈A mixture of glycerol esters of mono-, di-and triglycerides of fatty acids having a melting point of from 37 ℃ to 40 ℃; and

888ATO, glyceryl behenate, melting point 65 ℃ to 77 ℃.

The mixture of triglycerides, diglycerides or monoglycerides which may be added to castor oil to form a semi-solid gel according to the present invention includes

E85(WIT E85), melting point 42 ℃ to 44 ℃; and

e76(WIT E76) having a melting point of 37 ℃ to 39 ℃.

In addition, other gelling agents that are well compatible with castor oil, such as the sterol ester lanolin, which has a melting point of 38℃, can be added to castor oil to form a semi-solid gel.

The concentration of gelling agent added to the castor oil may vary. For example, the concentration of the gelling agent (wt%, based on the total weight of the pharmaceutical composition) may be about 1 to 30 wt%, preferably about 5 to 25 wt%. In some embodiments, the weight ratio of castor oil to gelling agent is 50:1 to 2:1(w/w), preferably 8: 1 to 2.5: 1, preferably 6: 1 to 3: 1 (w/w). The amount of the gelling agent to be used may be appropriately selected depending on the gelling effect to be obtained and the gelling ability of the gelling agent.

Once injected into the body (37 c), the delivery vehicle formed by the castor oil mixed with the gelling agent (final delivery vehicle) and the additional active substance, will form a depot with a morphology and will gradually degrade/erode and dissolve in the body fluids, the semi-solid lipids will eventually be hydrolysed to natural free glycerol and free fatty acids by a process known as lipolysis with lipases.

Preparation of castor oil semisolid gel preparation

The castor oil semisolid gel formulations containing active substances according to the present invention can be prepared by direct mixing of castor oil and gelling agent or by mixing with the already formed semisolid gel matrix. The mechanical mixing process is carried out at a suitable temperature, typically between 60 ℃ and 90 ℃, to completely melt the gelling agent and castor oil into solution and dissolve or grind the active drug by any mechanical means to form a clear solution or a homogeneous suspension. Vacuum may be applied to avoid air bubbles, and nitrogen may be applied to reduce oxidation of the active drug and delivery vehicle components. After a uniform and consistent pharmaceutical composition is obtained, the active substance semi-solid gel formulation may be cooled to room temperature.

Semi-solid gel formulation composition comprising active ingredient

Preferred active ingredients for topical delivery are selected from celecoxib, triamcinolone acetonide, betamethasone, loteprednol etabonate and latanoprost, or other pharmaceutically acceptable active ingredients.

The active substance (free base) can be readily converted into salts with fatty acids and other pharmaceutically acceptable acids. Saturated and unsaturated fatty acids such as lauric acid, myristic acid, palmitic acid and oleic acid are all natural fatty acids and can be used. Such transformation may increase its compatibility and solubility in the semi-solid carrier. The selected active substance may be pre-converted to a salt prior to incorporation into the semi-solid carrier, or may be added simultaneously to the semi-solid carrier during formulation preparation at a molar ratio of 1:1 or other molar ratio.

The amount of active agent or agents in the composition can vary over a wide range depending on several factors, such as the therapeutically effective amount of the active agent, the time required for a biological or therapeutic effect, and the release profile of the composition. The concentration of the active substance in the composition may be in the range of 0.01 to 60 wt.%, preferably in the range of 1 to 40 wt.%, or more preferably in the range of 1 to 20 wt.%.

The glyceride mixture comprises ricinoleic acid triglyceride and gelling agent in the relative proportions of 50:1 to 2:1, preferably 20: 1 to 2.5: 1, more preferably 10: 1 to 2.5: 1, more preferably 8: 1 to 2.5: 1, most preferably 6: 1 to 3: 1 (w: w).

The concentration of the gelling agent (% by weight, based on the total weight of the composition) may be in the range of 1 to 30% by weight, preferably around 5 to 25% by weight. In some embodiments, the concentration of the gelling agent in the pharmaceutical composition is 10-25% by weight.

In addition, other pharmaceutically acceptable agents such as penetration enhancers may be added, including natural penetrating ingredients such as oleic acid, linoleic acid and synthetic ingredients such as azone, propylene glycol, N-methylpyrrolidone, antioxidants, preservatives and other inert agents such as coloring or flavoring agents.

The semi-solid pharmaceutical gel composition of the semi-solid formulation of the present invention has a smooth semi-solid gel texture. Thus, the composition may be loaded into a 21-25 gauge needle syringe for subcutaneous, subconjunctival, intradermal, intramuscular, epidural or intrathecal injection, or may also be conveniently applied to a site that has been opened, such as a surgical wound/site or exposed skin or mucosa.

Following administration by injection or topical application, the active substance is released from the composition in a sustained and controlled manner. The rate of release can be adjusted in different ways to suit the duration of the desired therapeutic effect. For example, the release rate can be increased or decreased by using different amounts of low solubility semi-solid lipids and different amounts of salts of low solubility actives. The release rate can also be increased or decreased by selecting different modifying excipients or by varying the amount of the excipient, or both. Furthermore, less water-soluble active substances, for example in their base form, or as complexes with fatty acids, can be used to delay the release of the active substance.

Medical application

The semi-solid gel pharmaceutical compositions described herein can be filled into a syringe and injected locally directly at the site of disease or injury, and the pharmaceutical product can be treated locally.

Other semisolid gel pharmaceutical formulations

Exemplary compositions of the semisolid formulations described herein and uses thereof include compositions comprising: ophthalmic drugs for the treatment of ocular inflammation, corticosteroids such as loteprednol etabonate; glaucoma drugs such as latanoprost for the treatment of open angle glaucoma or ocular hypertension; anti-angiogenic drugs such as bepotastine for the treatment of macular degeneration and retinal angiogenesis; and other compositions for the controlled release of ophthalmic drugs into the eye. Despite the widespread use of topical eye drop formulations, this means of drug delivery is not ideal and may be associated with poor patient compliance. In most formulations, the bioavailability of eye drops is poor; experts estimate that less than 5% of the applied dose of topical formulations reaches intraocular tissues. Studies have shown that patients vary greatly in their success in delivering ophthalmic drops.

The amount of active substance or substances in the composition according to the invention may vary within wide limits depending on many factors, such as the therapeutically effective amount of the active drug, the duration of the biological or therapeutic effect, and the release profile of the composition. The concentration of the active substance may be about 0.01 to 60% by weight, preferably about 1 to 10% by weight. The injectable formulations described in the present invention have another advantage over many topical formulations: the injectable preparation contains no preservative, such as benzalkonium chloride (BAK).

Background

Castor Oil (CO)

Castor oil is a stable excipient in terms of composition and physical properties such as viscosity. Castor oil is an oil solution and not a sustainable "depot". After injection, it can cause vascular occlusion and potential pulmonary oil microembolism, especially with large doses (3-5 ml), the release of castor oil in large amounts and rapidly burst can be an adjuvant safety issue.

Gelling agent

One objective to be solved by the present invention is to change castor oil into a stable gel to control drug release and also to control the release of castor oil into the surrounding tissue. Another object is to prevent rapid release of the drug and/or burst release of castor oil.

Pharmaceutically acceptable gelling agents are tested. Commonly used aluminum salts of fatty acids, such as aluminum stearate and magnesium stearate, are used. Polymers such as carboxymethyl cellulose, polyvinyl alcohol and polyvinyl pyrrolidone are also used. Polysaccharides such as natural pectin and starch are commonly used in aqueous systems, and they are not compatible with CO. Due to variations in molecular size and chemical composition, it was found that pectins from different sources provide different gelling abilities. As with other natural polymers, a major problem with pectin is inconsistency of reproducibility between samples, which may lead to poor reproducibility of drug delivery properties.

The gel experiments were performed as follows. The target amounts of gellant and castor oil were weighed and transferred to a glass bottle and sealed. The mixture was heated in a water bath to about 96 ℃ for about 10 minutes and then vortexed for 1 minute. This procedure was repeated three times for 30 minutes to dissolve the gelling agent into castor oil. The three polymers, carboxymethyl cellulose, polyvinyl alcohol and polyvinyl pyrrolidone, were tested at a 0.2% level (2 mg polymer added to 1g castor oil, heated at 96 ℃ and vortexed for 30 minutes, all of which were insoluble in castor oil.

Experiments were carried out with the addition of aluminium distearate at concentrations of 0.1%, 0.5% and 1% to castor oil. The results show that aluminum distearate has a solubility in castor oil of less than 0.1% after heating and vortexing at 96 ℃ for 30 minutes. When cooled to room temperature overnight, no gel was formed.

None of the "gelling agents" tested above were soluble in or compatible with castor oil.

The relatively high melting glycerides were then tested and the time from onset of gelation to complete gelation recorded as well as the castor oil release in water at 37 c. In vitro and in vivo studies have shown that formulations containing glycerides with relatively high melting points and castor oil provide better control of bupivacaine release and thus improved analgesic efficacy. Further, castor oil is a triglyceride and exhibits less inflammation than commercial S701, which is a mixture of mono-, di-and triglycerides.

Semi-solid gel formulations for topical delivery

Solubility of bupivacaine in pure castor oil

The solubility of bupivacaine in castor oil is determined by dissolving bupivacaine in castor oil and mixing the components at an elevated temperature of 70-80 ℃ to form a clear solution which forms a clear oil solution when cooled to ambient temperature. From 5% to 20% bupivacaine can be readily dissolved in castor oil.

Amount of SUP DM required for the Castor oil gel formed

The amount of gelling agent required to form a castor oil semisolid gel formulation with 8 wt% bupivacaine is determined by mixing the components at an elevated temperature of 70-80 deg.C to form a clear solution and cooling to room temperature to provide a homogeneous, translucent or opaque gel formulation. The results in table 1 show that the gelling agent SUP DM can form a translucent or opaque semi-solid gel formulation in the range of 10% to 30%.

When the gelling agent SUP DM is 5 wt%, gelling occurs very slowly at room temperature (flowable at 37 ℃ body temperature). When SUP DM is equal to or higher than 10 wt%, gelation occurs at 21 ℃. As the amount of SUP DM increases, less time is required to start gelling. At the 20 wt% level, the semi-solid gel formed was still a soft gel and could be injected with a 21 gauge needle. When the amount of SUP DM was increased to 30 wt%, the formed semi-solid gel became a relatively hard gel and was difficult to inject with a 21 gauge needle. The results show that 10 to 20 wt% SUP DM can be used as gelling agent, forming bupivacaine semi-solid gel formulations with good injectability.

Table 1: castor oil/gel ratio study: bupivacaine semisolid gel preparation

The castor oil gel formed is characterized as a gel that has the property of changing from a fluid at room temperature to a gel at room temperature and that retains some form when the semi-solid gel is placed in water at 37 ℃. The castor oil bupivacaine semisolid gel formulation used for the above test at 37 ℃ in water was prepared with 15% SUP DM.

In addition, a very slow release of castor oil into water was observed, probably due to the cohesion between castor oil and gelling agent and the relatively hydrophobic semi-solid gel structure.

Bupivacaine in the range of 5% to 15% can be easily dissolved in a semi-solid lipid mixture of castor oil and SUP DM. Although up to 15% bupivacaine is soluble in the final semi-solid gel formulation mixture, less than 10% is selected to avoid potential drug crystallization that may form during long term storage.

Other gelling Agents

The above experimental procedure was used to select suitable additional castor oil compatible gelling agents that would form a semisolid gel formulation of bupivacaine. In addition to SUP DM, C₁₂To C₁₈Mixtures of triglycerides having a melting point of 42.5 to 46 ℃, other solid or semi-solid triglycerides including

D(SUP D)，C₁₂To C₁₈A mixture of triglycerides having a melting point temperature of 42 ℃ to 45 ℃;

378(S378)，C₁₀to C₁₈Triglycerides of fatty acids having a melting point of 39 ℃ to 42 ℃; and hydrogenated castor oil having a melting point of 85 ℃ to 88 ℃. These were also tested as gelling agents to allow castor oil to form a semi-solid gel formulation in the presence of bupivacaine.

The semisolid pharmaceutical composition prepared by the present invention is as follows: the active ingredient, castor oil and gelling agent are added to a glass container and then heated to about 60 ℃ to 90 ℃ depending on the nature of the vehicle components and topical anesthetic used, to completely melt the semi-solid lipid and gelling agent into a solution, and the active drug is completely dissolved in the drug delivery vehicle with constant stirring to form a clear solution. After a homogeneous and homogeneous pharmaceutical composition is achieved, the topical anesthetic semi-solid formulation may be naturally cooled to ambient temperature.

Examples

The present invention will be illustrated below by way of specific examples. It is to be understood that these examples are illustrative only and are not intended to limit the scope of the present invention. The materials and methods used in the examples are, unless otherwise indicated, those conventional in the art. All release tests in the examples were performed in PBS at 37 ℃ and pH7.4, as described in example 15.

The commercial products of table 2 are used herein and GMP quality and quantity compliant products are commercially available.

Table 2: commercial triglyceride mixtures

Example 1.SUP D

C₁₂To C₁₈SUP D mixture of triglycerides with melting point 42 ℃ to 45 ℃. The results of the castor oil and SUP D ratio studies are shown in table 3. The target amount of each component was weighed into a glass vial and heated to about 50 ℃. Place in a 75 ℃ water bath, mix/vortex until all components are completely dissolved and a clear solution is formed.

SUP D requires approximately the same time as SUP DM to start and complete gelation because they have similar properties and melting points. Approximately 1mL of the hot solution was loaded into a 5mL pre-filled syringe and steam sterilized at 121 ℃ for 20 minutes. Whether steam sterilized or not, they appeared as uniform opaque gels after cooling to room temperature at 10-20 wt% gellant levels and could be injected with a 21 gauge needle.

Table 3: castor oil and SUP D ratio study

Sample numbering	Castor oil (g)	SUP D(g)	Bupivacaine (mg)
				SUP D F01	1.64	0.20	160
SUP D F02	1.54	0.30	160
				SUP D F03	1.44	0.40	160

Example 2.SUP CM

C₁₂To C₁₈The SUP CM mixture of triglycerides has a melting point of 37.8 to 39.8 ℃. The castor oil and SUP CM ratio studies are shown in table 4. The target amount of each component was weighed into a glass vial and heated to about 75 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed.

Because SUP CM has a lower melting point, SUP CM requires a longer time to start and complete gelation than SUP DM.

Approximately 1mL of the hot solution was loaded into a 5mL pre-filled syringe and steam sterilized at 121 ℃ for 20 minutes. Whether steam sterilized or not, they appeared as uniform opaque gels after cooling to room temperature at 10-20 wt% gellant levels and could be injected with a 21 gauge needle.

Table 4: studies of the castor oil to SUP CM ratio

Sample numbering	Castor oil (g)	SUP CM(g)	Bupivacaine (mg)
				SUP CM F01	1.64	0.20	160
SUP CM F02	1.54	0.30	160
				SUP CM F03	1.44	0.40	160

Example 3.S378

C₁₀To C₁₈An S378 mixture of fatty acid triglycerides having a melting point of 39 ℃ to 42 ℃ and being in a semi-solid state. At higher amounts/concentrations, the gelling power is lower than in the hard solid state compared to other solid triglycerides. At the 40 wt% level, it took about 6 minutes and 30 seconds for S378 to start gelling, but 36 minutes for complete gelling.

The castor oil and S378 ratio studies are shown in table 5. The target amount of each component was weighed into a glass vial and heated to about 75 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed.

Approximately 1mL of the hot solution was loaded into a 5mL pre-filled syringe and steam sterilized at 121 ℃ for 20 minutes. Whether steam sterilized or not, they appeared as uniform opaque gels after cooling to room temperature at a 30-50 wt% gellant level and could be injected with a 21 gauge needle. At the 20 wt.% level, the formulation was still flowable after cooling to room temperature.

Table 5: castor oil and S378 ratio study

Sample numbering	Castor oil (g)	S378(g)	Bupivacaine (mg)
				S378F01	1.44	0.40	160
S378F02	1.24	0.60	160
				S378F03	1.04	0.80	160
S378F04	0.84	1.00	160

Example 4 hydrogenated Castor oil

Hydrogenated castor oil solid triglycerides (HCO) have a higher melting point of 85 to 88 ℃. Due to its higher melting point, the gelling agent needs to be heated above 88 ℃ to completely melt and mix well with castor oil to form a semi-solid gel.

The castor oil and hydrogenated castor oil ratio studies are shown in table 6. The target amount of each component was weighed into a glass vial and heated to about 90 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed. Approximately 1mL of the hot solution was loaded into a 5mL pre-filled syringe and steam sterilized at 121 ℃ for 20 minutes. Whether steam sterilized or not, they appeared as uniform opaque gels after cooling to room temperature at 10-15 wt% gellant levels and could be injected with a 21 gauge needle. At a level of 20 wt%, it took 1 minute and 25 seconds to start gelation and 5 minutes to complete gelation. The formulation became a relatively hard gel that was difficult to inject with a 21-gauge needle.

Table 6: studies on the ratio of Castor oil to hydrogenated Castor oil

Sample numbering	Castor oil (g)	Hydrogenated Castor oil (g)	Bupivacaine (mg)
				HCO F01	1.64	0.20	160
HCO F02	1.54	0.30	160
				HCO F03	1.44	0.40	160

Solid partial glycerides of fatty acids include G43/01, C₈To C₁₈A mixture of triglycerides having a melting point of 42 ℃ to 45 ℃; GELEOL^TMGlyceryl monostearate, having a melting point of from 54 ℃ to 64 ℃; COM, glyceryl behenate, melting point 65 ℃ -77 ℃; and G39/01, C₁₂To C₁₈A mixture of glycerides of fatty acid monoglycerides, diglycerides and triglycerides having a melting point of from 37 ℃ to 40 ℃. These were tested as gelling agents to allow castor oil to form a semi-solid gel formulation in the presence of bupivacaine.

Example 5G 43/01

C₈To C₁₈The melting point of the triglyceride G43/01 mixture is 42 to 45 ℃. The castor oil and G43/01 ratio studies are shown in Table 7. The target amount of each component was weighed into a glass vial and heated to about 75 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed.

The onset of gelation took approximately 8 minutes 30 seconds and 6 minutes 30 seconds, and 15 wt% and 20 wt% of G43/01 took 15 minutes and 13 minutes, respectively, to complete gelation.

Table 7: studies of the castor oil and G43/01 ratio

Sample numbering	Castor oil (g)	G43/01(g)	Bupivacaine (mg)
				G43/01 F01	1.64	0.20	160
G43/01 F02	1.54	0.30	160
				G43/01 F03	1.44	0.40	160

Example 6 COM

The castor oil and COM ratio studies are shown in table 8. The melting point of the solid glyceryl behenate was 65 to 77 ℃. The target amount of each component was weighed into a glass vial and heated to about 80 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed.

Approximately 1mL of the hot solution was loaded into a 5mL pre-filled syringe and steam sterilized at 121 ℃ for 20 minutes. Whether steam sterilized or not, they appeared as uniform opaque gels after cooling to room temperature at 10-20 wt% gellant levels and could be injected with a 21 gauge needle. Injections were available with 21 gauge needles at the 10 and 15 wt% level. At the 20 wt% level, the formulation became a relatively hard gel and could not be injected with a 21-gauge needle.

Table 8: castor oil and COM ratio study

Sample numbering	Castor oil (g)	COM(g)	Bupivacaine (mg)
				Com F01	1.64	0.20	160
Com F02	1.54	0.30	160
				Com F03	1.44	0.40	160

Example 7 GEL

The castor oil and GEL ratio studies are shown in table 9. The melting point of the solid glyceryl monostearate is 54 to 64 ℃. The target amount of each component was weighed into a glass vial and heated to about 75 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed.

Table 9: castor oil and GEL ratio study

Sample numbering	Castor oil (g)	GEL(g)	Bupivacaine (mg)
				Gel F01	1.64	0.20	160
Gel F02	1.54	0.30	160
				Gel F03	1.44	0.40	160

Example 8 WIT E85 and WIT E76

A mixture of triglycerides, diglycerides or monoglycerides (e.g. WIT E85, melting point 42 ℃ to 44 ℃ and WIT E76, melting point 37 ℃ to 39 ℃) were tested as gelling agents to enable castor oil to form a semi-solid gel formulation in the presence of bupivacaine.

The castor oil and WIT E85 ratio studies are shown in table 10. The target amount of each component was weighed into a glass vial and heated to about 75 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed.

The start of gelation takes about 8 minutes 30 seconds and 6 minutes 30 seconds, and about 15 minutes and 13 minutes 30 seconds to complete gelation.

Table 10: castor oil and WIT E85 ratio study

Sample numbering	Castor oil (g)	WIT E85(g)	Bupivacaine (mg)
				Wit F01	1.64	0.20	160
Wit F02	1.54	0.30	160
				Wit F03	1.44	0.40	160

Example 9 Natural sterol ester, Lanolin (LAN)

Lanolin is an "ester", structurally similar to a "glyceride", and is compatible with the triglyceride castor oil. Its melting point is 38 ℃. Lanolin requires about 3 minutes and 30 seconds to start gelling at an 18 wt% level, but takes 7 minutes to complete gelling due to its high viscosity.

The castor oil and lanolin ratio studies are shown in table 11. The target amount of each component was weighed into a glass vial and heated to about 75 ℃ in a water bath and mixed/vortexed until all components were completely dissolved and a clear solution was formed.

Table 11: study on the ratio of Castor oil to Lanolin

Sample numbering	Castor oil (g)	Lanolin (g)	Bupivacaine (mg)
				Lan F01	1.64	0.20	160
Lan F02	1.54	0.30	160
				Lan F03	1.44	0.40	160

Example 10 loteprednol etabonate

Loteprednol etabonate (C)

Or

) Loteprednol etabonate in ester form is a corticosteroid used in ophthalmology. The ophthalmic applications of the drug include the treatment of ocular inflammation due to allergy (according to the prescription information table), and slow releaseSexual keratitis (e.g., adenovirus or Thygeson's keratitis), vernal keratoconjunctivitis, tonsillitis, and episcleritis. The medicine has little effect on eye pressure. The semi-solid loteprednol etabonate loaded gel formulation may be injected to treat ocular inflammation and pain.

Castor oil, SUP DM and loteprednol etabonate (Lote) were weighed in weight percentages of 77.8%, 19.5% and 2.7%, added to a glass vial and the cap was screwed down. Heating in water bath to 90 deg.C to melt the carrier component, dissolving loteprednol etabonate to form clear solution, and cooling to room temperature to obtain translucent soft gel.

Figure 1 shows the release of loteprednol etabonate in a castor oil gel formulation gelled by SUP DM, which has a loteprednol etabonate release profile for 7 days due to its relatively good water solubility.

Example 11 Latanoprost

Latanoprost

For treating glaucoma or ocular hypertension by lowering intraocular pressure. Single dose subconjunctival injections of a semisolid gel formulation loaded with Latanoprost (LATA) can be used to treat glaucoma.

Two semi-solid formulations, Gel001 and Gel002, respectively, were prepared by weighing castor oil, SUP CM or SUP DM and the drug into a glass vial and tightening the vial cap, where Gel001 was CO/SUPCM/LATA (73.8/21.4/4.8) and Gel002 was CO/SUPCM/LATA (80/15/5). Heating to 75 ℃ in a water bath melted the carrier component and dissolved latanoprost to form a clear solution and became a translucent soft gel upon cooling to room temperature.

Figure 2 shows latanoprost release in castor oil gel formulations gelled by SUP DM and SUP CM. Latanoprost is a very hydrophobic drug and it was surprisingly found that sustained release with both gelling agents was sustained for up to 2 months, whereas the bupivacaine castor oil gel formulation was sustained for only about 1-2 weeks.

Example 12 celecoxib

Celecoxib is prepared as followsTrade name sale:

ARTI

ART

ART

CADITA

CEFINIX、

CELEBRA and

celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor, a non-steroidal anti-inflammatory drug (NSAID), useful in the treatment of symptoms of various types of arthritic pain, including osteoarthritis and Familial Adenomatous Polyposis (FAP), to reduce colon precancerous polyps. The semi-solid gel formulation loaded with celecoxib is useful as a long-acting, topically effective therapeutic method by intra-articular injection to treat chronic inflammation and pain associated with knee osteoarthritis.

The semi-solid formulation Gel001CEL was prepared by weighing castor oil, SUP CM or SUP DM and the drug Celecoxib (CEL) into a glass vial and screwing the vial cap down: CO/SUPCM/CEL (73.8/21.4/4.8), Gel002 CEL: CO/SUPDM/CEL (80.9/14.3/4.8). Heating to 75 ℃ in a water bath melts the carrier component and partially dissolves celecoxib (about 1% by weight dissolved in the carrier) to form a clear solution in which the micronized celecoxib drug particles are suspended. After cooling to room temperature, a homogeneous, translucent, soft gel formed.

The results in figure 3 show that SUP DM and SUP CM have important implications for the release of celecoxib in castor oil gel formulations. Celecoxib is a very hydrophobic drug, and the celecoxib release on day 43 was approximately 27.5% and 29.3% for both suspension gel formulations, respectively. It was surprisingly found that celecoxib was released continuously for more than 3 months.

Example 13 triamcinolone acetonide

Triamcinolone acetonide is sold as an acetyl salt under the trade name: ARIS TO

AZMA

RATIO-TRIA

TRIA DERM、

TRICORTONE、TRILONE、TRIS

And VOLON

Routes of administration include oral, topical, intramuscular, intraarticular and intrasynovial. Triamcinolone acetonide is a corticosteroid used to treat various inflammatory states of the body ranging from allergic rhinitis to the acute exacerbation of multiple sclerosis. Triamcinolone acetonide has also been used as an adjunct treatment for osteoarthritic knee pain. The semi-solid gel formulation loaded with triamcinolone acetonide can be injected intra-articularly to treat chronic inflammation and pain associated with knee osteoarthritis.

The semi-solid formulation Gel001 TA was prepared by weighing castor oil, SUP CM or SUP CM and the drug Triamcinolone Acetonide (TA) into a glass vial and tightening the vial cap: CO/SUP CM/TA (73.8/21.4/4.8), Gel002 TA: CO/SUPDM/TA (80.9/14.3/4.8). Heating to 75 ℃ in a water bath melts the carrier component and partially dissolves the triamcinolone acetonide (less than 1% by weight dissolved in the carrier) to form a clear solution in which the micronized triamcinolone acetonide drug particles are suspended. After cooling to room temperature, a homogeneous, translucent, soft gel formed.

Figure 4 shows the release of triamcinolone acetonide from the castor oil gel formulations of the SUP DM and SUP CM gels, at day 43 the release of triamcinolone acetonide in both gel formulations was 41.6% and 43.9%, respectively. It was surprisingly found that triamcinolone acetonide released continuously for more than 2 months.

Example 14 betamethasone valerate

Betamethasone valerate salts are sold under the trade names: BETAME

LUX

BET

BET

CELESTO DERM、CELESTO

And ECTOSONE. It is a glucocorticoid administered orally, parenterally, by local injection, inhalation, or topically for the treatment of a variety of conditions, where corticosteroids are used to treat pain in the knee including osteoarthritis. The semisolid gel formulation loaded with betamethasone valerate can be injected intra-articularly to treat chronic inflammation and pain associated with knee osteoarthritis.

The semi-solid formulation Gel001BETV was prepared by weighing castor oil, SUP DM or SUP CM and the drug betamethasone valerate (BETV) into a glass bottle and screwing the bottle cap down: CO/SUP CM/BETV (75.9/22.1/2.0), Gel002 BETV: CO/SUP DM/BETV (83.3/14.7/2.0). Heating to 75 deg.C in water bath to melt the carrier component, dissolving betamethasone valerate to form clear solution, and cooling to room temperature to form a translucent soft gel.

Figure 5 shows release of betamethasone valerate from a castor oil gel formulation of SUP DM and SUP CM gels. Betamethasone valerate is a relatively hydrophobic drug, and at day 43, the release of betamethasone in both gel formulations was about 50%. Surprisingly, it was found that betamethasone is released continuously for more than 2 months.

Example 15 in vitro Release

The following semi-solid local anesthetic compositions were prepared: the topical anesthetic, castor oil, and gelling agent are added together in a glass container and then heated to about 70 c to 90 c with constant agitation to melt the gelling agent completely into solution, completely dissolving the active agent in the delivery vehicle to form a clear solution. After a homogeneous and homogeneous pharmaceutical composition is achieved, the topical anesthetic semi-solid formulation may be naturally cooled to ambient temperature. The semi-solid formulation may become a translucent or opaque gel.

Gel 001 LOTE：CO/SUP DM/LOTE(77.8/19.5/2.7)

Gel 001 LATA：CO/SUP CM/LATA(73.8/21.4/4.8)

Gel 002 LATA：CO/SUP DM/LATA(80/15/5)

Gel 001 CEL：CO/SUPCM/CEL(73.8/21.4/4.8)

Gel 002 CEL：CO/SUPDM/CEL(80.9/14.3/4.8)

Gel 001 TA：CO/SUP CM/TA(73.8/21.4/4.8)

Gel 002 TA：CO/SUPDM/TA(80.9/14.3/4.8)

Gel 001 BETV：CO/SUPCM/BETV(75.9/22.1/2.0)

Gel 002 BETV：CO/SUP DM/BETV(83.3/14.7/2.0)

The in vitro release profile of bupivacaine was evaluated by weighing approximately 50mg of the semi-solid formulation and encapsulating it in a porous semi-permeable membrane in a glass vial with 100mL of PBS, ph7.4, without stirring. At different time points, samples were taken and the local anesthetic content was analyzed by UV-Vis at 220nm, loteprednol etabonate by UV-Vis at 277nm, latanoprost by UV-Vis at 210 nm. The content of celecoxib, triamcinolone acetonide and betamethasone valerate is analyzed by high performance liquid chromatography. The chromatographic conditions were as follows: (1) a chromatographic column: welch Xtimate C18, 5 μm, 4.6x250 mm; (2) mobile phase: 20mM ammonium acetate (pH 8.0): acetonitrile (38: 62); (3) detection wavelength: the Retention Time (RT) of celecoxib at 210nm is 9.9 min; triamcinolone acetonide has a Retention Time (RT) at 240nm of 4.0 min; the Retention Time (RT) of betamethasone valerate at 270nm is 10.5 min; (4) temperature of the column: 21 ℃; (5) sample introduction volume: 100 mul; (6) flow rate: 1.0ml/min (7) run time: for 15 minutes.

Controlled release mechanisms for the formulations described in the present invention

When a semi-solid gel formulation is placed in an aqueous environment, water will diffuse into the semi-solid lipid matrix and the active substance on the surface of the formulation will gradually dissolve first into the surrounding aqueous medium. When the aqueous medium penetrates into the semisolid lipid gel, the semisolid lipids gradually erode through surface and volume erosion and gradually dissolve into the surrounding aqueous medium, and the active substance will gradually diffuse and be released into the surrounding aqueous medium in a sustained manner over a period of time.

Factors affecting drug release rate

The semi-solid gel carrier component and the active itself have an effect on the release rate and can be adjusted in a variety of ways to achieve the desired duration and therapeutic effect desired.

The release rate of the active substance from the semi-solid gel carrier can be increased or decreased by using different types/levels/contents/ratios of hydrophobic glyceride gelling agents having different water solubilities and/or dissolution rates. When the water solubility and dissolution rate of a semi-solid gel decreases, the semi-solid gel takes longer to dissolve and absorb, thus resulting in a longer duration of drug release as long as the active substance has a sufficiently low solubility.

Furthermore, less water-soluble forms of the active ingredient, such as its base form, or complexes with fatty acids, may be used to delay the release of the active ingredient.

EXAMPLE 16 viscosity measurement

The purpose of the semi-solid formulation viscosity measurement is to demonstrate that the semi-solid formulations disclosed herein have very low viscosity characteristics and are easily injected through a 23-21 gauge injection needle.

The viscosity measurement method comprises the following steps:

viscosity measurements for the semi-solid formulations were made on a calibrated Brookfield RVDV-I Prime CP model viscometer with a conical spindle CPE-51. First, a semi-solid formulation sample stored in a sealed glass bottle becomes a fluid viscous liquid after being heated to about 40-50 ℃ in an oven. Then, about 0.5 grams of the sample was weighed into the center of the heated sample cup. Air bubbles are avoided as much as possible. The sample cup was mounted on the viscometer and rotated at the appropriate speed to maintain the% torque between 10% and 100% while measuring the viscosity. The viscosity and torque% at the target temperature are recorded. Since these materials exhibit ointment properties at room temperature, the viscosity of the semisolid formulation is measured at 30 ℃ when the semisolid formulation forms a fluid viscous liquid under pressure. Centipoise (cP) and millipascal-seconds (mpa.s) are CGS and SI units of viscosity. 1 centipoise (1cP) 1 mpa · s (mpa.s). The viscosity of all semisolid formulations was determined at 30 ℃.

Viscosity data

Excellent physicochemical Properties-Low viscosity gel formulation

Castor oil is a liquid with a viscosity of about 700cP at 25 c and about 451cP at 30 c.

The viscosity values of the castor oil gel formulations consisting of the active ingredient show low viscosity characteristics, varying from 285cP to 347cP at 30 ℃. The gelling agent serves two purposes, one is to gel the castor oil and the other is to reduce the viscosity of the formulation to improve injectability.

Although these formulations are in gel form, they are easily injected through a 21-gauge needle, and a single injection, with or without a needle, can be injected more easily into the incision site.

Viscosity number of Castor oil gel formulations

The viscosity results for the castor oil gel formulations containing different active ingredients are summarized in table 12. The viscosity of all semi-solid formulations was measured at 30 ℃.

Table 12: viscosity results of castor oil gel formulations containing different active ingredients

Viscosity values of castor oil gel formulations containing different active ingredients showed lower viscosity characteristics, ranging from 285cP to 347cP at 30 ℃. All gels are waxy solids and act as lubricants to reduce the viscosity of the gel formulation due to the waxy nature of the long alkyl chains of the fatty acids. The active substance may also act as a plasticizer and reduce the viscosity of the gel formulation.

The castor oil gel formulations containing the different active ingredients listed in table 12 were easily injected with mechanical pressure (shear) using a 21 gauge needle.

Example 17 evaluation of skin reactions

The following Bupivacaine (BUP) castor oil gel formulations with and without anti-inflammatory effect and the semi-solid formulation previously developed using S701 were administered to each rat by subcutaneous injection on the dorsal side of a clean shave of the chest.

Semi-solid S701: S701/SUP A/BUP (79/13/8),

semi-solid S701+ BetV S701/SUP A/BUP (78.95/13/8/0.05),

Gel DM:CO/SUP DM/BUP(81/11/8),

Gel DM+BetV:CO/SUP DM/BUP/BetV(80.95/11/8/0.05).

data for the evaluation of edema/erythema response at the injection site are shown in Table 13

TABLE 13 skin response assessment

The injection site edema/erythema results for the test formulations are shown in tables 14 and 15. Due to the semi-solid formulation, animals had a distinct palpable lump immediately after injection in all dosing areas (edema score 2 to 3). Semi-solid S701 exhibited edema on days 1 and 2 and gradually regressed from day 3 to day 8. In the presence of 0.05% betamethasone valerate, the edema was eliminated. Semi-solid S701 also showed moderate erythema on days 1 and 2 and gradually regressed from day 3 to day 8. Erythema was reduced on days 1 and 2 in the presence of 0.05% betamethasone valerate.

The castor oil Gel formulation Gel DM showed only very slight or minimal edema and erythema at the injection site. This effect is lower in the presence of betamethasone valerate.

Table 14: 0.5mL subcutaneous injection produced a cutaneous response (edema)

Number of semisolid preparation	Day 1	Day 2	Day 3	Day 4	Day 5	Day 6	Day 7	Day 8
									S701	4.0	4.0	3.3	2.3	2.0	2.0	1.3	1.3
S701+BetV	2.0	1.7	1.7	1.0	1.0	1.0	1.0	0.7
									Gel DM	3.0	2.5	2.5	2.5	2.0	2.0	1.5	1.5
CO DM+BetV	2.5	2.0	2.0	1.5	1.5	1.5	1.0	1.0

TABLE 15 skin reaction (erythema) following subcutaneous injection of 0.5mL

The semi-solid gel preparation of loteprednol etabonate, latanoprost, celecoxib, triamcinolone acetonide and betamethasone is injected into rats subcutaneously, shows good in vivo biocompatibility, and has only minimal edema at the injection part and no erythema. Under anesthesia, the administration site of the semisolid gel formulation injection was reopened two weeks after the injection and was observed with the naked eye. The site of administration appeared pink and was normal, with no inflammation, and only a small amount of depot residue was observed at the site of administration.

EXAMPLE 18 rat sciatic nerve blockade assay

Male rats with a body weight of 200-250 g were used in the test to evaluate the duration of nerve block for each of the different semisolid formulations. The animals were treated daily and the rats were acclimated for more than one hour in the experimental environment prior to the experiment. The blocking test for sensory and motor nerves is as follows. In addition to the sensory test, the motor function test was conducted by detecting the gait posture and foot lifting and lowering of the rat moving hind legs at each time point. The handling and care of animals is in compliance with institutional, state, and federal animal welfare regulations. The protocol was agreed to IACAC.

All rats are anesthetized with 3.5-4% isoflurane oxygen and then maintained under anesthesia with 1.5-2% isoflurane. Under sterile conditions, the left leg area was shaved and an incision was made at the upper portion 1/3. The thigh muscles were gently separated by blunt dissection to expose the sciatic nerve. Under direct visualization, the semi-solid gel formulation was injected near the sciatic nerve deep in the hamstrings of the fascia plane. The most superficial fascia layer is closed with a single suture. The cut outer skin edges are aligned and closed with surgical staples. For all rats, a semi-solid formulation containing the drug was implanted on the left side of the sciatic nerve.

Hot plate experiment: at each time point, rats were placed on a hot plate at 56 ℃ and the delay of lifting (latency of lifting) time (for both feet of the animal) was recorded three times with at least 5 minutes intervals. The cut-off time was set to 10 seconds to prevent hyperalgesia or injury. The average of the 3 readings was taken as the final reading at a particular time point.

Recovery of foot lifting ability (Paw playing) test: for both feet, the animals were gently held by a trained researcher and one dorsum foot was slowly slid over the edge of the test platform at a time until the toes were reached and repeated five times. Each time, the rat scored 1 if it successfully placed its test foot on the platform surface (thus, the maximum score per foot was 5) and 0 if it failed.

Return on walking exercise ability (Paw motor ability) test: retention of ambulation test animals were evaluated according to the following levels using a scale of 1 to 4 (Castillo,1996, Anesthesiology 85: 1157-66):

(1)1 minute: normal appearance;

(2) and 2, dividing: dorsiflexion is complete, but toe opening is abnormal when the tail of the rat is lifted;

(3) and 3, dividing: complete plantarflexion without splaying ability;

(4) and 4, dividing: gait abnormalities occur.

The return walking motion capability assessment is also used for each time point. For both feet, the animals were held lightly on their backs by a trained experimenter.

Two weeks after bupivacaine administration, the skin of the surgical site was examined to see if wound healing was affected. Then, the administration site of the semisolid formulation was reopened under anesthesia and visually observed.

Bupivacaine castor oil gel preparation

When evaluated in a rat sciatic nerve block model, the pharmacodynamic activity of bupivacaine released from the castor oil gel formulation produced a greater analgesic effect than a pure castor oil bupivacaine oil formulation. A castor oil solution formulation of bupivacaine containing 8% by weight bupivacaine was used as a control formulation. Due to its relatively high viscosity and relatively slow dissolution of bupivacaine free base into body fluids, castor oil bupivacaine oil solutions can produce a limited analgesic response in the rat sciatic nerve block model for about 4-6 hours.

However, with the help of the gelling agent, the castor oil bupivacaine gel formulation provides a strong sensory and motor-blocking effect within the first 24 hours and prolonged partial block for up to 72 hours, giving the desired analgesic effect (moderate block on day two, partial block on day three, which matches the pain intensity profile of a typical surgical patient with extreme pain on day one, moderate pain on day two, and only slight pain on day three).

The bupivacaine castor oil solution formulation produced only 2 hours of strong motor retardation and 6 hours of partial motor retardation. To provide effective analgesia, a strong motor block is required for the first 24 hours after traumatic surgery. Motor function was reversible in all groups and returned to normal 72 hours after dosing.

Stability of castor oil semisolid gel formulations

The castor oil gel preparation containing the five active ingredients, loteprednol etabonate, latanoprost, celecoxib, triamcinolone acetonide and betamethasone is stable at room temperature and does not generate phase separation or precipitation or drug crystallization in one month of storage.

Claims

1. A pharmaceutical composition comprising:

(A) a glyceride mixture comprising: (i) ricinoleic acid triglyceride; and (ii) glycerides having a melting point between 37 ℃ and 100 ℃, preferably between 37 ℃ and 75 ℃, as gelling agents; wherein the weight ratio of (i) to (ii) is 50: 1-2: 1; and

(B) a therapeutically effective amount of an active ingredient; wherein the active ingredient comprises loteprednol or a pharmaceutically acceptable salt thereof, latanoprost or a pharmaceutically acceptable salt thereof, celecoxib or a pharmaceutically acceptable salt thereof, triamcinolone acetonide or a pharmaceutically acceptable salt thereof, and/or betamethasone or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1,

the ricinoleic acid triglyceride is castor oil; and/or

The glycerides having a melting point between 37 ℃ and 100 ℃ are selected from the following glycerides: (a) c₁₂To C₁₈A mixture of fatty acid triglycerides; (b) c₈To C₁₈A mixture of triglycerides; (c) mixtures of hydrogenated coconut glycerides; and (d) C₁₀To C₁₈A mixture of fatty acid triglycerides; and/or

The glyceride mixture has an aqueous solubility of less than 1mg/ml, preferably 0.1mg/ml or less, in a physiological pH buffer at 37 ℃.

3. The pharmaceutical composition of claim 2,

said C is₁₂To C₁₈The mixture of fatty acid triglycerides is SUP DM or SUP CM;

said C is₈To C₁₈The mixture of triglycerides is G43/01;

the mixture of hydrogenated cocoglycerides is WIT E85 or WIT E76;

said C is₁₀To C₁₈The mixture of fatty acid triglycerides is SUP D.

4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the active ingredient is present in an amount of 0.01 to 60% by weight, preferably 1 to 20% by weight, based on the total weight of the pharmaceutical composition.

5. The pharmaceutical composition of claim 1, wherein the active ingredient further comprises one or more of a second corticosteroid, a second analgesic, or a second anti-inflammatory agent;

preferably, the second corticosteroid is a glucocorticoid;

preferably, the second class of analgesics is selected from aspirin and atropine;

preferably, the second class of anti-inflammatory agent is a non-steroidal anti-inflammatory agent (NSAID) selected from the group consisting of ketoprofen, naproxen, meloxicam, COX-1 inhibitors and COX-2 inhibitors.

6. The pharmaceutical composition of any one of claims 1-5, wherein the pharmaceutical composition has one or more of the following characteristics:

the pharmaceutical composition is free of preservatives;

the pharmaceutical composition is a semi-solid gel;

the pharmaceutical composition is biocompatible, bioerodible, and homogeneous;

the viscosity of the pharmaceutical composition at 30 ℃ is 50-700cPS, preferably 200-400 cPs, more preferably 285-347 cPs; and

less than 80% of the active ingredient is released from the semi-solid gel in less than one week when tested in vitro at 37 ℃; preferably, the pharmaceutical composition releases the active ingredient for at least one week, preferably more than 4 weeks, when tested in vitro at 37 ℃; preferably, less than 80% of the active ingredient is released from the semi-solid gel within 1 to 16 weeks.

7. The pharmaceutical composition according to claim 1, wherein the weight ratio of the ricinoleic acid triglyceride to the glyceride having a melting point between 37 ℃ and 100 ℃ is 20: 1 to 2.5: 1, preferably 8: 1 to 2.5: 1, more preferably 6: 1 to 3: 1.

8. the pharmaceutical composition of claim 1, wherein the ricinoleic acid triglyceride comprises castor oil, and the glyceride having a melting point between 37 ℃ and 75 ℃ comprises SUP DM or SUP CM; wherein, the weight ratio of the castor oil to the SUP DM or the SUP CM is 6: 1 to 3: 1 and the water solubility of the glyceride mixture is less than 1mg/ml, preferably less than 0.1mg/ml, in a physiological pH buffer at 37 ℃.

9. Use of a pharmaceutical composition according to any one of claims 1 to 8, wherein the active ingredient comprises celecoxib, triamcinolone acetonide or betamethasone, for the preparation of a medicament for the treatment or prevention of pain and inflammation.

10. Use of a pharmaceutical composition comprising loteprednol etabonate or latanoprost as an active ingredient according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment or prevention of an ophthalmic disorder, and use of a pharmaceutical composition comprising loteprednol etabonate as an active ingredient according to any one of claims 1 to 8 in the manufacture of a medicament for the treatment or prevention of tonsillitis.