HK1204771B - Stable formulations for parenteral injection of small molecule drugs - Google Patents

Description

Stable formulations of small molecule drugs for parenteral injection

Cross Reference to Related Applications

The present application claims the benefit of U.S. provisional application No. 61/665021 filed on day 27, 2012 and U.S. non-provisional application No. 13/829937 filed on day 14, 3, 2013, the contents of which are incorporated herein by reference.

Background

A. Field of the invention

The present invention relates to pharmaceutical formulations, and more particularly to pharmaceutical formulations of small molecule drugs with improved solubility and stability, and methods of using such pharmaceutical formulations for the treatment of various diseases, conditions, and disorders.

B. Description of the related Art

Although many small molecule drugs are orally bioavailable, parenteral injection is also used in the following cases: drugs have insufficient oral bioavailability, patients cannot receive the drug orally, or require a more rapid onset of drug action. For example, the administration of benzodiazepines for the emergency treatment of epileptic seizures, catecholamines for allergic reactions, and "triptans" for the treatment of migraine represents a situation where oral administration is not effective or desirable, and therefore these drugs must be administered via a non-oral route, often parenterally.

Standard practice for preparing formulations containing small molecule drugs has been to develop aqueous solutions for parenteral injection. The main reason for this is that the majority of the human body consists of water, including plasma, which is an aqueous environment. Thus, there is a natural trend towards administering pharmaceutical formulations that are compatible with the environment that the drug is intended to reach. However, some small molecule drugs have limited solubility and poor stability in such aqueous environments. This problem has been addressed, at least in part, by the use of co-solvents and stabilizers to more effectively dissolve and stabilize small molecule drugs in formulations.

One example of some of the problems that can be seen with parenteral injection of small molecule drugs is sedation. This drug for the emergency treatment of epileptic seizures is limited by its poor water solubility. Thus, currently available emergency treatments include rectal gels. Attempts have also been made to develop large volume (up to 3ml) intramuscular injections based on aqueous formulations with co-solvents (larger volumes are required due to the lower solubility of neuroleptics). However, the development of such drugs has been limited by difficulties in delivering deep, large volumes of intramuscular injections to patients in tics, and the pain associated with such large dose volumes.

Further, due to stability problems of small molecule drugs in aqueous environments, current products are often sold as lyophilized powders that need to be reconstituted in an aqueous carrier prior to injection. This allows for a longer shelf life of the active drug. Some products are even sold as liquids requiring further dilution with sterile water, phosphate buffered saline or isotonic saline prior to injection.

Disclosure of Invention

The present invention provides a solution to the current problems faced by the use of small molecule drugs in therapeutic applications. In particular, the solution is premised on dissolving and stabilizing a small molecule drug in a non-aqueous environment, and then directly injecting the dissolved drug into a patient via parenteral administration. The formulation may be in liquid form. After preparation of the formulation, it can be stored for long periods of time (even in an injection device) and injected directly into a subject (e.g., a human) without the reconstitution or dilution steps found in current products. In fact, this solution is contrary to the current industry standards. In this regard, the inventor's solution results in a more stable environment for the drug and a more efficient and effective method for actually providing life-saving drugs to those in need of treatment. Importantly, the inventors' findings can be widely applied to the delivery of a variety of small molecule drugs that have poor or limited stability and solubility in aqueous environments as stable.

In one aspect of the invention, a stable liquid formulation for parenteral injection is disclosed comprising a small molecule drug or a salt thereof and a biocompatible non-aqueous solvent, wherein the small molecule drug is dissolved in the non-aqueous solvent. One unique aspect of the present invention is that it can be used for a wide variety of small molecule drugs, including those currently being administered via parenteral injection. Some examples include benzodiazepines, catecholamines, and triptans. In a particular aspect, the compound is a benzodiazepine such as diazepam. For example, the solubility of diazepam may be greater than that typically seen for current products (e.g., examples show that the solubility of diazepam in DMSO can reach levels of 500nM, which would allow for a wide range of dosage options, e.g., reduced dosage volumes-e.g., a diazepam formulation in DMSO can contain 100mM to 500mM, 150mM to 400mM, 175mM to 350mM, or 200mM to 300mM of a drug, where each concentration provides a greatly reduced volume for delivering the same amount of drug as compared to a water-based diazepam formulation. In the present inventionOther non-limiting small molecule drugs that may be used in the context of the present invention include epinephrine, sumatriptan, mitoxantrone, chemotherapy small molecule (mitoxantrone), corticosteroid small molecule (e.g., methylprednisolone), immunosuppressive small molecule (e.g., azathioprine, cladribine, cyclophosphamide, methotrexate), anti-inflammatory small molecule (e.g., salicylic acid, acetylsalicylic acid, diflunisal, magnesium trisalicylate, salicylate, benorilate, flufenamic acid, mefenamic acid, meclofenamic acid, triflumic acid, diclofenac, fenclofenac, fentiazac, ibuprofen, flurbiprofen, profen, naproxen, fenoprofen, benbufen, suprofen, indoprofen, phenytoin, benzensulfonic acid, phenytoin, phenytol, etcLophane, pirprofen, toluoylpyridine acetic acid, zomepirac, clofibric acid, indomethacin, sulfinyl indene cool acid, phenylbutazone, oxybuprazone, azapropazone, feprazone, piroxicam, isoxicam, small molecules for the treatment of neurological diseases (e.g., cimetidine, ranitidine, famotidine, nizatidine, tacrine, donepezil, trichlorophosphate, rivastigmine, selegilene, imipramine, fluoxetine, olanzapine, sertindole, risperidone, hemi-sodium valproate, gabapentin, carbamazepine, topiramate, phenytoin) and small molecules for the treatment of cancer (e.g., vincristine, vinblastine, paclitaxel, docetaxel, cisplatin, irinotecan, topotecan, gemcitabine, temozolomide, imatinib, bortezomib), statins (e.g., atorvastatin, amlodipine, celebratine, picloratadine, cilazalatrine, valsartan, simvastatin, small molecules for the treatment of pulmonary diseases (e.g., small molecules for example, small molecules for use in anticonvulsants), small molecules (e), small molecules such as anti-lovastatin, simvastatin, and other anti-therapeutic agents, e for example, e, as anti-pro-drug, e, or anti-pro-drug for the treatment of pulmonary diseasesSmall molecule agents (e.g., cromolyn sodium), small molecule anesthetics, and small molecule antiarrhythmic agents (e.g., lidocaine), small molecule antibacterial agents (e.g., tobramycin, ciprofloxacin), small molecule antimigraine agents (e.g., sumatriptan), and small molecule antihistamines (e.g., diphenhydramine). Further, the amount of small molecule drug in a dosage formulation may vary depending on the amount currently acceptable, the needs of the subject/patient, and the like. As for the biocompatible nonaqueous solvent, examples thereof include an aprotic polar solvent, an alkyl or aryl benzoate solvent, a lipid solvent, a protic solvent, or a mixture thereof. Non-limiting examples of aprotic solvents include dimethyl sulfoxide (DMSO), Dimethylformamide (DMF), ethyl acetate, N-methylpyrrolidone (NMP), Dimethylacetamide (DMA), propylene carbonate, or mixtures thereof. However, in certain examples, the formulations of the present invention do not necessarily include the aforementioned solvents (i.e., other solvents may be used). For example, in one example, the formulation does not include a non-aqueous aprotic polar solvent and/or does not include a non-aqueous protic solvent (e.g., polyethylene glycol (PEG), Propylene Glycol (PG), polyvinylpyrrolidone (PVP), methoxypropylene glycol (MPEG), glycerol, glycofurol, and mixtures thereof). As mentioned above, increased solubility of small molecule drugs can result in small dose volumes (and thus small storage devices and containers), which provides for a simpler and less painful parenteral administration. Non-limiting examples of aryl or alkyl benzoate solvents include methyl benzoate, ethyl benzoate, propyl benzoate, C12-C15 alkyl benzoate where R is a C12-C15 alkyl group, C16-17 alkyl benzoate where R is a C16-17 fatty alcohol group, and benzyl benzoate. One non-limiting example of a lipid is triacetin, which is a triester of triglyceride and acetic acid. Non-limiting examples of protic solvents include polyethylene glycol (PEG), Propylene Glycol (PG), polyvinylpyrrolidone (PVP), methoxypropylene glycol (MPEG), glycerol, glycofurol, or mixtures thereof. In some aspects, the formulation does not include a co-solvent, while in other aspects it may include a co-solvent. In one example, the formulation may comprise a separate/sole biocompatible non-aqueous solvent (i.e., in a clean or pure form).In other aspects, the formulation includes a mixture of two, three, four, or more biocompatible non-aqueous solvents. In still further aspects, the formulation can comprise co-solvents, salts, and other ingredients that can aid or increase the solubility of the small molecule drug in the non-aqueous solvent. For example, a formulation may consist of or consist essentially of a small molecule drug and a non-aqueous solvent (or a mixture of non-aqueous solvents), and still be directly injected into a subject by parenteral administration ("consisting essentially of in this sentence means excluding other ingredients that may increase the solubility of the drug in the non-aqueous solvent (or a mixture of non-aqueous solvents-e.g., preservatives may be included to further preserve the injectable formulation.) further, the formulation of the present invention may be non-aqueous or substantially non-aqueous (e.g., less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5% or less by weight or volume of water). The dried small molecule drug has a pH memory about equal to the pH of the small molecule drug in the presence of the aqueous buffer such that the pH of the small molecule drug dissolved in the biocompatible non-aqueous solvent is about equal to the pH of the small molecule drug in the presence of the aqueous buffer. The memory pH may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or more, or may be in the range of 1 to 3, 2 to 4, 3 to 5, 4 to 6, 5 to 7, 6 to 8, 7 to 9, 8 to 10, or 9 to 11. In some aspects, the buffer is a non-volatile buffer (non-limiting examples include glycine buffer, citrate buffer, or phosphate buffer, or mixtures thereof). In other examples, the buffer may be a volatile buffer. Further, the small molecule drug may have a water content of less than 5%, 4%, 3%, 2%, 1%, 0.5% or less w/w. In some aspects, the formulation comprises a small molecule from 0.5mg/mL to about 300mg/mL, from 10mg/mL to 50mg/mL, from 20mg/mL to 50mg/mL, from 5mg/mL to 15mg/mL, or from 0.5mg/mL to 2mg/mL of the drug. In some examples, the amount of small molecule drug can be as high as 400mg/mL, 500mg/mL, 600mg/mL, 700mg/mL, 800mg/mL, 900mg/mL, 1000mg/mL, 2000mg/mLOr 3000mg/mL or more. One of the unique aspects of the present formulation is that the formulation may contain a high content of drug, but the dose of the formulation may be relatively low (e.g. 0.1 μ l, 1 μ l, 10 μ l, 20 μ l, 50 μ l, 75 μ l, 100 μ l, 200 μ l, 300 μ l, 400 μ l, 500 μ l, 600 μ l, 700 μ l, 800 μ l, 900 μ l, 1ml, 2ml or 3ml, or more as required (e.g. 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, 10ml or more). in some examples, the volume of the liquid formulation to be parenterally injected is 3ml or less (e.g. 3, 2.5, 2, 1.5, 1, 0.5, 0.1ml or less) or 0.1 μ l to 3ml or 0.1 μ l to 1 μ l or 1 μ l to 10 μ l or 10 μ l to 1 μ l or 0.5 μ l to 1 μ l or 0.1 μ l to 1 μ l or 0.5 μ l to 1 μ l to 0.1 μ l to 1 μ l or 0.1 μ l to 1 μ In a container or device, can be stored, and can be prepared directly for parenteral injection on an as-needed basis without reconstitution or dilution of the formulation. The device may be a syringe, pen injection device, auto-injector device, device that can pump or administer the formulation (e.g., an automated or non-automated external pump, implantable pump, etc.), or an infusion bag. It is also contemplated to use additional ingredients/pharmaceutical excipients in the formulation, non-limiting examples of which include: antioxidants (examples include ascorbic acid, cysteine, methionine, monothioglycerol, sodium thiosulfate, sulfite, BHT, BHA, ascorbyl palmitate, propyl gallate, or vitamin E); chelating agents (examples include EDTA, EGTA, tartaric acid, glycerol or citric acid); or preservatives (examples include alkyl alcohols, benzyl alcohols, methyl or propyl parabens or mixtures thereof). The formulation may be in liquid form, semi-solid form, or gel form. As discussed below, the formulation may have a desired viscosity range (which may range from 0.5 centipoise to 1.5 centipoise, in one non-limiting example). The preparation can be: at least 65% of the small molecule drug in the formulation remains chemically and physically stable when the formulation is stored at room temperature for two months, or at least 80% of the therapeutic agent in the formulation remains chemically and physically stable when the formulation is stored at room temperature for two months.

In one particular aspect of the invention, a stable liquid formulation for parenteral injection is disclosed comprising a salt which is diazepam or has a water content of less than 1% w/w, and a biocompatible non-aqueous solvent, wherein the diazepam is dissolved in the non-aqueous solvent, wherein the water content of the formulation is less than 5% w/v, wherein the volume of the formulation to be subjected to parenteral injection is from 50 μ l to 1000 μ l or any range therein (e.g. 75 μ l, 100 μ l, 150 μ l, 200 μ l, 300 μ l, 400 μ l, 500 μ l, 600 μ l, 700 μ l, 800 μ l, 900 μ l, etc.). As explained above, such a formulation may be contained in a container selected from a sealed syringe, a sealed pen injection device, a sealed auto-injector device or a pump. As also explained above, the diazepam is dried in the presence of a buffer prior to being dissolved in a non-aqueous solvent. This can provide dried stabilization with a pH memory about equal to the stabilized pH in the presence of an aqueous buffer, such that the stabilized pH dissolved in a biocompatible non-aqueous solvent is about equal to the stabilized pH in the presence of an aqueous buffer (e.g., the aforementioned non-volatile buffers such as glycine buffer, citrate buffer, or phosphate buffer, or mixtures thereof).

Also disclosed are methods of administering the formulations of the invention by parenteral administration of the formulations to a subject in need thereof. Administration can be carried out without having to reconstitute and/or dilute the formulation. Further, administration may be performed using a syringe, pen injection device, auto-injector device, pump, or irrigation bag. The formulation may also be stored in said syringe, pen injection device, auto-injector device, pump or infusion bag which may be used immediately thereafter (again without reconstitution and/or dilution of said formulation). Further, and as described above, the amount of formulation administered may be 1. mu.l, 10. mu.l, 20. mu.l, 50. mu.l, 75. mu.l, 100. mu.l, 200. mu.l, 300. mu.l, 400. mu.l, 500. mu.l, 600. mu.l, 700. mu.l, 800. mu.l, 900. mu.l, 1ml, 2ml, 3ml, 4ml, 5ml, 6ml, 7ml, 8ml, 9ml, or 10ml, or more as desired. In some aspects, the formulation is: the small molecule drug remains stable and soluble (i.e., no aggregation or crystallization of the small molecule drug) when stored at room temperature (about 20-25 ℃) for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.

In another aspect of the invention, methods for treating or preventing a condition, disease, disorder, etc., are disclosed that comprise administering to a subject in need thereof any one of the formulations of the invention in an amount effective to treat or prevent the condition, disease, disorder, etc. For example, with respect to the aforementioned neuroleptic formulations, such formulations may be used to treat epileptic seizures, especially severe seizures in emergency situations. In this example, the method can comprise administering to a subject in need thereof a soluble and stable neuroleptic formulation of the invention in an amount effective to treat the seizure. The aforementioned methods of administration (e.g., parenterally, preloaded containers, etc.) may be used. In some aspects, the disorder can be anxiety, a muscle spasm, or a seizure (e.g., a seizure).

Methods of stabilizing the formulations of the present invention are also contemplated. The method can include obtaining a small molecule drug and adding one or more biocompatible non-aqueous solvents in an amount sufficient to solubilize the small molecule drug in the solvent. The method may further comprise storing the formulation in a container such as a vial or in a syringe, pen injection device, auto-injector device, pump or infusion bag. The process may also include pre-drying the small molecule drug in the presence of a buffer prior to addition to the non-aqueous solvent. In a broader aspect, the process can be applied to formulate any small molecule drug with limited or poor solubility or stability in aqueous environments.

As mentioned briefly above, it is also contemplated that the viscosity of the formulation may be selected to achieve the desired result, e.g., depending on the type of composition desired, the route of administration, and the like. In one example, the viscosity of the formulation can be about 0.5 centipoise to well in excess of 1 million centipoise, or any range or integer derivable therein (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000, 100000, 200000, 300000, 400000, 500000, 600000, 700000, 900000, 1000000 centipoise, etc., as measured on a brookfield viscometer with a TC axis at 2.5rpm at 25 ℃). However, in particular aspects, a viscosity range of from 0.5 centipoise to about 100 centipoise, or from about 0.5 centipoise to about 15 centipoise can be used.

It is contemplated that any embodiment discussed in this specification can be practiced for any method or composition of the invention and vice versa. Furthermore, the compositions of the present invention may be used to carry out the methods of the present invention.

By "aprotic polar solvent" is meant a polar solvent that does not contain acidic hydrogen and does not act as a hydrogen bond donor. Examples of polar aprotic solvents include dimethyl sulfoxide (DMSO), Dimethylformamide (DMF), N-methylpyrrolidone (NMP), Dimethylacetamide (DMA), and propylene carbonate.

"alkyl or aryl benzoate" refers to the following compounds:

wherein R is alkyl or aryl. Examples of alkyl benzoates include methyl benzoate, ethyl benzoate, propyl benzoate, C12-C15 alkyl benzoates wherein R is a C12-C15 alkyl group, and C16-17 alkyl benzoates wherein R is a C16-17 fatty alcohol group. One non-limiting example of an aryl benzoate includes benzyl benzoate.

"parenteral injection" refers to administration of a small molecule drug via injection under or across one or more layers of skin or mucosa of an animal, such as a human. Standard parenteral injections are performed in areas of the animal, such as a human patient, that are subcutaneous, intramuscular, or intradermal. The reason for targeting these deep locations is that the tissue is more easily expanded to accommodate the injection volume of 0.1-3.0cc (ml) required to deliver most therapeutic agents, relative to a shallow dermal site.

By "pharmaceutically acceptable carrier" is meant a pharmaceutically acceptable solvent, suspending agent, or carrier for delivering the pharmaceutical compound of the invention to a mammal, such as an animal or human.

A "pharmaceutically acceptable" ingredient, excipient, or component is one that is suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.

"chemical stability" refers to the percentage of degradation products produced by chemical pathways such as oxidation or hydrolysis that are acceptable for small molecule drug formation. In particular, if stored at the intended product storage temperature (e.g., room temperature) for one year; or the product is stored for one year at 30 ℃/60% relative humidity; or the product forms no more than about 20% decomposition products after storage for one month, preferably three months, more preferably six months at 40 ℃/75% relative humidity, the formulation is considered chemically stable.

By "physically stable" is meant that crystals or other aggregates (e.g., dimers, trimers, etc.) form an acceptable percentage with respect to small molecule drugs. In particular, if stored at the intended product storage temperature (e.g., room temperature) for one year; or the product is stored for one year at 30 ℃/60% relative humidity; or the product forms no more than about 15% aggregates after storage for one month, preferably three months, more preferably six months at 40 ℃/75% relative humidity, the formulation is considered physically stable.

By "stable formulation" is meant a small molecule drug that is chemically and physically stable leaving at least about 65% after storage for two months at room temperature. In some aspects, the formulation retains at least 80% of the chemically and physically stable small molecule drug under these conditions. Even further, some stable formulations are those that do not exhibit degradation after germicidal irradiation (e.g., gamma, beta, or electron beam).

"bioavailability" refers to the degree to which a subject absorbs a small molecule drug from a formulation.

By "systemic" is meant that the therapeutic agent is detectable at biologically significant levels in the plasma of the subject with respect to delivery or administration of the small molecule drug to the subject.

By "controlled release" is meant that the small molecule drug is released at a rate such that the blood (e.g., plasma) concentration remains within the therapeutic range but below toxic concentrations for a period of about one hour or more, preferably 12 hours or more.

By "patient," "subject," or "individual" is meant a mammal (e.g., a human, primate, dog, cat, cow, sheep, pig, horse, mouse, rat, hamster, rabbit, or guinea pig).

"inhibit" or "reduce" or any variation of these terms, when used in the claims and/or specification, includes any measurable decrease or complete inhibition that achieves the intended result.

"effective," "treatment," or "prevention," or any variation of these terms, when used in the claims and/or the specification, is meant to indicate that a desired, expected, or intended result is achieved.

The term "about" or "approximately" is defined as "close to" as understood by one of ordinary skill in the art, and in one non-limiting embodiment the term is defined to be within 10%, preferably within 5%, more preferably within 1%, and most preferably within 0.5%. Additionally, "substantially anhydrous" means less than 5%, 4%, 3%, 2%, 1%, or less by weight or volume of water.

When used in the claims and/or the specification with the term "comprising", elements may be preceded by the word "a" or "an" without the use of a quantitative term, but it also conforms to the meaning of "one or more", "at least one" and "one or more than one".

The words "comprising," "having," "including," or "containing" are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

The compositions and methods of use may "comprise," consist essentially of, "or" consist only of any of the disclosed ingredients or steps throughout the specification. With respect to the transitional phrase "consisting essentially of … …," in one non-limiting aspect, the basic and novel features of the formulations and methods disclosed herein include the stability and solubility of small molecule drugs in the formulations. Thus, ingredients that may positively or negatively affect the stability or solubility of a small molecule drug in a formulation are excluded from formulations described in the examples where the claim uses the transitional form "consisting essentially of … …".

Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the examples, while indicating specific embodiments of the invention, are given by way of illustration only. In addition, it is contemplated that variations and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Drawings

FIG. 1: by specifying Xerisol in solvent^TMPlasma diazepam levels in rats following subcutaneous injection of diazepam or administration of 1mg diazepam by means of a Diastat rectal gel. Curves represent 5 animals per group unless otherwise indicated.

Detailed Description

As discussed above, the difficulties associated with formulating small molecule drugs for parenteral administration are well documented. Current solutions to such difficulties are also well documented and accepted as standard practice in the formulation art. Briefly, the problem begins with the desire to invent aqueous formulations of small molecule drugs that are well tolerated and dispersed in the body (especially in the bloodstream), despite the fact that large multimeric small molecule drugs have low solubility and stability in aqueous environments. This often results in the use of co-solvents and drug stabilizers which can result in large and/or multiple doses (e.g., 3ml or more) to ensure that a sufficient amount of drug is administered. Further, the added reconstitution and/or dilution steps prior to injection can be costly and time consuming.

To address the problems currently associated with parenteral administration of small molecule drugs, the inventors provide a unique approach that is contrary to widely accepted and conventional formulation standards. In particular, the inventors have discovered that by dissolving a small molecule drug in a non-aqueous environment, the resulting formulation not only highly concentrates the drug (which can then lead to a smaller dosage volume of the formulation), but also provides increased stability and solubility of the drug. This in turn leads to a more stable formulation enjoying a longer shelf/shelf life which can be directly injected into a subject without the use of reconstitution or dilution steps. Thus, the formulations of the present invention may be stored in a device that can be used directly for parenteral administration.

These and other non-limiting aspects of the invention are discussed below.

A. Small molecule drugs

In the context of the present invention, a "small molecule drug" is a biologically active compound (and salts thereof) that is capable of bringing about a desired, beneficial and/or pharmacological effect to a subject. These "small molecule drugs" are organic or inorganic compounds, but they are not polymers (e.g., polypeptides, proteins, polypeptides, carbohydrates, and nucleic acids). Thus, small molecule drugs are not polymeric compounds in the context of the present invention. Generally, the molecular weight of a small molecule drug is less than about 1000 daltons. Some small molecule drugs are "moisture sensitive" because they are increasingly unstable in the presence of water. In addition, salts that can be used with small molecule drugs are known to those skilled in the art and include salts with inorganic acids, organic acids, inorganic bases, or organic bases.

Several classes of small molecule drugs that can be used in the context of the present inventionNon-limiting examples of (a) include benzodiazepines, catecholamines and "triptans". As mentioned in the examples, one such neuroleptic has been shown to be very effective in the context of the present invention, as evidenced by its increased stability and solubility in non-aqueous solvents. Other non-limiting examples include epinephrine, sumatriptan, mitoxantrone, chemotherapy small molecules (mitoxantrone), corticosteroid small molecules (e.g., methylprednisolone, beclomethasone dipropionate), immunosuppressive small molecules (e.g., azathioprine, cladribine, cyclophosphamide monohydrate, methotrexate), anti-inflammatory small molecules (e.g., salicylic acid, acetylsalicylic acid, diflunisal, magnesium trisilalate, salicylate, benorilate, flufenamic acid, mefenamic acid, meclofenamic acid, triflumicic acid, diclofenac, fenclofenac, fentiazac, ibuprofen, flurbiprofen, profen, naproxen, fenoprofen, benbufen, suprofen, indoprofen, phenytoin, benzensulfonic acid, phenytoin, etcLoxen, pirprofen, toluoylpyridine acetic acid, zomepirac, clavulanic acid, indomethacin, sulfinyl indene cool acid, phenylbutazone, oxybupruzone, azapropazone, feprazone, piroxicam, isoxicam), small molecules for the treatment of neurological diseases (e.g., cimetidine, ranitidine, famotidine, nizatidine, tacrine, donepezil, trichlorophosphate, rivastigmine, selegilene, imipramine, fluoxetine, olanzapine, sertindole, risperidone, hemi-sodium valproate, gabapentin, carbamazepine, topiramate, phenytoin), and small molecules for the treatment of cancer (e.g., vincristine, vinblastine, paclitaxel, docetaxel, cisplatin, irinotecan, topotecan, gemcitabine, temozolomide, imatinib, bortezomib), statins (e.g., atorvastatin, amlodipine, and amlodipine) Sitagliptin, simvastatin, fluvastatin, pitavastatin, lovastatin, pravastatin, simvastatin), and other taxane derivatives, small molecules (e.g., rifampin) for the treatment of tuberculosis, small molecule antifungal agents (e.g., fluvastatinAzoles) small molecule anxiolytic and small molecule anticonvulsants (e.g., chlordiazepoxide), small molecule anticholinergics (e.g., atropine), small molecule β -agonist drugs (e.g., albuterol sulfate), small molecule cell stabilizers and small molecule agents for treating allergies (e.g., sodium cromoglycate), small molecule anesthetics and small molecule antiarrhythmics (e.g., lidocaine), small molecule antibacterial agents (tobramycin, ciprofloxacin), small molecule antimigraine agents (e.g., sumatriptan), and small molecule antihistamines (e.g., diphenhydramine).

Each of the foregoing drugs is well known and commercially available from a variety of sources. Further, the amount of small molecule drug in a dosage formulation may vary depending on the amount currently acceptable, the needs of the subject/patient (e.g., age, weight, nature and extent of the condition), and the like. Unique within the context of the present invention is the fact that: given the increased solubility and stability of small molecule drugs in the formulations of the present invention, the dosage volume can be reduced and concentrated liquid formulations of the compounds can be preformed and stored.

B. Biocompatible non-aqueous solvent

In the context of the present invention, "biocompatible non-aqueous solvent" means substantially to completely anhydrous and capable of dissolving small molecule drugs. The solvent is also biocompatible in that it is commensurate with a reasonable benefit/risk ratio, suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response).

Some non-limiting examples of suitable biocompatible non-aqueous solvents include aprotic polar solvents, alkyl or aryl benzoates, and lipids. Examples of polar aprotic solvents include dimethyl sulfoxide (DMSO), Dimethylformamide (DMF), ethyl acetate, N-methylpyrrolidone (NMP), Dimethylacetamide (DMA), propylene carbonate, and mixtures thereof. Non-limiting examples of alkyl benzoates include methyl benzoate, ethyl benzoate, propyl benzoate, C12-C15 alkyl benzoates wherein R is a C12-C15 alkyl group, and C16-17 alkyl benzoates wherein R is a C16-17 fatty alcohol group. One non-limiting example of an aryl benzoate includes benzyl benzoate. One non-limiting example of a lipid is triacetin, which is a triester of triglyceride and acetic acid.

Each of the foregoing non-aqueous solvents is well known and commercially available from a variety of sources.

C.pH memory

In addition to the non-aqueous solvent aspect of the present invention, the inventors have discovered further processing steps that can be used to further stabilize the small molecule drug within the formulation. In particular, the small molecule drug may be mixed with a non-volatile buffer and then dried to obtain a small molecule drug powder. The drug is susceptible to hydrolysis at some specific bonds, so the use of a non-volatile buffer in the formulations of the present invention is believed to beneficially affect its chemical stability. The result of this processing step is to produce a "pH memory" of the small molecule drug after its reconstitution in a non-aqueous solvent.

In particular, the "pH memory" of a small molecule drug is the resulting charge distribution (protonated state) after drying the drug in a buffered aqueous solution (e.g., in a non-volatile buffer). The protonation state, and thus solubility and stability, of a drug in a very low or zero moisture non-aqueous solvent is affected by the pH of the aqueous solution of the drug before drying and the drying conditions employed. Similarly, the stability of uncharged drugs is affected by the pH in aqueous solutions and, therefore, by pH memory in the dry state or in non-aqueous solvents. When a drug is dried in a buffer substance where both the acidic and basic components are non-volatile, the pH memory of the dried drug will be about equal to the pH of the drug in the non-volatile buffer. See, e.g., enzymaticReactions in Organic Media, Koskinen, A.M.P. and Klibanov, A.M., eds., Springer (1996). In addition, the pH of the buffered aqueous solution in which the drug is dried (e.g., a non-volatile buffer) can be optimized to produce a pH memory of the drug that results in optimal stability, maximum solubility, and minimal degradation upon reconstitution in a non-aqueous solvent (e.g., an aprotic polar solvent) after the dried drug. It should be noted that many non-aqueous solvents do not have exchangeable protons. Thus, when the dried drug is reconstituted into such a solvent, the drug in the reconstituted formulation will retain the solubility and stability characteristics of optimal pH memory. In particular embodiments, the drug in the formulation will have a pH memory of about 2.0 to 3.0 to ensure maximum stability/minimal degradation. In other embodiments, the drug in the formulation will have a pH memory of about 3.0 to 5.0 to ensure maximum stability/minimal degradation. In still further embodiments, the drug will have a pH memory of about 4.0 to 6.0 to ensure maximum stability/minimal degradation. In still further embodiments, the drug will have a pH memory of about 6.0 to 11.0 to ensure maximum stability/minimal degradation.

The pH memory of a drug can be measured in several ways. In one method, the pH memory of the drug is measured by reconstituting the dried drug into unbuffered water and measuring the pH of the reconstituted drug using a pH indicator such as pH paper or a calibrated pH electrode. Alternatively, for a drug that has been reconstituted in a non-aqueous solvent, the pH memory of the drug can be determined by adding at least 20% water to the non-aqueous solvent and measuring the pH using a pH indicator. See, for example, Baughman and Kreevoy, "Determination of action in 80% Dimethyl Sulfoxide-20% Water," Journal of physical Chemistry, 78(4):421-23 (1974). The measurement of pH in aprotic polar solvent-water solutions may require small corrections (i.e. not exceeding 0.2pH units according to Baughman and kreevoy (supra)) as described above.

In view of the foregoing, non-volatile buffers useful in the formulations described herein are those that help establish a pH of maximum stability/minimum degradation, as well as those that help remove residual water content from the dried drug powder. Non-volatile buffers include those that do not evaporate in a similar manner to water after drying/lyophilization. Suitable non-volatile buffers include, for example, glycine buffer, citrate buffer, phosphate buffer. In a preferred embodiment, the non-volatile buffer is a glycine buffer or a citrate buffer.

In the foregoing methods, the drying of the pharmaceutical compound with the non-volatile buffer can be carried out using spray drying techniques, freeze drying techniques, or lyophilization techniques. Spray drying techniques are well known to those skilled in the art. Spray drying includes the steps of atomizing a solution containing one or more solids (e.g., therapeutic agents) via a nozzle carousel or other device, and then volatilizing the solvent from the droplets. The properties of the resulting powder are a function of several variables including the starting solute concentration, the size distribution of the droplets generated, and the rate of solute removal. Depending on the rate and conditions of solvent removal, the resulting particles may comprise aggregates of primary particles composed of crystalline and/or amorphous solids.

A spray drying process for the preparation of ultrafine powders of pharmaceuticals is described, for example, in us patent No. 6051256. Freeze-drying procedures are well known in the art and are described, for example, in U.S. patent No. 4608764 and U.S. patent No. 4848094. Spray-freeze-drying processes are described, for example, in U.S. patent No. 5208998. Other spray drying techniques are described in U.S. patent nos. 6253463; 6001336, respectively; 5260306, respectively; and PCT international publication nos. WO 91/16882 and WO 96/09814.

Lyophilization techniques are well known to those skilled in the art. Basically, lyophilization is a dehydration technique of the product in the frozen state and under vacuum (ice sublimation under vacuum) and by means of micro-thermal drying. These conditions stabilize the product and minimize oxidation and other degradation processes. The conditions of freeze-drying allow the process to be carried out at low temperatures, and therefore thermally unstable products can be protected. The freeze drying step comprises pretreatment, freezing, primary drying and secondary drying. Pretreatment includes any method of treating the product prior to freezing. This may include concentrating the product, formulation modifications (i.e., adding components to increase stability and/or improve handling), reducing high vapor pressure solvents, or increasing surface area. The pretreatment method comprises the following steps: freeze concentration, solution phase concentration and in particular formulation to preserve the product appearance or to provide freeze-drying protection for reactive products and is described, for example, in U.S. patent No. 6199297. "Standard" lyophilization conditions are described, for example, in U.S. Pat. No. 5031336 and "Freeze Drying of pharmaceuticals" (Deluca, Patrick P., J.Vac.Sci.Technol., Vol.14, phase 1, January/February 1977); and "The physiology of Pharmaceuticals: A Literture Review" (Williams, N.A. and G.P.Polli, Journal of molecular Science and Technology, Vol.38, 2 nd, March/April 1984).

In some aspects, the lyophilization cycle can be performed in part at a temperature above the glass transition temperature (Tg) of the therapeutic agent formulation to cause the mass to collapse to form a dense cake containing residual moisture. In other embodiments, the lyophilization cycle is performed at a temperature below the glass transition temperature to avoid collapse, thereby achieving complete drying of the particles.

D. Moisture content of the formulation

Another key aspect of the formulations of the present invention is that they have a low moisture content due to the use of the non-aqueous solvents described above. This provides additional stability to both the formulation and the small molecule drug. For example, a stable formulation of the invention can have a moisture content of less than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.25%, 0.1%, 0.05%, 0.025%, 0.01% to 0% by weight or volume of the formulation. In some examples, the formulation includes from about 0.01% to about 3%, from about 0.01% to about 2%, from about 0.01% to about 1.5%, or from about 0.01% to about 1% water by weight or volume of the formulation.

E. Dosage form

Any suitable dose of the drug may be administered using the formulations of the present invention. Of course, the dosage administered will vary depending on known factors, such as: the pharmacodynamic properties of a particular drug, salt, or combination thereof; the age, health, or weight of the subject; the nature and extent of the disorder; metabolic characteristics of the therapeutic agent and the patient, the nature of concurrent therapy; the frequency of treatment; or a desired effect. Generally, the drug in the formulation is present in the formulation in an amount of about 0.5mg/ml to 3000mg/ml or up to the solubility limit of the drug in the formulation. In some embodiments, the drug is present in the formulation in an amount from about 10mg/mL to about 50 mg/mL. In other embodiments, the drug is present in the formulation in an amount from about 20mg/mL to about 50 mg/mL. In still other embodiments, the drug is present in the formulation in an amount from about 5mg/mL to about 15 mg/mL. In still other embodiments, the drug is present in the formulation in an amount from about 0.5mg/mL to about 2 mg/mL. Furthermore, it will be readily apparent to the skilled artisan that the dosage of the drug may vary depending on the drug used and the disease, disorder or condition to be treated, and that the concentration of the drug in the formulation may vary depending on the solubility of the drug, the dosage and the method of administration.

F. Additional ingredients/pharmaceutical excipients

While it is sufficient and useful for the formulations of the present invention to have a small molecule drug and a biocompatible non-aqueous solvent (see example 1, tables 1-2), the formulations may include additional ingredients/pharmaceutical excipients to further develop formulations with desirable tactile properties, viscosity ranges, or to further protect the active drug. For example, the formulation may further comprise an antioxidant (non-limiting examples of which include ascorbic acid, cysteine, methionine, monothioglycerol, sodium thiosulfate, sulfite, BHT, BHA, ascorbyl palmitate, propyl gallate, or vitamin E, or any combination thereof); chelating agents (non-limiting examples of which include EDTA, EGTA, tartaric acid and salts thereof, glycerol, and citric acid and salts thereof); and/or preservatives (non-limiting examples of which include alkyl alcohol, benzyl alcohol, methyl or propyl parabens, and mixtures thereof), in any one, in any combination, or all. Additionally, the formulations of the present invention may also contain nonaqueous protic solvents (non-limiting examples of which include polyethylene glycol (PEG), Propylene Glycol (PG), polyvinylpyrrolidone (PVP), methoxypropylene glycol (MPEG), glycerol, glycofurol, and mixtures thereof).

G. Kit/container

Kits are also contemplated for use in particular aspects of the invention. For example, the formulation of the present invention may be contained within a kit. The kit may comprise a container. In one aspect, for example, the formulation may be contained within a container that is ready for parenteral administration to a subject without having to reconstitute or dilute the formulation. That is, the formulation to be administered can be stored in a container and easily used as needed. The container may be a device. The device may be a syringe, pen injection device, auto-injector device, device that can pump or administer the formulation (e.g., an automated or non-automated external pump, implantable pump, etc.), or an infusion bag. Suitable pen/auto injector devices include, but are not Limited to, those manufactured by Becton-Dickenson, Swedish Healthcare Limited (SHLGroup), YpsoMed Ag, and the like. Suitable pump devices include, but are not limited to, those manufactured by Tandem Diabetes Care, inc.

Alternatively, the kits of the invention may comprise multiple containers or multiple compartments within a container. Each container or compartment may be used for separate storage of, for example, a biocompatible non-aqueous solvent and a small molecule drug. The solvent and drug can then be mixed together as desired and administered directly or stored for a period of time as desired.

Examples

The present invention will be described in more detail by way of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily recognize a variety of noncritical parameters that may be varied or altered to produce substantially the same results.

Example 1

(stability and solubility in biocompatible non-aqueous solvents)

Diazepam, which is a small molecule anxiolytic/anticonvulsant drug (MW 284.7 g/mol; anhydrous, Sigma-Aldrich, st. louis, MO) powder, is mixed in 50mg increments with various biocompatible non-aqueous solvents until no longer dissolved. The maximum solubility that is stable at this resolution was therefore determined and recorded in table 1 together with the corresponding injection volumes for the 20mg dose at these concentrations.

TABLE 1

Highest concentration tested. This value is expected to be at least 125mg/ml based on the solubility of diazepam alone in DMSO and NMP.

Table 2 provides the solubility definitions used in table 1 and the tables that follow.

TABLE 2

	Parts of solvent per 1 part of solute	Solubility Range (g/ml)	Solubility (mg/ml)
				Is very soluble in water	<1	>1	>1000
Is easy to dissolve	1-10	0.1-1.0	100-1000
				Soluble in water	10-30	0.03-0.1	30-100
Is difficult to dissolve	30-100	0.01-0.03	10-30
				Slightly soluble	100-1000	0.001-0.01	1-10
Is extremely insoluble	1000-10000	0.0001-0.001	0.1-1
				Hardly soluble or insoluble	>10000	<0.0001	<0.1

Stable solutions were prepared at various concentrations and evaluated for stability over one to six months. The solutions in table 3 were prepared by diluting the concentration test samples and stored in glass vials under ambient conditions, and the solutions in table 4 were prepared using the following method and stored in syringes in a stability chamber.

(1) Any mixture of solvents (e.g., 70:30DMSO: NMP) was prepared in their specified ratios and mixtures.

(2) Weigh the appropriate amount of diazepam dry powder for a final concentration of 50100mg/mL or 100 mg/mL.

(3) The stabilizing powder was dissolved in approximately 70% of the final volume of solvent in a glass volumetric flask fitted with a frosted glass stopper.

(a) The solution is stirred or sonicated.

(b) A dissolution time of less than 20 minutes is required.

(4) Make up solvent was added to reach the final solution volume.

(5) The stopper was stoppered and mixed by inversion at least 10 times.

(6) The content and purity of the drug are verified by RP-HPLC.

After 10 days, in the highest concentration solution present in table 3, all prepared solutions remained clear by visual observation and no crystals were observed by light microscopy at 100x magnification. Drug content and purity were evaluated using a validated USPRP-HPLC method. The absence of particles was assessed by measuring the transmittance at 630nm using visible light spectral analysis. These data are recorded in detail in tables 3 and 4.

TABLE 3

The formulations in table 4 were placed into a syringe (e.g., Daikyo Crystal Zenith syringe). Place 500 μ L of the formulation into a syringe fitted with a needle cap to fill the syringe. Is placed along the inner wall of the syringe tube cavity (1)¹/₂Foot) 20 gauge needle and draw the plug down into the lumen until the plug passes over the head of the needle. This allows air to escape without holding the sampleThe syringe is pushed out. Release tests were performed to fill the syringe to determine the drug content (RP-HPLC), purity (RP-HPLC) and transmission (at 630 nm) of the formulation released from the syringe. All release samples, except for both formulations, had target drug contents of 100.1% to 105.2%, had a purity of at least 99.97% and a transmittance of at least 99.3%.

Example 2

(pharmacokinetics of neuroleptic agents)

A study was conducted to establish Pharmacokinetic (PK) profiles in rats for four concentrated Subcutaneous (SC) formulations of diazepam compared to a control formulation of rectally administered diazepam gel (home treatment of epidemic epilepsy). Briefly, five jugular vein-cannulated female Sprague-Dawley rats were dosed by SC injection of 10 μ L of a liquid stable test sample, or rectally with 200 μ L of a control formulation using a volumetric pipette. Animals were fasted for 12 hours and a small application of rectal glycerol was used prior to the Diastat administration in control animals to minimize defecation and drug discharge. 0 (before), 3, 6, 9, 12, 20, 30, 45 minutes after administration of the drug in the conical tube preloaded with anticoagulant potassium EDTA; 1. whole blood samples were collected at 1.5, 2, 3, and 4 hours. Plasma stability was analyzed as described below. The results are shown in FIG. 1. Preclinical studies were performed in SouthwestBio-Labs (Las crucibles, NM). The study design is summarized in table 5.

TABLE 5

^aThe Diastat rectal gel is a sterile, stable gel provided in a pre-filled unit dose rectal delivery system.

The Diastat rectal gel comprises 5mg/mL diazepam, propylene glycol, ethanol (10%), hypromellose, sodium benzoate, benzyl alcohol (1.5%), benzoic acid and water, and has a pH of 6.5-7.2.

There are several notable departures from the study plan. Jugular vein cannulation presents some difficulty to the investigator and does not remain open throughout the study. The collection of some blood was therefore delayed by a few minutes (investigators recorded each actual collection time). The problem of JVC leads to Xerisol^TMEach animal in the group required blood sampled from the intra-orbital sinus at a different time point. In Diastat and Xerisol^TMEach animal in the DMSO group was removed from the study due to complete cannula failure (prior to intraorbital blood replacement). The actual collection time is used to generate a time-concentration curve for each animal from which pharmacological parameters are derived.

The stable plasma concentrations were measured in ICON development solution (LLC (Whitesboro, NY)). ICON validated the determination of diazepam in rat plasma using the LC/MS/MS method. Samples were frozen at the preclinical study site and loaded onto ICON on dry ice. Figure 1 shows the mean stable concentration for all groups at nominal time intervals after administration.

Pharmacokinetic parameters were calculated from each individual animal and averaged for treatment groups. Using standard non-compartmental approach to C_max(maximum stable concentration), T_max(Observation of C_maxTime of administration, related to dose administration) and AUC (area under the curve of settled concentration versus time from time 0 to 240 minutes). In addition, a parameter T is calculated_1/2max(time to half maximal concentration observed). When C is present_maxAppear within broad peaks, or when C is reached and maintained rapidly as observed in some groups_maxThis parameter is useful at near levels. By linear regression during the initial absorption phase of the curve and using equation T_1/2max＝[(0.5×C_max) - (y-intercept)]Slope to obtain T_1/2max. Analysis of pharmacokinetic parameters was performed using SAS statistical software. Bioequivalence could not be determined due to incomplete clearance of the XeriSol diazepam formulation at the end of the study. The data are shown in table 6.

TABLE 6

Group of	Cmax，ng/mL	Area under curve	TmaxMinute of	T1/2maxMinute of
					Diastat	285.00(44.10)	10380(5233)	4.5(1.7)	1.9(0.4)
NMP	378.34(467.53)	31719(16921)	8.0(4.2)	3.6(1.8)
					DMSO	89.28(34.55)	13936(2591)	129.8(127.6)	5.1(3.1)
DMSO/NMP	92.90(35.20)	14967(5989)	100.2(127.6)	3.0(1.0)
					Benzyl benzoate	22.06(15.61)	4093(3332)	204.0(80.5)	N/A

These data indicate that in Xerisol^TMIn the group, the order of effectiveness of the formulations was NMP>NMP:DMSO>DMSO>Benzyl benzoate. It is clear that Xerisol^TMNMP in the formulation had the most favorable PK profile and was most comparable to the Diastat control. Albeit all of the Xerisol^TMThe formulations (except benzyl benzoate) all had increased AUC relative to Diastat, but there were three XeriSol formulations^TMC of the preparation not reaching Diastat_maxOne third of the total. On the other hand, Xirisol^TMNMP over Diastat C_max33 percent. Diastat does have the shortest T of all groups_maxHowever, Xerisol^TMThe formulation (again except benzyl benzoate) improved plasmatability in a relatively shorter time. However all T_max(Remove Xerisol^TMOther than NMP) are large, T_1/2maxThis proved to be an artifact of the maintenance of plasmatan at concentrations close to (or slightly above) that are reached early in the time course (no calculation of the T for benzyl benzoate)_1/2maxSince C is achieved in only one animal_max(ii) a Plasma homeostasis continued to increase in the other four animals).

XeriSol^TMC between the preparations_maxThe difference may be related to solubility, since C_maxThe tendency of (c) is consistent with the solubility of diazepam in the solvent. If a precipitation event occurs upon introduction into the aqueous subcutaneous environment, an event that is more likely to have a lower solubility limit in the vehicle, the time that occurs in the blood can be controlled in part by the time required for solubilization. The information pair is obtained by solvent combinationIt may be useful to adjust the PK profile.

Relating to Xerisol^TMThe sustained elevation of plasmapheresis in the group relative to the Diastat control may account for differences in blood flow. Diazepam is presumed to enter the systemic circulation from the site of subcutaneous injection and has more time to accumulate in the blood than the rapid direct discharge from the rectal blood supply to the liver for metabolism as is possible in the case of Diastat. This persistent concentration phenomenon can be more difficult to control. However, when measuring bioequivalence to Diastat, it occurred throughout the study at all Xerisol^TMSustained plasmapheresis in the group may prove effective not only for treating active episodes but also for preventing subsequent or cluster episodes. Combined with its rapid absorption curve and high C_maxTaking into account that^TMThis benefit will be especially appreciated in NMP formulations. Such PK profiles can also indicate Xerisol^TMDiazepam can be used to achieve a therapeutic level of diazepam using less of the drug substance per dose than Diastat.

Example 3

(solubility of Chloroxdiazepam in biocompatible non-aqueous solvents)

Chlordiazepoxide, a small molecule anxiolytic/anticonvulsant (MW 321.16g/mol), was mixed in about 10mg increments with 1 gram of the following biocompatible non-aqueous solvents until no longer dissolved: benzyl benzoate, DMSO, NMP, triacetin, and PEG 300. After 50mg of drug has been added to the solution (and the drug is still fully dissolved in the solvent), the incremental amount of drug added at each step is increased to about 25mg and maintained at about 25mg until it is no longer fully dissolved in the solution. This enables the determination of the maximum solubility of chlordiazepoxide in each of the five biocompatible non-aqueous solvents at this resolution, as shown in table 7.

TABLE 7

Solvent(s)	Solubility (mg/mL)	Solubility in water
			Benzyl benzoate	10	Is difficult to dissolve
DMSO	100	Is easy to dissolve
			NMP	480	Is easy to dissolve
Triacetin	20	Is difficult to dissolve
			PEG 300	80	Soluble in water

Example 4

(solubility of salbutamol sulfate in biocompatible non-aqueous solvents)

Salbutamol sulfate, which is a small molecule immunosuppressive/anticancer agent (MW 288.35g/mol), is mixed with the following biocompatible non-aqueous solvents (benzyl benzoate, DMSO, NMP, 70:30(v/v) DMSO: NMP, triacetin, and PEG300) in an amount sufficient to prepare an increasing concentration mixture. Specifically, the concentrations examined were 0.1mg/mL, 1.0mg/mL, 5mg/mL, 10mg/mL, 30mg/mL, 50mg/mL, 100mg/mL, and increments of 50mg/mL were added until the small molecule drug was no longer completely dissolved in the solvent. Accordingly, this enabled the maximum solubility of salbutamol sulphate for each of the six biocompatible non-aqueous solvents to be determined at this resolution, as shown in table 8.

TABLE 8

Solvent(s)	Solubility (mg/mL)	Solubility in water
			Benzyl benzoate	<0.1	Is almost insoluble
DMSO	5	Slightly soluble
			NMP	<0.1	Is almost insoluble
70:30DMSO:NMP	5	Slightly soluble
			Triacetin	<0.1	Is almost insoluble
PEG 300	<0.1	Is almost insoluble

Example 5

(solubility of atropine in biocompatible non-aqueous solvents)

Atropine, a small molecule anticholinergic (MW 289.4g/mol), was mixed with the following biocompatible non-aqueous solvents (benzyl benzoate, DMSO, NMP, 70:30(v/v) DMSO: NMP, triacetin, and PEG300) in an amount sufficient to prepare an increased concentration mixture. Specifically, the concentrations examined were 0.1mg/mL, 1.0mg/mL, 5mg/mL, 10mg/mL, 30mg/mL, 50mg/mL, 100mg/mL, and increments of 50mg/mL were added until the small molecule drug was no longer completely dissolved in the solvent. Accordingly, this enabled the maximum solubility of atropine for each of the six biocompatible non-aqueous solvents to be determined at this resolution, as shown in table 9.

TABLE 9

Solvent(s)	Solubility (mg/mL)	Solubility in water
			Benzyl benzoate	30	Soluble in water
DMSO	500	Is easy to dissolve
			NMP	750	Is easy to dissolve
70:30DMSO:NMP	650	Is easy to dissolve
			Triacetin	5	Slightly soluble
PEG 300	30	Soluble in water

Example 6

(solubility of cromolyn sodium in a biocompatible non-aqueous solvent)

Cromolyn sodium, a small molecule mast cell stabilizer (MW 512.3g/mol), was mixed with the following biocompatible non-aqueous solvents (benzyl benzoate, DMSO, NMP, 70:30(v/v) DMSO: NMP, triacetin, and PEG300) in an amount sufficient to prepare a mixture of increasing concentrations. Specifically, the concentrations examined were 0.1mg/mL, 1.0mg/mL, 5mg/mL, 10mg/mL, 30mg/mL, 50mg/mL, 100mg/mL, and increments of 50mg/mL were added until the small molecule drug was no longer completely dissolved in the solvent. Accordingly, this enabled the maximum solubility of cromolyn sodium for each of the six biocompatible non-aqueous solvents to be determined at this resolution, as shown in table 10.

Watch 10

Solvent(s)	Solubility (mg/mL)	Solubility in water
			Benzyl benzoate	0.1	Is extremely insoluble
DMSO	50	Soluble in water
			NMP	0.1	Is extremely insoluble
70:30DMSO:NMP	5	Slightly soluble
			Triacetin	0.1	Is extremely insoluble
PEG 300	50	Soluble in water

Example 7

(solubility of Lidocaine in biocompatible non-aqueous solvents)

Lidocaine, which is a small molecule (MW 234.34g/mol), is mixed with the following biocompatible non-aqueous solvents (benzyl benzoate, DMSO, NMP, 70:30(v/v) DMSO: NMP, triacetin, and PEG300) in an amount sufficient to prepare a mixture of increasing concentrations. Specifically, the concentrations examined were 0.1mg/mL, 1.0mg/mL, 5mg/mL, 10mg/mL, 30mg/mL, 50mg/mL, 100mg/mL, and increments of 50mg/mL were added until the small molecule drug was no longer completely dissolved in the solvent. Accordingly, this enabled the determination of the maximum solubility of lidocaine for each of the six biocompatible non-aqueous solvents at this resolution, as shown in table 11.

TABLE 11

Solvent(s)	Solubility (mg/mL)	Solubility in water
			Benzyl benzoate	900	Is easy to dissolve
DMSO	2000	Is very soluble in water
			NMP	1750	Is very soluble in water
70:30DMSO:NMP	1750	Is very soluble in water
			Triacetin	400	Is easy to dissolve
PEG 300	200	Is easy to dissolve

Example 8

(solubility of Rifampicin in biocompatible non-aqueous solvents)

Rifampicin as a small molecule anti-tubercular agent (MW 822.94g/mol) was mixed with the following biocompatible non-aqueous solvents (benzyl benzoate, DMSO, NMP, 70:30(v/v) DMSO: NMP, triacetin, and PEG300) in an amount sufficient to prepare a mixture with increasing concentration. Specifically, the concentrations examined were 0.1mg/mL, 1.0mg/mL, 5mg/mL, 10mg/mL, 30mg/mL, 50mg/mL, 100mg/mL, and increments of 50mg/mL were added until the small molecule drug was no longer completely dissolved in the solvent. Accordingly, this enabled the maximum solubility of rifampicin for each of the six biocompatible non-aqueous solvents to be determined at this resolution, as shown in table 12.

TABLE 12

Solvent(s)	Solubility (mg/mL)	Soluble in water
			Benzyl benzoate	50	Soluble in water
DMSO	150	Is easy to dissolve
			NMP	400	Is easy to dissolve
70:30DMSO:NMP	150	Is easy to dissolve
			Triacetin	5	Slightly soluble
PEG 300	5	Slightly soluble

Example 9

(solubility of epinephrine bitartrate in biocompatible non-aqueous solvents)

Epinephrine bitartrate, which is a small molecule sympathomimetic (MW 333.3g/mol), is mixed with the following biocompatible non-aqueous solvents (benzyl benzoate, DMSO, NMP, 70:30(v/v) DMSO: NMP, triacetin, and PEG300) in an amount sufficient to prepare an increased concentration mixture. Specifically, the concentrations examined were 0.1mg/mL, 1.0mg/mL, 5mg/mL, 10mg/mL, 30mg/mL, 50mg/mL, 100mg/mL, and increments of 50mg/mL were added until the small molecule drug was no longer completely dissolved in the solvent. Accordingly, this enabled the maximum solubility of epinephrine bitartrate for each of the six biocompatible non-aqueous solvents to be determined at this resolution, as shown in table 13.

Watch 13

Solvent(s)	Solubility (mg/mL)	Solubility in water
			Benzyl benzoate	<0.1	Is almost insoluble
DMSO	700	Is easy to dissolve
			NMP	400	Is easy to dissolve
70:30DMSO:NMP	500	Is easy to dissolve
			Triacetin	<0.1	Is almost insoluble
PEG 300	0.1	Is extremely insoluble

Example 10

(solubility of acetylsalicylic acid in biocompatible non-aqueous solvents)

Acetylsalicylic acid, which is a small molecule analgesic (MW 180.16g/mol), was mixed with the following biocompatible non-aqueous solvents (benzyl benzoate, DMSO, NMP, 70:30(v/v) DMSO: NMP, triacetin, and PEG300) in an amount sufficient to prepare an increasing concentration mixture. Specifically, the concentrations examined were 0.1mg/mL, 1.0mg/mL, 5mg/mL, 10mg/mL, 30mg/mL, 50mg/mL, 100mg/mL, and increments of 50mg/mL were added until the small molecule drug was no longer completely dissolved in the solvent. Accordingly, this enabled the maximum solubility of acetylsalicylic acid for each of the six biocompatible non-aqueous solvents to be determined at this resolution, as shown in table 14.

TABLE 14

Solvent(s)	Solubility (mg/mL)	Solubility in water
			Benzyl benzoate	30	Soluble in water
DMSO	2000	Is very soluble in water
			NMP	1200	Is very soluble in water
70:30DMSO:NMP	1450	Is very soluble in water
			Triacetin	5	Slightly soluble
PEG 300	5	Slightly soluble

Example 11

(solubility of beclomethasone dipropionate in biocompatible non-aqueous solvents)

Beclomethasone dipropionate, a small molecule corticosteroid (MW 521.04g/mol) was mixed with the following biocompatible non-aqueous solvents (benzyl benzoate, DMSO, NMP, 70:30(v/v) DMSO: NMP, triacetin, and PEG300) in an amount sufficient to prepare an increased concentration mixture. Specifically, the concentrations examined were 0.1mg/mL, 1.0mg/mL, 5mg/mL, 10mg/mL, 30mg/mL, 50mg/mL, 100mg/mL, and increments of 50mg/mL were added until the small molecule drug was no longer completely dissolved in the solvent. Accordingly, this enabled the maximum solubility of beclometasone dipropionate for each of the six biocompatible non-aqueous solvents to be determined at this resolution, as shown in table 15.

Watch 15

Solvent(s)	Solubility (mg/mL)	Soluble in water
			Benzyl benzoate	50	Soluble in water
DMSO	1700	Is very soluble in water
			NMP	1800	Is very soluble in water
70:30DMSO:NMP	1700	Is very soluble in water
			Triacetin	5	Slightly soluble
PEG 300	30	Soluble in water

Example 12

(solubility of sumatriptan succinate in biocompatible non-aqueous solvents)

Sumatriptan succinate, a small molecule corticosteroid (MW 413.49g/mol), was mixed with the following biocompatible non-aqueous solvents (benzyl benzoate, DMSO, NMP, 70:30(v/v) DMSO: NMP, triacetin, and PEG300) in an amount sufficient to prepare a mixture of increasing concentrations. Specifically, the concentrations examined were 0.1mg/mL, 1.0mg/mL, 5mg/mL, 10mg/mL, 30mg/mL, 50mg/mL, 100mg/mL, and increments of 50mg/mL were added until the small molecule drug was no longer completely dissolved in the solvent. Accordingly, this enabled the determination of the maximum solubility of sumatriptan succinate for each of the six biocompatible non-aqueous solvents at this resolution, as shown in table 16.

TABLE 16

Solvent(s)	Solubility (mg/mL)	Soluble in water
			Benzyl benzoate	<0.1	Is almost insoluble
DMSO	350	Is easy to dissolve
			NMP	100	Is easy to dissolve
70:30DMSO:NMP	300	Is easy to dissolve
			Triacetin	<0.1	Is almost insoluble
PEG 300	0.1	Is extremely insoluble

Example 13

(solubility of diphenhydramine hydrochloride in biocompatible non-aqueous solvents)

Diphenhydramine hydrochloride, which is a small molecule antihistamine (MW 291.82g/mol), was mixed with the following biocompatible non-aqueous solvents (benzyl benzoate, DMSO, NMP, 70:30(v/v) DMSO: NMP, triacetin, and PEG300) in an amount sufficient to prepare a mixture of increasing concentrations. Specifically, the concentrations examined were 0.1mg/mL, 1.0mg/mL, 5mg/mL, 10mg/mL, 30mg/mL, 50mg/mL, 100mg/mL, and increments of 50mg/mL were added until the small molecule drug was no longer completely dissolved in the solvent. Accordingly, this enabled the determination of the maximum solubility of diphenhydramine hydrochloride for each of the six biocompatible non-aqueous solvents at this resolution, as shown in table 17.

TABLE 17

Solvent(s)	Solubility (mg/mL)	Soluble in water
			Benzyl benzoate	0.1	Is extremely insoluble
DMSO	300	Is easy to dissolve
			NMP	100	Is easy to dissolve
70:30DMSO:NMP	150	Is easy to dissolve
			Triacetin	0.1	Is extremely insoluble
PEG 300	50	Soluble in water

Example 14

(solubility of fluconazole in biocompatible non-aqueous solvents)

Fluconazole, which was a small molecule antifungal agent (MW 306.27g/mol), was mixed with the following biocompatible non-aqueous solvents (benzyl benzoate, DMSO, NMP, 70:30(v/v) DMSO: NMP, triacetin, and PEG300) in an amount sufficient to prepare a mixture of increasing concentrations. Specifically, the concentrations examined were 0.1mg/mL, 1.0mg/mL, 5mg/mL, 10mg/mL, 30mg/mL, 50mg/mL, 100mg/mL, and increments of 50mg/mL were added until the small molecule drug was no longer completely dissolved in the solvent. Accordingly, this enabled the determination of the maximum solubility of fluconazole for each of the six biocompatible non-aqueous solvents at this resolution, as shown in table 18.

Watch 18

Solvent(s)	Solubility (mg/mL)	Solubility in water
			Benzyl benzoate	5	Slightly soluble
DMSO	900	Is easy to dissolve
			NMP	800	Is easy to dissolve
70:30DMSO:NMP	850	Is easy to dissolve
			Triacetin	5	Slightly soluble
PEG 300	50	Soluble in water

Example 15

(solubility of tobramycin in biocompatible non-aqueous solvents)

Tobramycin, a small molecule aminoglycoside antibiotic (MW 467.51g/mol), was mixed with the following biocompatible non-aqueous solvents (benzyl benzoate, DMSO, NMP, 70:30(v/v) DMSO: NMP, triacetin, and PEG300) in an amount sufficient to prepare a mixture of increasing concentrations. Specifically, the concentrations examined were 0.1mg/mL, 1.0mg/mL, 5mg/mL, 10mg/mL, 30mg/mL, 50mg/mL, 100mg/mL, and increments of 50mg/mL were added until the small molecule drug was no longer completely dissolved in the solvent. Accordingly, this enabled the determination of the maximum solubility of tobramycin for each of the six biocompatible non-aqueous solvents at this resolution, as shown in table 19.

Watch 19

Solvent(s)	Solubility (mg/mL)	Solubility in water
			Benzyl benzoate	<0.1	Is almost insoluble
DMSO	<0.1	Is almost insoluble
			NMP	<0.1	Is almost insoluble
70:30DMSO:NMP	<0.1	Is almost insoluble
			Triacetin	0.1	Is extremely insoluble
PEG 300	0.1	Is extremely insoluble

Example 16

(solubility of cyclophosphamide in biocompatible non-aqueous solvents)

Cyclophosphamide, a small molecule immunosuppressive/anticancer agent (MW 279.10g/mol), was mixed with the following biocompatible non-aqueous solvents (benzyl benzoate, DMSO, NMP, 70:30(v/v) DMSO: NMP, triacetin, and PEG300) in an amount sufficient to prepare an increasing concentration mixture. Specifically, the concentrations examined were 0.1mg/mL, 1.0mg/mL, 5mg/mL, 10mg/mL, 30mg/mL, 50mg/mL, 100mg/mL, and increments of 50mg/mL were added until the small molecule drug was no longer completely dissolved in the solvent. Accordingly, this enabled the maximum solubility of cyclophosphamide for each of the six biocompatible non-aqueous solvents to be determined at this resolution, as shown in table 20.

Watch 20

Solvent(s)	Solubility (mg/mL)	Soluble in water
			Benzyl benzoate	100	Is easy to dissolve
DMSO	2800	Is very soluble in water
			NMP	2100	Is very soluble in water
70:30DMSO:NMP	2700	Is very soluble in water
			Triacetin	150	Is easy to dissolve
PEG 300	100	Is easy to dissolve

**************

All of the ingredients, compositions, or methods disclosed and claimed in this specification can be made and executed without undue experimentation in light of the present disclosure. While the ingredients, compositions, or methods of this invention have been described in terms of specific embodiments, it will be apparent to those of skill in the art that variations may be applied to the ingredients, compositions, or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit, and scope of the invention.

Claims (13)

1. A stable liquid formulation for parenteral injection comprising:

(a) a biocompatible non-aqueous aprotic solvent selected from dimethyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), or mixtures thereof; and

(b) benzodiazepines or a salt thereof dissolved in the non-aqueous aprotic solvent,

wherein the liquid formulation comprises less than 10% by weight of residual water, and

wherein the volume of the liquid formulation to be parenterally injected is 3ml or less.

2. The stable liquid formulation of claim 1, further comprised within a device for dispensing the liquid formulation.

3. The stable liquid formulation of claim 2, wherein the device is a syringe, a pen injection device, an auto-injector device, an external or implantable pump, or a perfusion bag.

4. The stable liquid formulation of any one of claims 1-3, wherein the benzodiazepine is diazepam.

5. The stable liquid formulation of claim 4, wherein the liquid formulation comprises 50mg/ml to 300mg/ml of diazepam.

6. The stable liquid formulation of any one of claims 1 to 3, wherein the liquid formulation comprises less than 5% residual water by weight.

7. The stable liquid formulation of any one of claims 1-3, wherein the liquid formulation comprises 0.5mg/mL to 750mg/mL of the benzodiazepine.

8. The stable liquid formulation of any one of claims 1 to 3, wherein the volume of the liquid formulation to be parenterally injected is 0.1 to 1 μ l.

9. The stable liquid formulation of any one of claims 1 to 3, wherein the volume of the liquid formulation to be parenterally injected is 1 to 10 μ l.

10. The stable liquid formulation of any one of claims 1 to 3, wherein the volume of the liquid formulation to be parenterally injected is 10 μ l to 1 ml.

11. Use of the stable liquid formulation of claim 1 for the preparation of a substance for administration to a subject in need thereof.

12. The use of claim 11, wherein the liquid formulation is not diluted prior to administration.

13. Use of the stable liquid formulation of claim 1 for the preparation of a substance for treating or preventing a disorder.