Patent Description:
What is described herein relates to a controlled release, semi-solid pharmaceutical composition comprising a local anesthetic and an anti-inflammatory drug in a semi-solid lipid vehicle comprising castor oil and a gelling agent, in the form of an injectable formulation for controlled delivery of the local anesthetic for treatment of post-operative pain.

Approximately <NUM> million surgeries are performed each year in the US and systemic opioids are used to manage postoperative pain, and pain is only adequately controlled in half of patients. Opioid postoperative pain management prescriptions are fueling the opioid epidemic as <NUM> million U. surgical outpatient become long-term opioid users each year with <NUM>% of these becoming addicted to opioids. This dire scenario is a result of permissive opioid prescribing, and inadequate pain coverage particularly within the first <NUM> hours post-surgery. Moreover, only <NUM> % of opioids prescribed at discharge are used leaving a huge reservoir of pills available for misuse and illicit diversion.

In an effort to reduce the need for opioid medications, anesthetics are administered locally, via an epidural injection, peripheral nerve block, or local infiltration. Unfortunately, the duration of action of presently approved anesthetics is less than <NUM> hours. The <NUM>-hour period immediately following surgery is the most painful and requires robust analgesia coverage to ensure pain relief and opioid abstinence. As more outpatient surgeries are being performed, adequate pain control upon discharge is crucial.

A prolonged-release formulation of the approved anesthetic, bupivacaine encapsulated within liposomes (EXPAREL®) provides a longer duration of action compared to aqueous bupivacaine, pain relief is generally only for <NUM> hours with an associated slight reduction in opioid use.

In a Phase <NUM> bunionectomy study using HTX-<NUM>, a pharmaceutical formulation comprising an anti-inflammatory, meloxicam, and bupivacaine poly (ortho ester) to treat postoperative pain, <NUM>% of patients remained opioid free post bunionectomy, compared to <NUM>% of patients using aqueous bupivacaine alone.

Research effort has been made to synthesize hydrolysis-resistant polyesterpoly(lactic acid-co-castor oil) for sustained release formulations of bupivacaine. Bupivacaine has been incorporated into hydrophobic, hydrolysis-resistant polyester-poly(lactic acid-co-castor oil) at <NUM>% (w/v), resulting in a slower degradation rate, prolonged drug release, and <NUM> to <NUM> days of nerve block. <NPL>, and <NPL>. This fatty acid based biodegradable polymer released <NUM>% of stored bupivacaine during one week without a burst of drug release. A single injection of the formulation caused motor blockade for <NUM> hours and sensory blockade for <NUM> hours. However, the formulation suffered significant burst release that led to systemic toxicity. Increasing the bupivacaine concentration to <NUM>% (w/v) prolonged the duration of sensory blockade to <NUM> hours and exhibited less burst release than with <NUM>% bupivacaine. This effect was attributed to increased formulation density and hydrophobicity, resulting in reduced water penetration into the drug-polymer matrix.

<NUM>% (w/v) bupivacaine in injectable and biodegradable poly(sebacic-coricinoleic acid) was shown to prolong sciatic nerve blockade from <NUM> to <NUM> hours. Incorporation of anhydride bonds (which undergo hydrolysis) in the polymer backbone rendered the formulation biodegradable. In vitro, <NUM>% of the incorporated drug was released over the course of one week.

Much effort has been made to develop controlled release local anesthetic drug products. The drug delivery vehicle typically consists of a polymeric matrix from which drug is released by diffusion and/or degradation of the matrix. The local anesthetic is typically entrapped or encapsulated in microspheres or microparticles which can be administered into the surgical cavity by injection or infusion in the form of implant. Various publications describe release properties of local anesthetics from glyceride media, as follows.

<NPL>, discloses results of measuring rates of release of bupivacaine from various oils. Larsen discloses applying an in vitro measurement under nonsink conditions (rotating dialysis cell) to model drug release following intra-articular injection to a joint cavity. Larsen discloses rates of release of bupivacaine from fractionated coconut oil (a mixture of C<NUM> and C<NUM> saturated fatty acids) <NUM>% release of the bupivacaine from the oil in less than two hours. Larsen also discloses results of measuring release of bupivacaine from MYRITOL® <NUM> PH (a triglyceride having a mixture of C<NUM> and C<NUM> saturated fatty acids) that were comparable to coconut oil. Larsen discloses that castor oil is considered the preferred excipient to modify drug release from oil solutions based on its history of parenteral administration. Larsen also discloses release rates of naproxen from a variety of oils, including MYRITOL® <NUM> PH, castor oil, SOFTIGEN® <NUM> alone or in combination with isopropyl myristate (IPM), and IMWITOR® <NUM> in combination with IPM, and that drug release rates from castor oil were slower than from other vegetable oils, most likely reflecting the hydrogen bond donating capability of the ricinoleic acid hydroxy group.

Castor oil has been used as a solvent in a commercial drug product AVEED® (testosterone undecanoate) injection for testosterone replacement therapy for intramuscular (gluteal muscle) administration. The United States Food and Drug Administration (FDA) found care must be taken to avoid intravascular injection because inadvertent escape of AVEED® into the vascular system may lead to vascular occlusion and short-term (<NUM> minutes or less) consequences of pulmonary oil microembolism (POME) characterized primarily by cough, but sometimes with other associated symptoms. The mechanical occlusion of the pulmonary vasculature from oil microembolization can cause acute transient pulmonary hypertension, resulting in a wide range of symptoms, from mild cough to circulatory collapse. It is postulated that POME results from microembolization of the oil drops to the lung vasculature, causing respiratory symptoms. Although other drug products also contain castor oil, the volume of castor oil in AVEED® is relatively greater than that of other products. Immediate/rapid release/dump of high volume of castor oil by IM injection may lead to vascular occlusion and potential short-term /transient POME.

Sundberg <CIT> discloses an aqueous stabilized pharmaceutical gelling composition comprising (a) an anesthetically effective amount of one or more local anesthetics selected from bupivacaine or lidocaine, (b) a monoglyceride or diglyceride, or mixture thereof of a long chain fatty acid in an amount of between <NUM> to <NUM>% by weight, (c) a free long chain saturated or unsaturated fatty acid, and/or (d) one or more solubilizers consisting of polysorbates, sorbitan fatty acid ester, glycerol formal, or a polyoxyethylated castor oil, in an amount of between <NUM> to <NUM>% by weight. These compositions are for topical administration supported by results of an in vitro mucoadhesion test.

<CIT> discloses a semi-solid controlled release composition containing a biocompatible and bioerodible semi-solid lipid matrix incorporating local anesthetic agents to form a semi-solid solution as well as the methods of manufacture thereof.

Richlin <CIT> discloses a composition for topically delivering and localizing therapeutic agents, wherein the composition comprises a local anesthetic agent selected from bupivacaine or mepivacaine, and an anti-inflammatory agent selected from ketoprofen, meloxicam, and naproxen.

While the above systems are useful, their manufacture processes are complicated, cumbersome and expensive. In addition, they are often associated with an initial higher release of drug immediately after injection (also called "burst") followed by inconsistent and poor drug release kinetics, thus lack of reliability in pain relief in animal studies and human trials. There remains a need for controlled release of drugs suitable for pain management. Therefore, a more effective sustained release anesthetic is needed to effectively manage postsurgical pain with a rapid onset of action for coverage over the first crucial <NUM> hours and then prolonged duration through <NUM> hours.

One aspect of the description is a pharmaceutical composition, comprising.

wherein the active agents are solubilized in the glyceride mixture at a concentration of <NUM>-<NUM> wt%; and wherein the pharmaceutical composition is a semi-solid gel which is biocompatible, bioerodible, homogeneous, and a single phase; and wherein the pharmaceutical composition consists of a semi-solid gel with a viscosity of <NUM>-<NUM> mPas at <NUM>.

In one embodiment of the pharmaceutical formulation, the active agents comprise a corticosteroid, an analgesic or an anti-inflammatory agent, preferably wherein the corticosteroid is a glucocorticosteroid; or wherein the anti-inflammatory agent is a non-steroidal anti-inflammatory agent (NSAID) selected from the group consisting of ketoprofen, naproxen, meloxicam, COX-<NUM> inhibitors, and COX-<NUM> inhibitors.

In another embodiment, the glyceride mixture comprises castor oil: SUP DM, and the weight ratio is <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM> or <NUM>:<NUM> (w:w).

In another embodiment, less than <NUM>% of the bupivacaine is released from a depot of the semi-solid gel in five days when measured in vitro at <NUM>.

In another embodiment, the viscosity is less than <NUM> mPas (cP) at <NUM>.

In another embodiment, the pharmaceutical composition releases bupivacaine for at least one week when measured in vitro at <NUM>.

In another embodiment, the pharmaceutical composition releases bupivacaine for at least two weeks when measured in vitro at <NUM>.

In another embodiment, the glyceride mixture has an aqueous solubility of less than <NUM>/ml or less than <NUM>/ml in a buffer of physiological pH at <NUM>.

In another aspect of the description, the glyceride mixture comprises (i) castor oil, and the active agents comprise a corticosteroid, an analgesic or an anti-inflammatory agent, preferably wherein the corticosteroid is a glucocorticosteroid, or wherein the anti-inflammatory agent is a non-steroidal anti-inflammatory agent (NSAID) selected from the group consisting of ketoprofen, naproxen, meloxicam, COX-<NUM> inhibitors, and COX-<NUM> inhibitors. Preferably, the glyceride mixture comprises castor oil, and the glyceride mixture comprises castor oil:SUP DM, <NUM>:<NUM> (w:w). Preferably, less than <NUM>% of the bupivacaine is released from a depot of the semi-solid gel in five days when measured in vitro at <NUM>, the viscosity is less than <NUM> mPas (cP) at <NUM>, the pharmaceutical composition releases bupivacaine for at least one to two weeks when measured in vitro at <NUM>, and the glyceride mixture has an aqueous solubility of less than <NUM>/ml or less than <NUM>/ml in a buffer of physiological pH at <NUM>.

BRIEF DESCRIPTION OF THE DRAWINGS (In <FIG>, only the formulations falling within the scope of the claims are according to the invention; any other embodiment not falling within the scope of the claims is disclosed for illustrative purposes).

The formulations described herein provide a prolonged period of bupivacaine release such that therapeutic concentrations of the drug are achieved rapidly and maintained for at least <NUM> hours. The potential benefit of the prolonged release profile is to achieve rapid pain relief, maintaining higher levels of active drug at the site of the pain over time to potentially provide greater relief from pain, and to maintain pain relief for <NUM> hours following surgery.

The animal model studies described herein demonstrate continuous release of the pain-relieving agent bupivacaine for <NUM> hours.

No significant initial burst is found in the formulations described herein. Typically, controlled release injections are associated with an initial burst (higher release of drug immediately after injection). In vitro drug release and animal studies have shown that injectables based on our bioerodible semi-solid gel technology produce less post-injection burst that is typically associated with other commercially available injectable controlled release technologies. For example, NUTROPIN® (somatropin of rDNA origin for injection) has a drug release profile of huge burst followed by very slow drug release.

Drug concentration in the semi-solid gel technology described herein can be as high as <NUM>%, considerably greater than what is typical with other controlled release technologies. For example, a long-acting mepivacaine was developed using another semi-solid drug delivery technology in which only about <NUM> wt% of mepivacaine could be loaded into a polyorthoester vehicle due to the drug's low solubility in the vehicle. In addition, the solubility of bupivacaine in typical vegetable oils is less than <NUM> wt%. The solubility of bupivacaine in olive oil, corn oil, sesame oil, and vegetable oil were determined to be <NUM> wt%, <NUM> wt%, <NUM> wt% and <NUM> wt% respectively.

The semi-solid gel formulations described herein have very low viscosity, preferably <NUM> mPa. s or less at <NUM>. Therefore, they can be injected through a small needle such as a <NUM> or even a <NUM> needle and will exhibit minimal pain (similar to aqueous solution injection) during injection. Additionally, since the semi-solid gel formulations described herein have a higher capacity for drug loading, less volume of drug product is required to be injected. Small injection volumes and low viscosity semi-solid formulations result in easier and less painful administration. Polyorthoester semisolid formulations have a viscosity of thousands of mPa. s, which is difficult to be injected with a <NUM> needle.

The formulations described herein comprise glycerides with natural fatty acids. These compounds are readily hydrolyzed to glycerol and free fatty acids by lipase. These compounds are non-toxic and exhibit excellent biocompatibility in the body. The formulations described herein are biodegradable, bioerodible, and fully resorbable. In animal studies, at two weeks after dosing, no adverse effect of the semi-solid formulation on wound healing was observed. The administration site appeared to be pinkish, and the sciatic nerve appeared to be normal, no inflammation, necrosis, ulceration, or infection was observed.

Compared to microspheres and other polymer-based controlled release injectable systems, the semi-solid gel formulations described herein are readily manufactured at low cost. The active ingredient(s) and semi-solid gel vehicle components are simply mixed without the use of solvents at relatively low elevated temperatures. Note that since relatively low-melting point solid glycerides (less than <NUM>) (gelling agents) are used, the manufacturing process is at about <NUM>.

Further, the formulations described herein can be administered directly for site specific delivery. The formulations provide a sustained drug release over a period of days to a month resulting in increased duration of pharmacological action, and reduced frequency of drug administration. The formulations also produce reduced side effects (due to local drug delivery) when compared with systemic administration. The ease of use should produce improved patient compliance.

All technical and scientific terms are used herein according to their conventional definitions as they are commonly used and understood by those of ordinary skill in the art of drug delivery. Specific terms for the description herein will be defined below.

"Active agent" includes any locally or systemically acting active agents which may be administered to a subject by topical application or by subcutaneous, subconjunctival, intradermal, intramuscular, intraocular, or intra-articular injection. Examples of these agents include, but not limited to, anti-infectives (including antibiotics, antivirals, fungicides such as itraconazole, scabicides or pediculicides), antiseptics (e.g., benzalkonium chloride, chlorhexidine gluconate, nitrofurazone, or nitromersol), steroids (e.g., estrogens, progestins, androgens, or adrenocorticoids), therapeutic polypeptides (e.g., exenatide, octreotide, insulin, erythropoietin, or morphogenic proteins such as bone morphogenic protein), corticosteroids, analgesics and anti-inflammatory agents (NSAIDs) (e.g., aspirin, ibuprofen, naproxen, ketorolac, indomethacin, meloxicam, COX-<NUM> inhibitors, or COX-<NUM> inhibitors), chemotherapeutic and anti-neoplastic agents (e.g., paclitaxel, mechlorethamine, cyclophosphamide, fluorouracil, thioguanine, carmustine, lomustine, melphalan, chlorambucil, streptozocin, methotrexate, vincristine, bleomycin, vinblastine, vindesine, dactinomycin, daunorubicin, doxorubicin, or tamoxifen), <NUM>-hydroxytryptophan (serotonin) <NUM> (<NUM>-HT<NUM>) receptor antagonists for the prevention and treatment of nausea and vomiting following chemotherapy (e.g., granisetron, ondansetron, or palonosetron), narcotics (e.g., morphine, meperidine, or codeine), antipsychotics including typical antipsychotics (e.g., haloperidol or fluphenazine) and atypical antipsychotics (e.g., risperidone, clozapine, olanzapine, or paliperidone), antiangiogenic agents (e.g., combrestatin, contortrostatin, or anti-vascular endothelial growth factor), polysaccharides, vaccines, antigens, DNA and other polynucleotides, antisense oligonucleotides, or siRNA.

Abbreviations used: bupivacaine, BUP; betamethasone, BET; betamethasone valerate, BETV; ketoprofen, KETO; methylprednisolone, MP; triamcinolone acetonide, TA; and meloxicam, MELO.

The present semi-solid formulation described herein may also be applied to other locally acting active agents, such as astringents, antiperspirants, irritants, rubefacients, vesicants, sclerosing agents, caustics, escharotics, keratolytic agents, sunscreens and a variety of dermatologics including hypopigmenting and antipruritic agents. Only the formulations falling within the scope of the claims, comprising bupivacaine, are according to the invention.

The term "semi-solid" denotes the physical state of a material that is flowable under a moderate pressure. More specifically, the semi-solid material has a viscosity of <NUM>-<NUM> mPa·s (cP) at <NUM>° C.

The term "bioerodible" refers to a material that gradually decomposes, dissolves, hydrolyzes and/or erodes in situ. Generally, the "bioerodible" semi-solid gel described herein are materials that are hydrolizable, and bioerode in situ primarily through both lipolysis and hydrolysis.

The semi-solid lipids, solvent and other agents of the description must be "biocompatible"; that is, they must not cause irritation or necrosis in the environment of use. The environment of use is a fluid environment and may comprise a subcutaneous, subconjunctival, intramuscular, intravascular (high/low flow), intramyocardial, adventitial, intratumoral, or intracerebral portion, wound sites, tight joint spaces or body cavity of a human or animal.

Castor oil is the triglyceride component of the semi-solid formulations described herein. Castor oil is a triglyceride in which approximately <NUM>% of fatty acid chains are ricinoleates. Oleate and linoleates are the other significant components. Castor oil has been used as a solvent (to emulsify and solubilize other water-insoluble substances) in some injectable pharmaceutical products, but is most widely used in topical formulations, including ophthalmic preparations, where it is used for its emollient effect.

Castor oil is a liquid with a viscosity of approximately <NUM> mPa (cP) at <NUM>. Although it is a relatively viscous vegetable oil, when a drop of castor oil is added to water or PBS at <NUM>, it will immediately spread out and dissipate on the surface of aqueous solution and eventually form small droplets. Therefore, castor oil is not suitable to serve as a sustained release depot.

However, once castor oil is converted to hydrogenated castor oil (castor wax), a hard, high melting point (<NUM> to <NUM>) wax, by the hydrogenation of castor oil using a catalyst, hydrogenated castor wax has been used as an extended release agent in oral and topical pharmaceutical formulations. In oral formulations, hydrogenated castor oil has been used to prepare sustained release tablets and used as capsule lubricant preparations. In topical formulations, it has been used to provide stiffness to creams and emulsions.

Experimental results disclosed below using bupivacaine castor oil solution formulation show that castor oil can only extend bupivacaine's analgesia effect from approximately two hours to four to six hours in a clinically relevant pain model, rat sciatic nerve blockade, due to its relatively high viscosity and relatively slow dissolution of bupivacaine free base into body fluid.

What is disclosed herein is the surprising finding that when a solid gelling agent such as SUPPOCIRE® DM (SUP DM) is added to castor oil, castor oil changes into a soft semisolid gel. When the SUP DM is at <NUM>%, gelation occurs very slowly at room temperature (flowable at <NUM> body temperature). Gelation occurs at room temperature when SUP DM is at or above <NUM>%. As the amount of SUP DM increases, it takes less time to start gelation. At a <NUM>% level, the semi-solid gel formed is still a soft gel and is injectable with <NUM> needle. When the amount of SUP DM increases to <NUM>%, the semi-solid gel formed became a relatively hard gel and is difficult to be injected with a <NUM> needle.

The castor oil gels formed are characterized by their property of changing from a fluid at room temperature to a gel at room temperature, and retain as a well-defined gel when the semi-solid gel is placed into water at <NUM>.

In addition, castor oil slowly released into water, probably due to the cohesive interaction between castor oil and the gelling agent and the relatively hydrophobic semi-solid gel structure. Results herein show the release kinetics of active drugs from formulations comprising CO. A stable gel formulation will ensure the formulation remains as a long-lasting well-defined depot once administrated into the human body to control the gradual release of active drugs and could prevent undesirably rapid release of castor oil into animal or human's bloodstream causing vascular occlusion and potential pulmonary oil microembolism. Furthermore, the low viscosity (approximately <NUM> mPa (cP) at <NUM>) nature of the soft semisolid gel formulation formed can be readily injected through a <NUM> needle or applied for local drug delivery.

The gelling agents for the present description are pharmaceutically acceptable and castor oil-compatible materials. As castor oil is a mixture of triglycerides, the solid or semisolid glycerides are compatible with castor oil to form a semi-solid gel.

More specifically, suitable gelling agents can be solid triglycerides of mixed esters, solid partial glycerides of fatty acids, mixtures of triglyceride, diglyceride or monoglyceride, and other castor oil compatible gelling agents such as sterol ester lanolin. Since these gelling agents are structurally similar to castor oil, they are expected to be compatible. Physically, these materials are in the form of a solid or semi-solid lipid at room temperature and should also have low solubility with an aqueous solubility of less than <NUM>/mL in physiological pH buffer at <NUM>, preferably less than <NUM>/mL. If the gelling agents are too hydrophilic and water soluble, it will cause a significant burst of the active drug(s), especially when the active drugs are relatively soluble, which may cause undesirable side effects. If the gelling agent is significantly more insoluble than the main semi-solid lipid, it will retain in the body significantly longer when the active drug and the main semi-solid lipid are completely dissolved and resorbed by the body.

Useful solid or semi-solid lipids compatible with castor oil to form a semi-solid gel delivery vehicle for active drugs include solid triglycerides of mixed esters, solid partial glycerides of fatty acids, mixtures of triglyceride, diglyceride or monoglyceride, and other castor oil compatible gelling agents such as sterol ester lanolin with a melting point of between <NUM> and <NUM>, and more preferably between <NUM> and <NUM>. When the melting point gets too high, especially at higher concentration (><NUM> wt%), it will cause the hardening of the semisolid gel, and affect the injectability of the semi-solid gel formulations.

Solid triglycerides that can be added to castor oil to form a semi-solid gel include SUP DM, a mixture of C<NUM> to C<NUM> triglycerides with a melting point of <NUM> to <NUM>; SUPPOCIRE® D (SUP D), a mixture of C<NUM> to C<NUM> triglycerides with a melting point of <NUM> to <NUM>; SUPPOCIRE® CM (SUP CM), a mixture of C<NUM> to C<NUM> triglycerides with a melting point of <NUM> to <NUM>; and SOFTISAN® <NUM> (S378), a triglyceride of C<NUM> to C<NUM> fatty acids with a melting point of <NUM> to <NUM>.

Solid partial glycerides of fatty acids that can be added to castor oil to form a semi-solid gel include GELUCIRE <NUM>/<NUM> (G43/<NUM>), a glyceride of C<NUM> to C<NUM> fatty acids with a melting point of <NUM> to <NUM>; GELEOL™, a glyceryl monostearate with a melting point of <NUM> to <NUM>; and GELUCIRE <NUM>/<NUM> (G39/<NUM>), a glyceride mixture of mono-, di-, and triglycerides of C<NUM> to C<NUM> fatty acids with a melting point of <NUM> to <NUM>.

Mixtures of triglyceride, diglyceride or monoglyceride that can be added to castor oil to form a semi-solid gel include WITEPSOL® E85 (WIT E85) with a melting point of <NUM> to <NUM>; and WITEPSOL® E76 (WIT E76) with a melting point of <NUM> to <NUM>.

Furthermore, other castor oil compatible gelling agents such as sterol ester lanolin with a melting point of <NUM>° can be added to castor oil to form a semi-solid gel.

The concentrations of gelling agents added to castor oil may vary. For example, the concentration (wt%) of the gelling agents may be in the range of about <NUM> to <NUM> wt%, preferably about <NUM> to <NUM> wt%.

The castor oil mixed with the gelling agents (the final delivery vehicle), and the delivery vehicle with the active ingredients can form a defined long-lasting depot once administered into the body at <NUM>° C, and will gradually degrade/erode, and be dissolved into the body liquids, and the semi-solid lipids will eventually be hydrolyzed to natural free glycerol and free fatty acids by lipase through a process called lipolysis.

The castor oil semi-solid gel formulation of an active agent described herein may be prepared by directly mixing together with castor oil and the gelling excipient, or by mixing with the semi-solid gel already formed. The mechanical mixing process is performed at a suitable temperature, typically between <NUM> and <NUM>, to completely melt the gelling excipients and castor oil into a solution, and dissolve or mill by any mechanical means the active drugs to form a clear solution or a homogeneous suspension. A vacuum may be applied to avoid air bubbles, and nitrogen may be applied to reduce oxidation of active drugs and the delivery vehicle components. After achieving a homogeneous and uniform pharmaceutical composition, the active agent semi-solid gel formulation can be cooled down to room temperature.

Local anesthetics induce a temporary nerve conduction block, and a local analgesic effect for pain relief in surgical procedures, dental procedures, and injuries.

Clinical local anesthetics belong to one of two classes: amide and ester local anesthetics. Amide local anesthetics include bupivacaine, ropivacaine, levobupivacaine, dibucaine, etidocaine, lidocaine and mepivacaine. Ester local anesthetics include benzocaine, chloroprocaine, cocaine, proparacaine and tetracaine. The local anesthetics may be present as the free base, or as an acid addition salt, or as a mixture thereof. A mixture of two different local anesthetics or a mixture of the same local anesthetics in two forms, the free base form and the acid addition salt, may be used to achieve the desired pharmacological effect and release rate and duration.

The active agents (free base) can be readily converted into a salt with fatty acids and other pharmaceutically acceptable acids. Both saturated and unsaturated fatty acids such as lauric acid, myristic acid, palmitic acid, and oleic acid are natural fatty acids, and can be used. This conversion can increase its compatibility and solubility in the semi-solid vehicle. The selected active agents can be converted into a salt in advance before being incorporated into the semi-solid vehicle or can be added into the semi-solid vehicle simultaneously at a <NUM>:<NUM> molar ratio or other molar ratios during the formulation manufacturing process.

The amount of active agent(s) present in the composition can vary over a wide range depending on a number of factors, such as the therapeutically effective dose of the active drug, the desired duration of biological or therapeutic effect, and the release profile of the composition. The concentration of the active agent is in the range of <NUM>-<NUM> wt%, preferably about <NUM> to <NUM> wt%, or more preferably about <NUM> to <NUM> wt%.

A corticosteroid, an analgesic or an anti-inflammatory agent can be added to the local anesthetic semi-solid gel formulation; preferably wherein the corticosteroid is a glucocorticosteroid; or wherein the anti-inflammatory agent is a non-steroidal anti-inflammatory agent (NSAID) selected from the group consisting of ketoprofen, naproxen, meloxicam, COX-<NUM> inhibitors, and COX-<NUM> inhibitors. The concentrations of the anti-inflammatories are selected based on the potency of the drugs and their clinical doses. The concentration of the anti-inflammatory agent may be in the range of about <NUM> to <NUM> wt%, preferably about <NUM> to <NUM> wt%, or more preferably about <NUM>% to <NUM>% for local inhibition of inflammation.

The glyceride mixture comprises castor oil:gelling agents having a relative concentration of <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM>, <NUM>:<NUM> or <NUM>:<NUM> (w:w).

The concentration (wt%) of the gelling agents may be in the range of about <NUM> to <NUM> wt%, preferably about <NUM> to <NUM> wt%.

In addition, other pharmaceutically acceptable agents such as penetration enhancers, including natural penetration 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 may be added.

This pharmaceutical semi-solid gel composition of the present semi-solid formulation described herein has a smooth semi-solid gel texture. Therefore, the composition can be filled into syringes with a <NUM> to <NUM> needle for subcutaneous, subconjunctival, intradermal, intramuscular, epidural or intrathecal injection, or can also be conveniently applied onto already-open sites such as surgical wounds/site or exposed skin or mucous membrane.

After administration by injection or topical application, the active agent is released from the composition in a sustained and controlled manner. The rate of release may be regulated in a variety of ways to accommodate the desired duration of therapeutic effect. For example, the rate may be increased or decreased by using different level of gelling agents. It may also be altered by selecting different gelling agents or by changing their amount, or the combination thereof. In addition, lower water solubility forms of active agents such as their base forms, or as complexes with fatty acids may be used to delay the release of active agents.

The local anesthetic semi-solid gel pharmaceutical compositions of the present description can be topically applied onto already-open sites such as skin or mucous membrane or filled into syringes and directly injected into the surgical cavity and at different layers within the wound, such as across the peritoneal incision and directly below the skin incision. This drug product enables localized treatment of both the incisional and deep visceral pain components normally associated with moderate and major surgery. This drug product provides pain relief for the first three days following surgery when pain is most debilitating. This product has the potential to be widely used to manage post-operative pain following moderate/major surgeries, e.g., abdominal, gynecological, thoracic, or orthopedic surgeries.

Exemplary compositions of this semi-solid formulation described herein, and their uses, include: compositions containing ophthalmic drugs, corticosteroids such as loteprednol for the treatment of inflammation of the eye; glaucoma drugs such as latanoprost for the treatment of open-angle glaucoma or ocular hypertension; antiangiogenic agents such as combrestatin for the treatment of macular degeneration and retinal angiogenesis; and other compositions for the controlled release of ophthalmic drugs to the eye. Only the formulations falling within the scope of the claims are according to the invention.

The amount of active agent(s) present in the composition can vary over a wide range depending on a number of factors, such as the therapeutically effective dose of the active drug, the desired duration of biological or therapeutic effect, and the release profile of the composition. The concentration of the active agent is in the range of <NUM>-<NUM> wt%, preferably about <NUM> to <NUM> wt%.

The concentration of the main semi-solid lipid may be in the range of about <NUM> to <NUM> wt%, preferably about <NUM> to <NUM> wt%. The concentration of the first modifying excipient may be in the range of about <NUM> to <NUM> wt%, preferably about <NUM> to <NUM> wt%. The concentrations of the second type of gelling agents may be in the range of about <NUM> to <NUM> wt%, preferably about <NUM> to <NUM> wt%. In addition, other pharmaceutically acceptable agents such as antioxidants, preservatives, and other inert agents such as coloring or flavoring agents may be added.

SOFTIGEN® <NUM> (S701) is manufactured through trans-esterification of castor oil with glycerol in the presence of sodium hydroxide. Castor oil (CO) is the starting material for S701. S701 only cause mild/moderate reversible inflammatory response at the administration site, but does not affect wound healing, or scar formation in rat, rabbit, and dog studies.

The inventors found that batches of S701 were inconsistent, i.e., appearance varied from liquid, to partial liquid/partial semi-solid, to semi-solid, or paste, and that this variation affected the physical state and in vitro release of formulations. For example, the in vitro release of a drug is faster if the batch of S701 used is a liquid.

CO is a consistent material with respect to composition and physical properties such as viscosity. Castor oil is an oil solution, not a sustainable "depot". Upon injection, it can cause vascular occlusion and potential pulmonary oil microembolism, especially using a large bolus (<NUM>-<NUM>). Rapid release or dumping of relatively large volume of castor oil could become a safety issue.

One object of studies summarized herein was to change castor oil into a stable gel that controls the release of a solubilized drug, and also controls the release of castor oil into surrounding tissue. Another object was to prevent rapid release of drug and/or dumping of castor oil.

Pharmaceutically acceptable gelling agents were tested. Aluminum salts of fatty acids such as aluminum stearate and magnesium stearate are commonly used. Polymers such as carboxymethyl cellulose, polyvinyl alcohol, and polyvinylpyrrolidone are also used. Polysaccharides such as natural pectin and starches are typically used for aqueous systems, and are not compatible with CO. It was found that pectin from different sources provides different gelling abilities, due to variations in molecular size and chemical composition. Like other natural polymers, a major problem with pectin is inconsistency in reproducibility between samples, which may result in poor reproducibility in drug delivery characteristics.

Gelling experiments were performed as follows. The targeted amounts of gelling agents and the castor oil were weighed and transferred to a glass vial and sealed. The mixture was heated to about <NUM> in a water bath for about ten minutes, and then vortexed for one minute. The procedure was repeated three times with a total of <NUM> minutes to dissolve the gelling agents into castor oil. Three polymers, carboxymethyl cellulose, polyvinyl alcohol, and polyvinylpyrrolidone were tested at <NUM>% level (<NUM> of polymer was added to <NUM> of castor oil, and heated and vortexed at <NUM> for <NUM> minutes. None of them were soluble at all in castor oil.

Aluminum distearate was tested at <NUM>%, <NUM>%, and <NUM>% in castor oil. Results showed that the solubility of aluminum distearate in castor oil was less than <NUM>% after being heated and vortexed at <NUM> for <NUM> minutes. No gel formation occurred when cooled to room temperature overnight.

None of the above "gelling agents" tested were soluble and compatible with CO.

Relatively high melting point glycerides were then tested measuring the time from start gelation and complete gelation, and release of castor oil at <NUM> in water. In vitro, and in vivo studies showed that formulations comprising relatively high melting point glycerides and CO provided significantly better controlled bupivacaine release, and thus improved analgesic efficacy. Further, CO is a triglyceride, and exhibited less inflammation than commercial S701, which is a mixture of mono-, di- and triglycerides.

Addition of an anti-inflammatory agent significantly improved efficacy.

The solubility of bupivacaine in castor oil was determined by dissolving bupivacaine into castor oil by mixing the components at an elevated temperature of <NUM>-<NUM> to form a clear solution which resulted as a clear oil solution when cooled down to ambient temperature. Bupivacaine ranging from <NUM>% up to <NUM>% can be readily dissolved into castor oil.

The required amount of gelling agent to form a castor oil semi-solid gel formulation in the presence of <NUM> wt% bupivacaine was determined by mixing the components at an elevated temperature of <NUM>-<NUM> to form a clear solution while mixing and resulted as a homogeneous semi-transparent or opaque gel formulation after cooling down to room temperature. The results in Table <NUM> show that gelling agent SUP DM ranging from <NUM>% up to <NUM>% can form a semi-transparent or opaque semi-solid gel formulation.

When the gelling agent SUP DM is at <NUM>%, gelation occurs very slowly at room temperature (flowable at <NUM> body temperature). When SUP DM is at or above <NUM>%, gelation occurs at <NUM>. As the amount of SUP DM increases, it takes less time to start gelation. At <NUM>% level, the semi-solid gel formed is still a soft gel and is injectable with <NUM> needle. When the amount of SUP DM increases to <NUM>%, the semi-solid gel formed became a relatively hard gel and is difficult to be injected with a <NUM> needle. The results suggest that <NUM> % to <NUM> % of SUP DM can be used as a gelling agent to form a nice bupivacaine semi-solid gel formulation with good syringeability. The sample "Gel F01" is not according to the invention.

The castor oil gels formed are characterized by their property of changing from a fluid at room temperature to a gel at room temperature, and retain as a well-defined gel when the semi-solid gel is placed into water at <NUM>. A castor oil bupivacaine semi-solid gel formulation was prepared with <NUM>% SUP DM when placed and tested in water at <NUM>.

In addition, it was observed that castor oil was very slowly released out into water, potentially due to the cohesive interaction between castor oil and the gelling agent and the relatively hydrophobic semi-solid gel structure.

Bupivacaine ranging from <NUM>% up to <NUM>% can be readily dissolved into the semisolid lipid mixture of castor oil and SUP DM mixture. Although up to <NUM>% of bupivacaine was soluble in the final semi-solid gel formulation mixture, less than <NUM>% was selected to avoid potential drug crystallization during long term storage.

The concentration of bupivacaine is selected based on its potency and clinical doses. The target bupivacaine concentration is <NUM>-<NUM>/mL based on the maximum recommended single adult dose of <NUM> bupivacaine hydrochloride (Bupivacaine PI) for a dose volume of <NUM>-<NUM> for a typical <NUM>-<NUM> length surgical opening.

Additional castor oil compatible gelling agents suitable to form a bupivacaine semi-solid gel formulation were identified using the above experimental approach. Besides SUP DM, a mixture of C<NUM> to C<NUM> triglycerides with a melting point of <NUM> to <NUM>, other solid or semi-solid triglycerides include SUPPOCIRE® D (SUP D), a mixture of C<NUM> to C<NUM> triglycerides with a melting point of <NUM> to <NUM>; SUPPOCIRE® CM (SUP CM), a mixture of C<NUM> to C<NUM> triglycerides with a melting point of <NUM> to <NUM>; and SOFTISAN® <NUM> (S378), a triglyceride of C<NUM> to C<NUM> fatty acids with a melting point of <NUM> to <NUM>. These were also tested as gelling agents to enable castor oil to form semi-solid gel formulations in the presence of bupivacaine.

The semi-solid local anesthetic pharmaceutical compositions below were prepared as follows: The local anesthetics, castor oil, and gelling agents were added to a glass container, and then heated to about <NUM> to <NUM> depending on the properties of local anesthetics and the vehicle components used to completely melt semi-solid lipid and gelling agents into a solution, and completely dissolve the active drugs into the delivery vehicle to form a clear solution while mixing. After achieving a homogeneous and uniform pharmaceutical composition, the local anesthetic semi-solid formulation can be cooled down to ambient temperature naturally.

Commercial products were used according to Table <NUM>, which are available in GMP quality and quantity. Only the glycerides having a melting point between <NUM> and <NUM> are according to the invention.

The SUP D mixture of C<NUM> to C<NUM> triglycerides has a melting point of <NUM>° to <NUM>° C. The CO and SUP D ratio study is shown in Table <NUM>. The targeted amount of each component was weighed to a glass vial and heated to about <NUM> in a water bath, and mixed/vortexed until all components are completely dissolved and form a clear solution.

It takes about the same time for SUP DM and SUP D to start and complete gelation because they exhibit similar properties and melting points. Approximately <NUM> of the hot solution was filled into a <NUM> prefilled syringe, and steam-sterilized under <NUM> for <NUM> minutes. They appeared as a homogeneous opaque gel with or without steam sterilization after cooling down to room temperature at <NUM> to <NUM> wt% gelling agent level, and are injectable with <NUM> needle.

The SUP CM mixture of C<NUM> to C<NUM> triglycerides has a melting point of <NUM> to <NUM>. The CO and SUP CM ratio study is shown in Table <NUM>. The targeted amount of each component was weighed to a glass vial and heated to about <NUM> in a water bath, and mixed/vortexed until all components are completely dissolved and form a clear solution.

It takes longer for SUP CM than those for SUP DM to start and complete gelation because SUP CM has a lower melting point.

Approximately <NUM> of the hot solution was filled into a <NUM> prefilled syringe, and steam-sterilized under <NUM> for <NUM> minutes. They appeared as a homogeneous opaque gel with or without steam sterilization after cooling down to room temperature at <NUM> to <NUM> wt% gelling agent level, and are injectable with <NUM> needle.

The S378 mixture of triglycerides of C<NUM> to C<NUM> fatty acids has a melting point of <NUM>° to <NUM> and is in the form of a semi-solid. Its gelling power is less than those in the form of hard solid, higher amount/concentration compared to other solid triglyceride was used. At <NUM> wt% S378 level, it takes about <NUM>:<NUM> minutes to start gelation, but <NUM>:<NUM> minutes to complete gelation.

The CO and S378 ratio study is shown in Table <NUM>. The samples "S378 F03" and "S378 F04" are not according to the invention. The targeted amount of each component was weighed to a glass vial and heated to about <NUM> in a water bath, and mixed/vortexed until all components are completely dissolved and form a clear solution.

Approximately <NUM> of the hot solution was filled into a <NUM> prefilled syringe, and steam-sterilized under <NUM> for <NUM> minutes. They appeared as a homogeneous opaque gel with or without steam sterilization after cooling down to room temperature at <NUM> to <NUM> wt% gelling agent level, and are injectable with <NUM> needle. At <NUM>% level, the formulation is still flowable after cooling down to room temperature.

Hydrogenated castor oil solid triglyceride (HCO) has a relatively high melting point of <NUM> to <NUM>. Due to its high melting point, this gelling agent needs to be heated above <NUM> to be completely melted and homogeneously mixed with castor oil to form a semi-solid gel.

The CO and HCO ratio study is shown in Table <NUM>. The targeted amount of each component was weighed to a glass vial and heated to about <NUM> in a water bath, and mixed/vortexed until all components are completely dissolved and form a clear solution. Approximately <NUM> of the hot solution was filled into a <NUM> prefilled syringe, and steam-sterilized under <NUM> for <NUM> minutes. They appeared as a homogeneous opaque gel with or without steam sterilization after cooling down to room temperature at <NUM> to <NUM> wt% gelling agent level and are injectable with <NUM> needle at <NUM> and <NUM> wt% level. At <NUM>% level, it takes <NUM>:<NUM> minutes to start gelation, and <NUM> minutes to complete gelation. The formulation became a relatively hard gel and is difficult to be injected with a <NUM> needle.

Solid partial glycerides of fatty acids include G43/<NUM>, a mixture of C<NUM> to C<NUM> triglycerides with a melting point of <NUM> to <NUM>; GELEOL™, a glyceryl monostearate with a melting point of <NUM> to <NUM>; COM, a glyceryl behenate with a melting point of <NUM> to <NUM>; and G39/<NUM>, a glyceride mixture of mono-, di-, and triglycerides of C<NUM> to C<NUM> fatty acids with a melting point of <NUM> to <NUM>. These were tested as gelling agents to enable castor oil to form semi-solid gel formulations in the presence of bupivacaine. The combination of castor oil with COM is not according to the invention.

The G43/<NUM> mixture of C<NUM> to C<NUM> triglycerides has a melting point of <NUM> to <NUM>. The CO and G43/<NUM> ratio study is shown in Table <NUM>. The targeted amount of each component was weighed to a glass vial and heated to about <NUM> in a water bath, and mixed/vortexed until all components are completely dissolved and form a clear solution.

It takes about <NUM>:<NUM> minutes and <NUM>:<NUM> minutes to start gelation, and <NUM>:<NUM> minutes and <NUM>:<NUM> minutes to complete gelation for <NUM>% and <NUM>% G43/<NUM> respectively.

The CO and COM ratio study is shown in Table <NUM>. This solid glyceryl behenate has a melting point of <NUM> to <NUM>. The targeted amount of each component was weighed to a glass vial and heated to about <NUM> in a water bath, and mixed/vortexed until all components are completely dissolved and form a clear solution.

Approximately <NUM> of the hot solution was filled into a <NUM> prefilled syringe, and steam-sterilized under <NUM> for <NUM> minutes. It appeared as a homogeneous opaque gel with or without steam sterilization after cooling down to room temperature at <NUM> to <NUM> wt% gelling agent level. It is injectable with <NUM> needle at <NUM> and <NUM> wt% level. At <NUM>% level, the formulation became a relatively hard gel and is not injectable with a <NUM> needle.

The CO and GEL ratio study is shown in Table <NUM>. This solid glyceryl monostearate has a melting point of <NUM> to <NUM>. The targeted amount of each component was weighed to a glass vial and heated to about <NUM> in a water bath, and mixed/vortexed until all components are completely dissolved and form a clear solution.

Mixtures of triglyceride, diglyceride or monoglyceride such as WIT E85 with a melting point of <NUM> to <NUM>, and WIT E76 with a melting point of <NUM> to <NUM>, were tested as gelling agents to enable castor oil to form semi-solid gel formulations in the presence of bupivacaine.

The CO and WIT E85 ratio study is shown in Table <NUM>. The targeted amount of each component was weighed to a glass vial and heated to about <NUM> in a water bath, and mixed/vortexed until all components are completely dissolved and form a clear solution.

It takes about <NUM>:<NUM> minutes and <NUM>:<NUM> minutes to start gelation, and about <NUM>:<NUM> minutes and <NUM>:<NUM> minutes to complete gelation.

LAN is an "ester", structurally similar to "glyceryl ester", and is compatible with triglyceride castor oil. It has a melting point of <NUM>°. At <NUM> wt% LAN, it takes about <NUM>:<NUM> minutes to start gelation, but <NUM>:<NUM> minutes to complete gelation due to its high viscosity.

The CO and LAN ratio study is shown in Table <NUM>. The targeted amount of each component was weighed to a glass vial and heated to about <NUM> in a water bath, and mixed/vortexed until all components are completely dissolved and form a clear solution.

Loteprednol (chloromethyl <NUM>-ethoxycarbonyloxy-<NUM>-hydroxy-<NUM>,<NUM>-dimethyl-<NUM>-oxo-<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>,<NUM>-octahydro-<NUM>-cyclopenta[a]phenanthrene-<NUM>-carboxylate) (ALREX® or LOTEMAX®) in the form of the ester loteprednol etabonate is a corticosteroid used in ophthalmology. Ocular applications for this drug include the treatment of inflammation of the eye due to allergies (according to the prescription information sheet), as well as chronic forms of keratitis (e.g., adenoviral or Thygeson's keratitis), vernal keratoconjunctivitis, pingueculitis, and episcleritis. The drug has little or no effect on intraocular pressure.

The semi-solid formulation, Gel <NUM> Lote: CO/ SUP DM/ loteprednol (<NUM>/ <NUM> /<NUM>), was prepared by weighing castor oil, SUP DM and the drug into a glass vial, and closing the lid. The vehicle components were melted by heating to <NUM> in a water bath, and loteprednol was dissolved to form a clear solution and became a semi-transparent of soft paste after cooling down to room temperature.

Latanoprost (XALATAN®) is used for treating glaucoma or ocular hypertension by reducing intraocular pressure.

The semi-solid formulation, Gel <NUM> Lata: CO/ SUP DM/ Latanoprost (<NUM>/<NUM>/<NUM>), was prepared by weighing castor oil, SUP DM and the drug into a glass vial, and closing the lid. The vehicle components were melted by heating to <NUM> in a water bath, and latanoprost was dissolved to form a clear solution and became a semi-transparent soft gel after cooling down to room temperature.

The semi-solid local anesthetic semi-solid pharmaceutical compositions below were prepared as follows: The local anesthetics, castor oil, and gelling agents, were added to a glass container, and then heated to about <NUM> to <NUM> to completely melt the gelling agents into a solution, and completely dissolve the active drugs into the delivery vehicle to form a clear solution while mixing. After achieving a homogeneous and uniform pharmaceutical composition, the local anesthetic semi-solid formulation was then cooled down to ambient temperature naturally. The semi-solid formulations described herein appeared as a semi-transparent or opaque soft gel.

The in vitro release profiles of bupivacaine were evaluated by placing approximately <NUM> of the formulation enclosed in porous membrane into a glass bottle with <NUM> of PBS at pH <NUM> without stirring. At various time points, samples were taken and analyzed for bupivacaine content by UV-Vis at <NUM>, for loteprednol by UV-Vis at <NUM>, and for latanoprost by UV-Vis at <NUM>.

The drug release profiles of all the listed semi-solid compositions are summarized in the <FIG>.

The bupivacaine castor oil gel formulations were intended to achieve rapid and sustained pain relief by delivering effective bupivacaine levels at the site for up to <NUM> hours following surgery. The semi-solid gel is expected to deliver comparable bupivacaine levels at an appropriate dose volume (up to <NUM>-<NUM>) for a regular <NUM>-<NUM> length surgical opening, and at the end of delivery, the semi-solid lipid gel is dissolved/eroded and absorbed. The immediate and rapid local pain relief results from dissolving bupivacaine on the formulation surface when aqueous media diffuse into the semi-solid gel. As aqueous media penetrates into the semisolid lipid gel, the semi-solid lipid erodes, both by surface and bulk erosion, and gradually dissolves into the surrounding aqueous media, bupivacaine will gradually diffuse out and will be released into the surrounding aqueous media in a sustained manner over a period of time.

As shown in <FIG>, a bupivacaine castor oil solution formulation containing <NUM> wt% bupivacaine was used as a control formulation. Castor oil bupivacaine oil solution yielded a significant burst of more than <NUM>% at <NUM> hours under static condition (without stirring) and more than <NUM>% at <NUM> hours, and almost <NUM>% at <NUM> hours. After an additional <NUM>% release from Day <NUM> to Day <NUM>, the in vitro release curve becomes flatten. Note that lower than <NUM>% recovery is due to the filtration loss of bupivacaine during sample preparation and inaccuracy of UV-Vis method. The poor bupivacaine release kinetics from castor oil was capable of extending analgesic response of approximately <NUM>-<NUM> hours in the rat sciatic nerve blockade model, thanks to its relatively high viscosity and relatively slow dissolution of bupivacaine free base into body fluid.

Once castor oil is gelled by either SUP DM ranging from <NUM>%-<NUM>% and SUP D, only about <NUM>% of bupivacaine was released at <NUM> hours, <NUM>-<NUM>% at <NUM> hours, <NUM>-<NUM>% at <NUM> hours, and <NUM>-<NUM>% at Day <NUM>. Due to the higher hydrophobicity of the two gelling agents and stable gel depot structure, bupivacaine is gradually released into the surrounding aqueous media.

As shown in <FIG>, with bupivacaine castor oil gel formulations gelled by WIT E85, G43/<NUM>, HCO, S378 and LAN, only about <NUM>% of bupivacaine was released at <NUM> hours, less than <NUM>% at <NUM> hours, <NUM>-<NUM>% at <NUM> hours, and <NUM>-<NUM>% at Day <NUM>. All the five gelling agents are very hydrophobic and can retard the penetration of water into the gel depot and slow the release of bupivacaine. Due to the low melting point of S378 and LAN, the gel depot formed is softer, and bupivacaine release is slightly faster. Again, for the <NUM> bupivacaine castor oil gel formulations, bupivacaine is gradually released into the surrounding aqueous media in a sustained manner over a <NUM>-<NUM> weeks. The use of HCO in combination with castor oil is not according to the invention.

<FIG> shows loteprednol etabonate release from castor oil gel formulation gelled by SUP DM, yielding loteprednol release profile for <NUM> days since loteprednol etabonate is relatively water soluble. This formulation, comprising loteprednol etabonate, is not according to the invention.

<FIG> shows latanoprost release from castor oil gel formulation gelled by SUP DM. Latanoprost is a very hydrophobic drug and only <NUM>% was released at Day <NUM>. Latanoprost is released in vitro in a sustained manner over a month. This formulation, comprising latanoprost, is not according to the invention.

When the semi-solid gel formulation is placed into an aqueous environment, water will diffuse into the semi-solid lipid matrix, the active agent on the formulation surface will first gradually dissolve into the surrounding aqueous media. As aqueous media penetrates into the semi-solid lipid gel, the semi-solid lipid erodes, both by surface and bulk erosion, and gradually dissolves into the surrounding aqueous media, the active agent will gradually diffuse out and will be released into the surrounding aqueous media in a sustained manner over a period of time.

The release rate of active agent is affected both by the semi-solid gel vehicle components and the active ingredient and can be regulated in a variety of ways to accommodate the desired duration of therapeutic effect.

For the semi-solid gel vehicles, the release rate of active agent can be increased or decreased by using different types/levels/amounts/ratios of hydrophobic glyceride gelling agents with different water solubility and/or dissolution rates. As water solubility and dissolution rate of the semi-solid lipids decrease, it will take longer for the semi-solid gel to be dissolved and absorbed, thus resulting in longer duration of drug release as long as the active agent exhibits sufficient low solubility.

In addition, lower water solubility forms of active agents such as their base forms, or as complexes with fatty acids may be used to delay the release of active agents.

Bupivacaine can be in the form of a free base or a salt such as bupivacaine hydrochloride which is widely marketed in commercial products under various trade names, including MARCAINE™, SENSORCAINE® and VIVACAINE®. The hydrochloride (HCl) salt of bupivacaine has a water solubility of <NUM>/mL (BASF MSDS sheet), while the free base form of bupivacaine has a predicted water solubility of <NUM>/mL (DrugBank data). In addition, if there is a need to further decrease the water solubility of the drug bupivacaine, one can convert the bupivacaine into a salt with fatty acids and other low solubility acids.

This purpose of the viscosity measurement for the semi-solid formulations is to demonstrate that the semi-solid formulations disclosed herein have a very low viscosity and are readily injectable through a <NUM> to <NUM> needle.

The viscosity of the semi-solid formulations was determined on a calibrated Brookfield RVDV-I Prime CP model viscometer using cone spindle CPE-<NUM>. The semi-solid formulation samples stored in sealed glass vials were first heated to about <NUM>° C to <NUM>° C in an oven until the samples became a flowable viscous liquid. Then approximately <NUM> gram of each sample was weighed into the center of the warmed sample cup. Avoid bubbles when possible. Attach the sample cup to the viscometer and measure the viscosity at an appropriate speed of rotation so that the percentage torque is between <NUM>% and <NUM>%. Record the viscosity and percentage torque at the target temperature. Due to the soft paste nature of these materials at room temperature, the viscosity of semi-solid formulations was determined at <NUM>° C at that point the semi-solid formulations become a flowable viscous liquid/semi-solid under pressure. Centipoise (cP) and milliPascal seconds (mPa. s) are respectively the CGS and SI units for viscosity. <NUM> cP = <NUM> mPa. The viscosity of all the semi-solid formulations was measured at <NUM>° C.

Castor oil is a liquid with a viscosity of approximately <NUM> mPa. s (cP) at <NUM> and <NUM> mPa·s (cP) at <NUM>.

The viscosity value of bupivacaine castor oil gel formulations with and without anti-inflammatory exhibited low viscosity characteristics, ranging from <NUM> mPa. s (cP) to <NUM> mPa. s (cP), with the majority of them below <NUM> mPa·s (cP) at <NUM>. The gelling agents served two roles, one is to gel castor oil, the other is to reduce formulation viscosity to improve syringeability and injectability.

Even if these formulations are in the form of gel, they are readily injected through a <NUM> needle allowing for a single easy instillation administration (with or without a needle) into the incision site.

The viscosity results for the bupivacaine castor oil gel formulations with and without anti-inflammatory agent were summarized in Table <NUM>. The viscosity of all the semi-solid formulations was measured at <NUM>.

The CO/HCO/bupivacaine (<NUM>/<NUM>/<NUM>) formulation is not completely melted at <NUM> due to the high melting point component of HCO, and its viscosity was not determined. This formulation is not according to the invention. The CO/S378/bupivacaine (<NUM>/<NUM>/<NUM>) formulation is also not according to the invention.

The viscosity value of bupivacaine castor oil gel formulations with and without anti-inflammatory agent exhibited low viscosity characteristics, ranging from <NUM> mPa·s (cP) to <NUM> mPa·s (cP), with the majority of them below <NUM> mPa·s (cP) at <NUM>. All the gelling agents except lanolin are waxy solids and acts as lubricant due to the waxy property from the long alkyl chains of fatty acids to reduce the viscosity of gel formulations. The active ingredient bupivacaine can also act as a plasticizer and reduce the viscosity of the gel formulations. The very small amounts of anti-inflammatory drugs typically do not affect the viscosity of the gel formulations.

All the bupivacaine castor oil gel formulations with and without anti-inflammatory agent listed in Table <NUM> are readily injectable with mechanical pressure (shear force) with a <NUM> needle.

The CO/HCO/bupivacaine (<NUM>/<NUM>/<NUM>) formulation (not according to the invention) is not completely melted at <NUM> due to the high melting point component of HCO, and its viscosity was not determined. However, this formulation is still injectable with a <NUM> needle.

The following bupivacaine castor oil gel formulations with and without anti-inflammatory agent along with previously developed semi-solid formulations using S701 were administered to each animal by subcutaneous injection at the cleanly shaved dorsal aspect of the thorax.

Injection site reaction of edema/erythema data were evaluated according Table <NUM>.

Injection site edema/erythema results for the tested formulations is shown in Tables <NUM> and <NUM>. Palpable masses (edema score of <NUM> to <NUM>), attributed to depositing of the semisolid formulations, were evident at the dosing area in all animals right after injection. Semi-solid S701 exhibited edema at Day <NUM> and Day <NUM>, and gradually subsided from Day <NUM> to Day <NUM>. In the presence of <NUM>% betamethasone valerate, edema was eliminated. Semi-solid S701also exhibited moderate erythema at Day <NUM> and Day <NUM>, and gradually subsided from Day <NUM> to Day <NUM>. In the presence of <NUM>% betamethasone valerate, erythema was reduced at Day <NUM> and Day <NUM>.

The bupivacaine castor oil gel formulation, Gel DM, only exhibited very slight or minimal edema and erythema at the injection sites.

Male rats weighing between <NUM> and <NUM> were used to assess the duration of nerve conduction block, which induced by each of the different semi-solid formulations had been tested. The rats were handled daily and habituated to the testing paradigm for at least <NUM> minute prior to examination. Sensory and motor blockade were examined as described below. In addition to sensory testing, motor testing was performed at each time point to examine the ability of the rats to move their hind leg by gait posture and paw placing. Animals were handled and cared in compliance with institutional, state, and federal animal welfare regulation. The protocol was approved by IACAC.

All rats were anesthetized with <NUM> % to <NUM> % isoflurane in oxygen and maintained with <NUM> %-<NUM> % isoflurane. Under aseptic condition, the left thigh area was shaved and an incision was made on the upper <NUM>/<NUM> portion. The thigh muscles were gently dissected by blunt dissection to expose the sciatic nerve. Semi-solid gel formulations were placed adjacent to the sciatic nerve under direct vision in the fascia plane deep to the hamstrings and the site. The most superficial fascia layer was closed with a single suture. The edges of the outer skin were approximated and closed with surgical staples. For all rats, drug-containing semi-solid formulations were implanted on the left side of sciatic nerve.

Hot-plate measurement: for each time-point, the rat was put on <NUM> hot-plate and the latency of lifting the hind paw was recorded (for both paws of the animal) for three times with intervals of at least <NUM> minutes. A cutoff latency of <NUM> seconds was used to prevent development of hyperalgesia or injury. The average of three readings was used as the final reading for the particular time-point.

Paw placing: for both paws, the animals were held gently by a trained researcher and the dorsal paw, one at a time, was slowly slid over a edge of test platform until the toes were reached and repeated five times. At each time, if the rat successfully places its testing paw onto the surface of the platform, it was scored as <NUM> (therefore, the maximum score is <NUM> for each paw) and as <NUM> if it fails.

Paw motor ability measurement: The paw motor ability test, utilizing a scale of <NUM> to <NUM>, evaluates the animal's ability to hop and place weight on its hind leg, according to following levels (<NPL>):.

The paw motor ability assessment was used for each time-point as well. For both paws, the animals were held gently by a trained researcher dorsally.

Dissection: At two week time points following the administration, and the surgical site skin was examined to observe if any affection on wound healing. Then after, the sites where the semi-solid formulation was administered were re-opened and examined visually by naked eyes under anesthesia. After the examination was finished, the rats were euthanized by CO<NUM>.

The first day immediately following surgery is extremely painful and demands robust analgesia coverage to ensure pain relief and opioid abstinence. If products do not provide sufficient analgesia for the first day, rescue opioid medication is needed.

Ideally, the bupivacaine semi-solid gel formulations provide (<NUM>) a fast enough release to provide the desired analgesic coverage through the first crucial <NUM> hours post traumatic injury, (<NUM>) a slow enough release to sufficiently prolong the duration of effect through <NUM> hour, (<NUM>) a dose adequate for release at the required rate over the prolonged period of time and (<NUM>) a volume small enough and viscosity low enough for convenient administration, which has been very difficult to achieve.

The pharmacodynamic activity of bupivacaine released from castor oil gel formulation yielded greater analgesic activity compared to bupivacaine in castor oil alone when evaluated in the rat sciatic nerve blockade model (<FIG>). Hotplate latencies versus time as a measure of sensory function for bupivacaine castor oil gel formulations are shown in <FIG>. Sensory blockade was evaluated using left hind paw latency response time recording on a <NUM> hotplate.

A bupivacaine castor oil solution formulation containing <NUM> wt% bupivacaine was used as a control formulation. Castor oil bupivacaine oil solution yielded a limited analgesic response of approximately <NUM>-<NUM> hours in the rat sciatic nerve blockade model, thanks to its relatively high viscosity and relatively slow dissolution of bupivacaine free base into body fluid.

However, with the help of gelling agents, castor oil bupivacaine gel formulations provides robust sensory and motor blockade over the first <NUM> hours, and extended partial blockade up to <NUM> hours commensurate with the degree of analgesia (moderate block for the second day, partial block for the third day, which underscores the pain intensity profile of typical surgical patients with extreme pain for the first day, moderate pain for the second day, and only minor pain for the third day.

Paw motor ability measurement versus time for bupivacaine castor oil gel formulations were presented in <FIG>. The paw motor ability test, utilizing the scale of <NUM> to <NUM>, evaluates the animal's ability to hop and place weight on its hind leg.

The bupivacaine castor oil gel formulations groups yielded dense motor blockade over the first <NUM> hours and extended partial blockade up to <NUM> hours commensurate with the degree of analgesia (<FIG>), while the bupivacaine castor oil solution formulation yielded dense motor blockade for <NUM> hours and extended partial blockade up to <NUM> hours. Dense motor blockade for the first <NUM> hours post traumatic surgery is necessary to offer effective analgesia. Motor function was reversible in all groups, which had returned to normal values <NUM> hours post administration.

At two week time points following the administration, the surgical site skin was examined to observe if any effect on wound healing. No adverse effect of the gel formulations on wound healing was observed, and the surgical sites healed well in approximately two weeks. Only slight edema and erythema was observed for bupivacaine castor oil gel formulations after formulation administration.

The sites where the gel formulation was administered were re-opened and examined visually by naked eyes under anesthesia. The administration site appeared to be pinkish, and the sciatic nerve appeared to be normal, no inflammation, necrosis, ulceration, or infection was observed. In addition, most of the gel formulation was dissolved and absorbed, and only a small amount of depot residue was observed at the administration site.

The inflammatory response after an acute injury, as with a surgical incision, results in postoperative inflammation which impairs the ability of local anesthetics, including bupivacaine, to block sensory nerve conduction. The latter is as a result of the acidic environment generated by the inflammatory response impeding the analgesic from penetrating the nerve cell membrane. Bupivacaine castor oil gel formulations with an anti-inflammatory agent were created to overcome the surgical inflammatory response by incorporating an anti-inflammatory agent, such as BET, BETV, MP, KETO, or TA, to maximize pain reduction through <NUM> hours.

With bupivacaine castor oil gel formulations with an anti-inflammatory agent, enhanced nerve blockade, compared to bupivacaine castor oil gel formulations without an anti-inflammatory agent, was observed through <NUM> hours.

As confirmed with the addition of the anti-inflammatory agent, bupivacaine castor oil gel formulations afforded greater analgesic effect (increased strength) over the first <NUM> hours with both dense sensory and motor blockade and moderate partial blockade through <NUM> hours post traumatic injury compared to bupivacaine castor oil gel formulations without an anti-inflammatory agent. In addition, bupivacaine castor oil gel formulations with anti-inflammatory agent even extend partial sensory blockade through <NUM> hours and up to <NUM> hours (<FIG>. Therefore, bupivacaine castor oil gel formulations with anti-inflammatory agent can be used for the management of post-operative pain for a wide range of different types of very painful surgeries such as moderate/major abdominal, gynecological, thoracic, and orthopedic surgeries etc. to expand clinical utility.

Claim 1:
A pharmaceutical formulation, comprising
(A) a glyceride mixture comprising
(i) castor oil; and
(ii) a glyceride with a melting point between <NUM> and <NUM>;
wherein the weight ratio of (i):(ii) is <NUM>:<NUM> to <NUM>:<NUM>; and
(B) active agents comprising (i) a therapeutically effective amount of bupivacaine to provide analgesia for at least two days; and, optionally, (ii) a corticosteroid, an analgesic or an anti-inflammatory agent;
wherein the active agents are solubilized in the glyceride mixture at a concentration of <NUM>-<NUM> wt%; and wherein the pharmaceutical composition is a semi-solid gel which is biocompatible, bioerodible, homogeneous, and a single phase; and wherein the pharmaceutical composition consists of a semi-solid gel with a viscosity of <NUM>-<NUM> mPa • s at <NUM>.