JP6474732B2 - Extreme pain treatment composition and method - Google Patents

Description

  This continuation-in-part application claims priority from US patent application Ser. No. 13 / 365,824, which is a continuation-in-part application filed on February 3, 2012 under Section 120 of the US Patent Act. This US patent application claims priority from International Application No. PCT / GB2011 / 052115 filed on October 31, 2011, and this International Application is filed on October 29, 2010. Claims priority of GB1018289.7. In addition, this continuation-in-part application includes US patent application No. 13 / 365,828 filed on February 3, 2012, and UK patent application GB 1113730.4 filed on August 10, 2011, 2011. It claims the priority of GB113729.6 filed on August 10, GB113728.8 filed August 10, 2011, and GB1101937.9 filed February 4, 2011. Each of these patent applications is incorporated herein by reference in its entirety.

  Pain is a subjective and highly complex sensory effect that is signaled to an individual where tissue damage has occurred or has occurred. Pain is transient and may last for a period of time until the harmful stimulus causing the pain is removed, or until the underlying injury or condition is healed, or persists beyond the healing of the injury , It may last for more than a few months. The pain response includes not only physiological elements but also psychological elements. Pain responses elicit a wide range of sensations that can be expressed as dull, aching pain, sharp piercing sensations, hot, cold, or icy-hot sensations, tingling, or itching or numbness. Pain can be felt in a region of the body, such as the back, abdomen, or chest, or it can be felt throughout the body, such as when all muscles of the body hurt due to fluency.

  Severe pain is the most common reason why individuals are involved in health care providers in the United States. Severe pain is a major symptom in many medical conditions and can greatly reduce a person's quality of life and general functioning. Thus, severe pain is an important and costly health problem.

  Current therapies for treating severe pain are limited and often involve the administration of multiple drugs, given the understanding that pain relief may not be complete and quality of life may not be restored. These therapies may require frequent dosing, with undesirable systemic side effects, and are often often inadequate relief. Thus, there remains a need for treatment options developed specifically for severe pain that provide sustained relief while minimizing the possibility of systemic side effects and drug-drug interactions.

  The present specification discloses pharmaceutical compositions and methods for treating individuals suffering from severe pain conditions. The pharmaceutical compositions disclosed herein are substantially lipid delivery systems that allow therapeutic compounds having anti-pain activity to be delivered more effectively to suppress pain responses. The end result is an improvement therapy for severe pain.

  Some embodiments herein disclose a pharmaceutical composition comprising a therapeutic compound and a pharmaceutically acceptable adjuvant. The therapeutic compound can have anti-pain activity. Another aspect of the present specification discloses a pharmaceutical composition comprising a therapeutic compound disclosed herein, a pharmaceutically acceptable solvent, and a pharmaceutically acceptable adjuvant. In other embodiments, the pharmaceutical compositions disclosed herein further comprise a pharmaceutically acceptable stabilizer.

  Another aspect of the specification discloses a method of preparing a pharmaceutical composition, the method contacting a therapeutic compound with a pharmaceutically acceptable adjuvant under conditions that allow the formation of the pharmaceutical composition. Process. Another aspect of the present specification discloses a method of preparing a pharmaceutical composition, the method comprising: a) a pharmaceutical agent under conditions that allow the therapeutic compound to be dissolved in a pharmaceutically acceptable solvent. Forming a solution by contacting a therapeutic compound with an acceptable solvent, wherein the therapeutic compound has anti-pain activity, and b) the solution formed in step (a) Contacting with a pharmaceutically acceptable adjuvant under conditions that allow formation. In other aspects, the methods of preparation disclosed herein further comprise the step of c) removing a pharmaceutically acceptable solvent from the pharmaceutical composition.

  Another aspect of the specification discloses a pharmaceutical composition, the pharmaceutical composition comprising contacting the therapeutic compound with a pharmaceutically acceptable adjuvant under conditions that allow the formation of the pharmaceutical composition. Manufactured by the method. Another aspect of the present specification discloses a pharmaceutical composition, which comprises a) a pharmaceutically acceptable agent under conditions that allow the therapeutic compound to be dissolved in a pharmaceutically acceptable solvent. Forming a solution by contacting the therapeutic compound with a possible solvent, wherein the therapeutic compound has anti-pain activity, and b) forming the pharmaceutical composition from the solution formed in step (a). Contacting with a pharmaceutically acceptable adjuvant under conditions that allow. In another aspect, the method for producing a pharmaceutical composition disclosed herein further comprises the step of c) removing the pharmaceutically acceptable solvent from the pharmaceutical composition.

  Another aspect of the present specification discloses a method of treating a severely afflicted individual, the method comprising administering a pharmaceutical composition disclosed herein to an individual in need thereof, Administration results in a reduction in symptoms associated with the severe pain condition, thereby treating the individual.

  Another aspect of the present specification discloses the use of the pharmaceutical composition disclosed herein in the manufacture of a medicament for the treatment of severe pain conditions.

  Another aspect of the present specification discloses the use of the pharmaceutical composition disclosed herein for the treatment of severe pain conditions.

  In some aspects herein, a composition is disclosed. The compositions disclosed herein are usually administered as a pharmaceutically acceptable composition. As used herein, the term “pharmaceutically acceptable” is a molecular entity that, when administered to an individual, does not cause an adverse reaction, allergic reaction, or other adverse or undesirable reaction. Or means a composition. As used herein, the term “pharmaceutically acceptable composition” is synonymous with “pharmaceutical composition” and has a therapeutically effective concentration of an active ingredient (eg, disclosed herein). Any therapeutic compound). The pharmaceutical compositions disclosed herein are useful in medical and veterinary applications. The pharmaceutical composition may be administered to an individual alone or in combination with other supplemental active ingredients, reagents, drugs, or hormones.

  The pharmaceutical compositions disclosed herein can optionally include a pharmaceutically acceptable carrier that facilitates processing the active ingredient into a pharmaceutically acceptable composition. As used herein, the term “pharmaceutically acceptable carrier” is synonymous with “pharmaceutical carrier” and has substantially no long-term or permanent adverse effects when administered. Meaning any carrier, including terms such as “pharmaceutically acceptable vehicle, stabilizer, diluent, additive, adjuvant, or excipient”. In general, such carriers can be mixed with a therapeutic compound or can dilute or encapsulate the active compound and can be a solid, semi-solid, or liquid reagent. It will be appreciated that the therapeutic compound or active ingredient can be dissolved or delivered as a suspension in the desired carrier or diluent. For example, an aqueous medium such as water, saline, glycine, hyaluronic acid; for example, a solid carrier such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate; Any of a variety of pharmaceutically acceptable carriers may be used including, but not limited to: coatings; antibacterial and antifungal agents; isotonic and absorption delaying agents; or other inert ingredients. The choice of pharmaceutically acceptable carrier may vary depending on the method of administration. Any pharmaceutically acceptable carrier is intended for use in a pharmaceutically acceptable composition, as long as it is not incompatible with the active ingredient. Non-limiting examples of specific uses of such pharmaceutical carriers include: Pharmaceutical Dosage Forms and Drug Delivery Systems (Howard C. Ansel et al., Eds., Lippincott Williams & Wilkins EM 7T THE SCIENCE AND PRACTICE OF PHARMACY (Alfonso R. Gennaro ed., Lippincott, Williams & Wilkins, 20th ed. 2000); Goodman & Gilman's Thepharmaco. , Eds, McGraw-Hill Professional, 10th ed.2001);.. And Handbook of Pharmaceutical Excipients (Raymond C.Rowe et al, APhA Publications, can be found in the 4th edition 2003). These protocols are routine procedures, and any modifications thereof are well within the skill of the person skilled in the art and the teachings herein.

  The pharmaceutical compositions disclosed herein can optionally include other pharmaceutically acceptable ingredients (or pharmaceutical ingredients), including buffers, preservatives, tonicity. Examples include, but are not limited to, regulators, salts, antioxidants, osmotic pressure regulators, physiological substances, pharmacological substances, bulking agents, emulsifiers, wetting agents, sweeteners, or fragrances. A variety of buffering agents and pH adjusting means can be used to prepare the pharmaceutical compositions disclosed herein, provided that the resulting preparation is pharmaceutically acceptable. Such buffers include, but are not limited to, acetate buffer, citrate buffer, phosphate buffer, neutral buffered saline, phosphate buffered saline, and borate buffer. It will be appreciated that acids or bases can be used as needed to adjust the pH of the composition. Pharmaceutically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylhydroxyanisole, and butylhydroxytoluene. Useful preservatives include benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate, phenylmercuric nitrate, stabilized oxychlorocompositions, and chelating agents such as DTPA or DTPA bisamide, calcium DTPA, and CaNaDTPA bisamide. However, it is not limited to these. Tonicity modifiers useful in pharmaceutical compositions include, but are not limited to, salts such as sodium chloride, potassium chloride, mannitol or glycerin, and other pharmaceutically acceptable tonicity modifiers. . The pharmaceutical composition can be provided as a salt and can be formed using a variety of acids including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents compared to the corresponding free base form. It will be appreciated that these and other substances known in the field of pharmacology can be included in pharmaceutical compositions.

  In one embodiment, the pharmaceutical composition disclosed herein comprises a therapeutic compound having anti-pain activity and a pharmaceutically acceptable adjuvant. Anti-pain activity includes attenuating or loss of pain or nociceptive sensation activity without loss of consciousness, and includes but is not limited to analgesic activity and / or nociceptive activity. In another embodiment, the pharmaceutical composition disclosed herein comprises a therapeutic compound having anti-pain activity, a pharmaceutically acceptable solvent, and a pharmaceutically acceptable adjuvant. In some aspects of this embodiment, the pharmaceutical compositions disclosed herein can further comprise a pharmaceutically acceptable stabilizer. In another aspect of this embodiment, the pharmaceutical composition disclosed herein is pharmaceutically acceptable with a pharmaceutically acceptable carrier or pharmaceutically acceptable ingredient, or a pharmaceutically acceptable carrier. Both acceptable components can further be included.

  In some of the embodiments herein, therapeutic compounds are disclosed. A therapeutic compound is a compound that provides a pharmacological activity or other direct action in the diagnosis, cure, alleviation, treatment, or prevention of a disease, or that affects the structure or any function of the human or animal body It is. The therapeutic compounds disclosed herein can be used in the form of a pharmaceutically acceptable salt, solvate, or salt solvate, such as a hydrochloride salt. In addition, the therapeutic compounds disclosed herein can be provided as racemates or as individual enantiomers (including R- or S-enantiomers). Accordingly, the therapeutic compounds disclosed herein can include only the R-enantiomer of the therapeutic compound, only the S-enantiomer, or a combination of both the R-enantiomer and the S-enantiomer. The therapeutic compounds disclosed herein can have anti-pain activity.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce severe pain response. In some aspects of this embodiment, the therapeutic compound disclosed herein has a severe pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%. , At least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% reduced Has anti-pain activity. In other aspects of this embodiment, the therapeutic compounds disclosed herein have a severe pain response, such as from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%, About 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20 % To about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to About 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about Anti-pain activity that can be reduced in the range of 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%. Have.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce nociceptive pain responses. In some aspects of this embodiment, the therapeutic compound disclosed herein has a nociceptive pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, At least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least Has anti-pain activity that can be reduced by 95%. In other aspects of this embodiment, the therapeutic compound disclosed herein has a nociceptive pain response, eg, from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90% About 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10 % To about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70% Have a pain activity.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce nociceptor-mediated pain responses. In some aspects of this embodiment, the therapeutic compounds disclosed herein have a pain response mediated by nociceptors, such as at least 10%, at least 15%, at least 20%, at least 25%, At least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90 %, Or at least 95% reduced anti-pain activity. In other aspects of this embodiment, the therapeutic compound disclosed herein has a nociceptor-mediated pain response, eg, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% About 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80 %, About 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%. It has an anti-pain activity that can.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce somatic pain response. In some aspects of this embodiment, the therapeutic compound disclosed herein has a somatic pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95 % Of anti-pain activity. In other aspects of this embodiment, the therapeutic compound disclosed herein has a somatic pain response, such as from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100. %, About 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, About 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10 % To about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% Anti-pain activity that can be reduced in the range of about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70% A.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce visceral pain response. In some aspects of this embodiment, the therapeutic compound disclosed herein has a visceral pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35 %, At least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% Has reduced anti-pain activity. In other aspects of this embodiment, the therapeutic compound disclosed herein has a visceral pain response, such as from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%. About 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% About 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to Anti-pain activity that can be reduced in the range of about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70% A.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce pathologic pain responses. In some aspects of this embodiment, the therapeutic compound disclosed herein has a pathologic pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35 %, At least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% Has reduced anti-pain activity. In other aspects of this embodiment, the therapeutic compound disclosed herein has a pathologic pain response, such as from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%. About 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% About 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to Anti-pain activity that can be reduced in the range of about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70% A.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce a neuropathic pain response. In some aspects of this embodiment, the therapeutic compound disclosed herein has a neuropathic pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, At least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least Has anti-pain activity that can be reduced by 95%. In other aspects of this embodiment, the therapeutic compound disclosed herein has a neuropathic pain response, eg, from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90% About 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10 % To about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70% Have a pain activity.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce central neuropathic pain responses. In some aspects of this embodiment, the therapeutic compound disclosed herein has a central neuropathic pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30. %, At least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, Or have anti-pain activity that can be reduced by at least 95%. In other aspects of this embodiment, the therapeutic compound disclosed herein has a central neuropathic pain response, eg, about 10% to about 100%, about 20% to about 100%, about 30%. About 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90% About 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, About 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%. Having that anti-pain activity.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce peripheral neuropathic pain responses. In some aspects of this embodiment, the therapeutic compound disclosed herein has a peripheral neuropathic pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%. , At least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or Has anti-pain activity that can be reduced by at least 95%. In other aspects of this embodiment, the therapeutic compounds disclosed herein have a peripheral neuropathic pain response, such as from about 10% to about 100%, from about 20% to about 100%, from about 30% to About 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90 %, About 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, About 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%. Having that anti-pain activity.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce a mononeuropathic pain response. In some aspects of this embodiment, the therapeutic compound disclosed herein has a mononeuropathic pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%. , At least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or Has anti-pain activity that can be reduced by at least 95%. In other aspects of this embodiment, the therapeutic compounds disclosed herein have a mononeuropathic pain response, such as from about 10% to about 100%, from about 20% to about 100%, from about 30% to About 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90 %, About 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, About 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about It can be reduced in the range of 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%. Have a pain activity.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce multiple mononeuropathic pain responses. In some aspects of this embodiment, the therapeutic compound disclosed herein has a multiple mononeuropathic pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% Or have anti-pain activity that can be reduced by at least 95%. In other aspects of this embodiment, the therapeutic compound disclosed herein has a multiple mononeuropathic pain response, eg, about 10% to about 100%, about 20% to about 100%, about 30 % To about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to About 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90 %, About 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80% About 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%. With Kill anti-pain activity.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce multiple neuropathic pain responses. In some aspects of this embodiment, the therapeutic compound disclosed herein has a multiple neuropathic pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30. %, At least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, Or have anti-pain activity that can be reduced by at least 95%. In other aspects of this embodiment, the therapeutic compound disclosed herein has a multiple neuropathic pain response, eg, about 10% to about 100%, about 20% to about 100%, about 30%. About 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90% About 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, About 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%. Having that anti-pain activity.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce autonomic neuropathic pain responses. In some aspects of this embodiment, the therapeutic compound disclosed herein has an autonomic neuropathic pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%. , At least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or Has anti-pain activity that can be reduced by at least 95%. In other aspects of this embodiment, the therapeutic compounds disclosed herein have an autonomic neuropathic pain response, such as from about 10% to about 100%, from about 20% to about 100%, from about 30% to About 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90 %, About 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, About 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70% Having an anti-pain activity.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce neuralgia responses. In some aspects of this embodiment, the therapeutic compound disclosed herein has a neuralgia response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%. , At least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% reduced Has anti-pain activity. In other aspects of this embodiment, the therapeutic compound disclosed herein has a neuralgia response, such as from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%, About 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20 % To about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to About 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about Anti-pain activity that can be reduced in the range of 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70% A.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce complex local pain syndrome pain response. In some aspects of this embodiment, the therapeutic compounds disclosed herein have a combined local pain syndrome pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30. %, At least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, Or have anti-pain activity that can be reduced by at least 95%. In other aspects of this embodiment, the therapeutic compound disclosed herein has a combined local pain syndrome pain response, eg, about 10% to about 100%, about 20% to about 100%, about 30%. About 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90% About 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, Reduction in the range of about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70% Having it anti pain activity.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce the associated pain response. In some aspects of this embodiment, the therapeutic compound disclosed herein has an associated pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35 %, At least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% Has reduced anti-pain activity. In other aspects of this embodiment, the therapeutic compound disclosed herein has an associated pain response, eg, from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%. About 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% About 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to Anti-pain activity that can be reduced in the range of about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70% A.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce afferent blocking pain responses. In some aspects of this embodiment, the therapeutic compound disclosed herein has an afferent block pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%. , At least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or Has anti-pain activity that can be reduced by at least 95%. In other aspects of this embodiment, the therapeutic compounds disclosed herein have an afferent block pain response, such as from about 10% to about 100%, from about 20% to about 100%, from about 30% to About 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90 %, About 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, About 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about It can be reduced in the range of 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%. Have a pain activity.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce a dysfunctional pain response. In some aspects of this embodiment, the therapeutic compound disclosed herein has a dysfunctional pain response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, At least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least Has anti-pain activity that can be reduced by 95%. In other aspects of this embodiment, the therapeutic compound disclosed herein has a dysfunctional pain response, eg, from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90% About 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10 % To about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70% Have a pain activity.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce headache response. In some aspects of this embodiment, the therapeutic compound disclosed herein has a headache response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%. , At least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% reduced Has anti-pain activity. In other aspects of this embodiment, the therapeutic compound disclosed herein has a headache response, such as from about 10% to about 100%, from about 20% to about 100%, from about 30% to about 100%, About 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20 % To about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to About 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about Anti-pain activity that can be increased in the range of 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%. To.

  In one embodiment, the therapeutic compounds disclosed herein have anti-pain activity that can reduce a migraine response. In some aspects of this embodiment, the therapeutic compound disclosed herein has a migraine response, eg, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35. %, At least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% Has reduced anti-pain activity. In other aspects of this embodiment, the therapeutic compound disclosed herein has a migraine response, eg, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%. About 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% About 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to Anti-pain activity that can be reduced in the range of about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70% A.

  The therapeutic compound disclosed herein can have a log P value indicating that the compound is soluble in an organic solvent. As used herein, the term “log P value” represents the logarithm (base 10) of the partition coefficient (P) for a compound and is a measure of lipophilicity. Usually P is defined as the ratio of the concentration of non-ionized compounds in the two phases of a mixture of two immiscible solvents in equilibrium. That is, logP = Log10 (P) and P = [solute in immiscible solvent 1] / [solute in immiscible solvent 2]. With respect to the organic and aqueous phases, the log P value of the compound is constant for any given aqueous and organic solvent pair, such as shake flask assay, HPLC assay, and two immiscible electrolytes. It can be determined empirically by one of several phase partitioning methods known to those skilled in the art, including solution interface (ITIES) assays.

  In some aspects of this embodiment, the therapeutic compound disclosed herein can have a log P value that indicates that the compound is substantially soluble in an organic solvent. In some aspects of this embodiment, the therapeutic compound disclosed herein is at least 50% soluble in an organic solvent, for example, the compound is at least 50% soluble in an organic solvent, It can have a log P value that is 70% soluble, at least 80% soluble in an organic solvent, or at least 90% soluble in an organic solvent. In some aspects of this embodiment, the therapeutic compound disclosed herein is about 60% to about 100% in an organic solvent, for example, the compound is about 50% to about 100% soluble in the organic solvent. LogP that is soluble, about 70% to about 100% soluble in an organic solvent, about 80% to about 100% soluble in an organic solvent, or about 90% to about 100% soluble in an organic solvent Can have a value.

  In some aspects of this embodiment, the therapeutic compounds disclosed herein are, for example, greater than 1.1, greater than 1.2, greater than 1.4, greater than 1.6, greater than 1.8 Over 2.0, over 2.2, over 2.4, over 2.6, over 2.8, over 3.0, over 3.2, over 3.4 Or a log P value greater than 3.6. In other aspects of this embodiment, the therapeutic compounds disclosed herein are, for example, 1.8-4.0, 2.0-4.0, 2.1-4.0, 2.2- LogP values in the range of 4.0, or 2.3 to 4.0, 2.4 to 4.0, 2.5 to 4.0, 2.6 to 4.0, or 2.8 to 4.0 Can have. In other aspects of this embodiment, the therapeutic compounds disclosed herein are, for example, 3.0-4.0, 3.1-4.0, 3.2-4.0, 3.3- It may have a logP value in the range of 4.0, 3.4-4.0, 3.5-4.0, or 3.6-4.0. In yet another aspect of this embodiment, the therapeutic compound disclosed herein is, for example, 2.0-2.5, 2.0-2.7, 2.0-3.0, or 2. It can have a logP value in the range of 2-2.5.

The therapeutic compounds disclosed herein can have a hydrophobic polar surface area. As used herein, the term “polar surface area” refers to the surface sum of all polar atoms in the structure of a compound and is a measure of hydrophobicity. Usually, these polar atoms include, for example, oxygen, nitrogen, and their bonded hydrogens. In some aspects of this embodiment, the therapeutic compounds disclosed herein include, for example, less than 8.0 nm ^2, less than 7.0 nm ^2, less than 6.0 nm ^2, less than 5.0 nm ^2, 4.0 nm less than ^2, or 3.0nm may have less than ² polar surface area. In another aspect of this embodiment, the therapeutic compounds disclosed herein include, for ^{example, 3.0nm 2 ~6.5nm 2, 3.0nm 2} ~6.0nm 2, 3.0nm 2 ~5.5nm ^{2, 3.0nm 2 ~5.0nm 2, 3.0nm} 2 ~4.5nm 2, 3.5nm 2 ~6.5nm 2, 3.5nm 2 ~6.0nm 2, 3.5nm 2 ~5.5nm ^{2, 3.5nm 2 ~5.0nm 2, 3.5nm} 2 ~4.5nm 2, 4.0nm 2 ~6.5nm 2, 4.0nm 2 ~6.0nm 2, 4.0nm 2 ~5.5nm ^2, or 4.0 nm ² ～5.0Nm ^2, may have a polar surface area in the range of 4.0 nm ² ～4.5Nm ^2, or 4.5nm ² ~5.5nm ^2. In yet another aspect of this embodiment, the therapeutic compounds disclosed herein include, for ^{example, 2.0nm 2 ~6.5nm 2, 2.0nm 2} ~6.0nm 2, 2.0nm 2 ~5. ^{5nm 2, 2.0nm 2 ~5.0nm 2,} 2.0nm2~4.5nm2,2.5nm2~6.5nm2,2.5nm 2 ~6.0nm 2, 2.5nm 2 ~5.5nm 2, 2 .5nm ² ~5.0nm ^2, or may have a polar surface area in the range of 2.5nm ² ~4.5nm ^2.

  The therapeutic compound disclosed herein may be a non-steroidal anti-inflammatory drug (NSAID). NSAIDs belong to a large group of therapeutic compounds that have analgesic, anti-pain and antipyretic properties. NSAIDs include aceclofenac, acemetacin, actarit, arcofenac, aluminoprofen, ampenac, aroxipyrine, aminophenazone, anthraphenine, aspirin, azapropazone, benolylate, benoxaprofen, benzidamine, butybufen, celecoxib, chloritoxacin, chlortenoxacin Choline, Clometacin, Dexketoprofen, Diclofenac, Diflunisal, Emorphazone, Epirisol, Etodolac, Etlicoxib, Feclobzone, Ferbinac, Fenbufen, Fenclofenac, Flurbiprofen, Grafenine, Hydroxyethyl salicylate, Ibuprofen, Indomethacin, Indoprofen, Ketoprofen Ketorolac, lactylphenetidine, loki Profen, luminacoxib, mefenamic acid, meloxicam, metamizole, methazidic acid, mofebutazone, mofezolac, nabumetone, naproxen, nifenazone, niflumic acid, oxametacin, phenacetin, pipebzone, pranoprofen, propifenazone, procazone, protisalic acid, rofecomidato , Sulindac, suprofen, thiaramide, tinolidine, tolfenamic acid, valdecoxib, and zomepilac, but are not limited to these.

  NSAIDs can be classified based on their chemical structure or mechanism of action. Specific examples of NSAIDs include salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, Selective cyclooxygenase 1 (COX1) inhibitors and selective cyclooxygenase 2 (COX2) inhibitors are included. The NSAID may be prophen. Examples of suitable salicylic acid derivatives NSAIDs include, but are not limited to, acetylsalicylic acid (aspirin), diflunisal, and salsalate. Examples of suitable p-aminophenol derivatives NSAIDs include, but are not limited to, paracetamol and phenacetin. Examples of suitable propionic acid derivatives NSAIDs include aluminoprofen, benoxaprofen, dexketoprofen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, loxoprofen, naproxen, oxaprozin, pranoprofen, And suprofen. Examples of suitable acetic acid derivatives NSAIDs include aceclofenac, acemetacin, actarit, arcofenac, ampenac, clometacin, diclofenac, etodolac, felbinac, fenclofenac, indomethacin, ketorolac, methothic acid, mofezolac, nabumetone, naproxen, oxametacin, Including, but not limited to, zomepirac. Examples of suitable enolic acid (oxicam) derivatives NSAIDs include, but are not limited to, droxicam, isoxicam, lornoxicam, meloxicam, piroxicam, and tenoxicam. Examples of suitable fenamic acid derivatives NSAIDs include, but are not limited to, flufenamic acid, mefenamic acid, meclofenamic acid, and tolfenamic acid. Examples of suitable selective COX-2 inhibitors include, but are not limited to, celecoxib, etolicoxib, phylocoxib, luminacoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib.

  The therapeutic compound disclosed herein may be a PPARγ agonist. Examples of suitable PPARγ agonists include benzbromarone, cannabidiol, cilostazol, curcumin, delta (9) -tetrahydrocannabinol, glycyrrhetinic acid, indomethacin, irbesartan, monacin, mycophenolic acid, resveratrol, 6-shogaol , Thiazolidinediones such as telmisartan, rosiglitazone, pioglitazone, and troglitazone, NSAIDs, and fibrates, but are not limited to these. Other suitable PPARγ agonists are described in US Patent Application Publication No. 2011/0195993, Masson and Caumont-Bertrand, PPAR Agonist Compounds, Preparation and Uses, which is hereby incorporated by reference in its entirety. Be incorporated.

  The therapeutic compound disclosed herein may be a nuclear receptor binding agent. Examples of suitable nuclear receptor binders include retinoic acid receptor (RAR) binders, retinoid X receptor (RXR) binders, liver X receptor (LXR) binders, and vitamin D binders. However, it is not limited to these.

  The therapeutic compound disclosed herein may be an antihyperlipidemic agent. There are several types of antihyperlipidemic agents (also known as lipid lowering agents). They can differ in both effects and adverse effects on the cholesterol profile. For example, some can reduce low density lipoprotein (LDL) while others can preferentially increase high density lipoprotein (HDL). Clinically, drug selection depends on the individual's cholesterol profile, the individual's cardiovascular risk, and / or the individual's liver and kidney function. Examples of suitable antihyperlipidemic agents include fibrates, statins, tocotrienols, niacin, bile acid sequestrants (bile acid resins), cholesterol absorption inhibitors, pancreatic lipase inhibitors, and sympathomimetic amines However, it is not limited to these.

  The therapeutic compound disclosed herein may be a fibrate. Fibrates belong to a class of amphiphilic carboxylic acids that have lipid level modulating properties. These therapeutic compounds are used for a range of metabolic disorders. One non-limiting example is the use as an anti-hyperlipidemic agent, which can, for example, reduce triglyceride and LDL levels and increase HDL levels. Examples of suitable fibrates include but are not limited to bezafibrate, ciprofibrate, clofibrate, gemfibrozil, and fenofibrate.

  The therapeutic compound disclosed herein may be a statin. Statins (or HMG-CoA reductase inhibitors) are therapeutic compounds used to reduce LDL and / or cholesterol levels by inhibiting HMG-CoA reductase, which plays a central role in liver cholesterol production Belonging to the class. To compensate for the decrease in available cholesterol, liver LDL receptor synthesis is increased and blood-derived LDL particles are excreted. Examples of suitable statins include, but are not limited to, atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

  The therapeutic compound disclosed herein may be tocotrienol. Tocotrienols belong to another class of HMG-CoA reductase inhibitors, which are used to induce LDL and by upregulating hepatic LDL receptors and / or by reducing plasma LDL levels. / Or cholesterol levels can be reduced. Examples of suitable tocotrienols include, but are not limited to, γ-tocotrienol and δ-tocotrienol.

  The therapeutic compound disclosed herein may be niacin. Niacin belongs to a class of therapeutic compounds that have lipid level modulating properties. For example, niacin can reduce LDL by selectively inhibiting hepatic diacylglycerol acyltransferase 2, reduce triglyceride synthesis, and reduce VLDL secretion via the receptors HM74 and HM74A or GPR109A. These therapeutic compounds are used for a range of metabolic disorders. One non-limiting example is the use as an antihyperlipidemic agent, which can suppress the degradation of fat in adipose tissue. Niacin blocks the breakdown of fat, causing a decrease in free fatty acids in the blood, resulting in a decrease in the secretion of very low density lipoprotein (VLDL) and cholesterol by the liver. By reducing the level of VLDL, niacin can also increase the level of HDL in the blood. Examples of suitable niacins include, but are not limited to acipimox, niacin, nicotinamide, and vitamin B3.

  The therapeutic compound disclosed herein may be a bile acid sequestrant. Bile acid sequestrants (also known as bile acid resins) belong to the class of therapeutic compounds used to bind to specific components of bile in the gastrointestinal tract. They block the bile acid enterohepatic circulation by sequestering bile acids and prevent the bile acids from being reabsorbed from the digestive tract. Bile acid sequestrants are particularly effective in reducing LDL and cholesterol by sequestering cholesterol-containing bile acids released into the intestine and preventing it from being reabsorbed from the intestine. In addition, bile acid sequestrants can also increase HDL levels. Examples of suitable bile acid sequestrants include, but are not limited to, cholestyramine, colesevelam, and colestipol.

  The therapeutic compound disclosed herein may be a cholesterol absorption inhibitor. Cholesterol absorption inhibitors belong to the class of therapeutic compounds that inhibit the absorption of cholesterol from the intestine. Decreased cholesterol absorption results in increased expression of LDL receptors on the cell surface and increased LDL-cholesterol uptake into these cells, thereby reducing the level of LDL in plasma. Examples of suitable cholesterol absorption inhibitors include, but are not limited to, ezetimibe, phytosterol, sterol, and stanol.

  The therapeutic compound disclosed herein may be a fat absorption inhibitor. Fat absorption inhibitors belong to the class of therapeutic compounds that inhibit the absorption of fat from the intestine. Reduced fat absorption reduces caloric intake. In one aspect, the fat absorption inhibitor inhibits pancreatic lipase, an enzyme that degrades triglycerides in the intestine. An example of a suitable fat absorption inhibitor includes, but is not limited to, orlistat.

  The therapeutic compound disclosed herein may be a sympathomimetic amine. Sympathomimetic amines belong to a class of therapeutic compounds that mimic the action of sympathetic nervous system transmitters such as catecholamines, epinephrine (adrenaline), norepinephrine (noradrenaline), and / or dopamine. Sympathomimetic amines can act as α-adrenergic agonists, β-adrenergic agonists, dopamine agonists, monoamine oxidase (MAO) inhibitors, and COMT inhibitors. Such therapeutic compounds are used in particular for the treatment of cardiac arrest and hypotension, as well as for delaying preterm labor. Examples of suitable sympathomimetic amines include Clenbuterol, Salbutamol, Ephedrine, Pseudoephedrine, Methamphetamine, Amphetamine, Phenylephrine, Isoproterenol, Dobutamine, Methylphenidate, Risdexamphetamine, Casin, Cathinone, Metocathinone, Cocaine, Benzylpiperazine (BZP), methylenedioxypylovalerone (MDPV), 4-methylaminorex, pemoline, phenmetrazine, and propylhexedrine.

  The therapeutic compound disclosed herein may be an ester of a therapeutic compound. The ester of the therapeutic compound increases the log P value compared to the same therapeutic compound without ester modification. For example, an ester group can be attached to a therapeutic compound by a carboxylic acid or hydroxyl functionality present in the therapeutic compound. Esters of therapeutic compounds may increase hydrophobicity and therefore may be soluble in lesser amounts of the solvents disclosed herein. In some examples, the ester of the therapeutic compound can be combined directly with the adjuvants disclosed herein, thereby eliminating the need for a solvent. Even if the non-esterified form of the therapeutic compound is otherwise immiscible in the solvent disclosed herein, it may be an ester of the same therapeutic compound as long as it is an ester of the pharmaceutical composition disclosed herein. Manufacture may be possible. Esters of therapeutic compounds can be delivered in a manner that more effectively inhibits pro-inflammatory responses as long as the compound is combined with the adjuvants disclosed herein. In one embodiment, the therapeutic compound can be reacted with the ethyl ester to form the ethyl ester of the therapeutic compound.

  In another embodiment, the pharmaceutical composition disclosed herein does not comprise a pharmaceutically acceptable solvent disclosed herein. In one aspect of this embodiment, the pharmaceutical composition includes a therapeutic compound and a pharmaceutically acceptable adjuvant, but does not include a pharmaceutically acceptable solvent disclosed herein.

  The pharmaceutical compositions disclosed herein can contain a sufficient amount of the therapeutic compound to allow daily administration to an individual. In some aspects of this embodiment, the pharmaceutical compositions disclosed herein are, for example, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg. , At least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of the therapeutic compound. In other aspects of this embodiment, the pharmaceutical composition disclosed herein has, for example, at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, Treatment of at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1,300 mg, at least 1,400 mg, or at least 1,500 mg It may be a compound. In yet another aspect of this embodiment, the pharmaceutical composition disclosed herein has, for example, about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg. To about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg to It may be in the range of about 1,500 mg. In yet another aspect of this embodiment, the pharmaceutical composition disclosed herein has, for example, about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1,000 mg, About 10 mg to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about 250 mg, about 100 mg To about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1,000 mg, about 200 mg to about 1,500 mg, about 5 mg to about 1,500 mg, about 5 mg to about 1,0 0 mg, or from about 5mg~ about 250 mg.

  Some embodiments herein disclose, in part, pharmaceutically acceptable solvents. A solvent is a liquid, solid, or gas that dissolves another solid, liquid, or gas (solute) to form a solution. Solvents useful in the pharmaceutical compositions disclosed herein include pharmaceutically acceptable polar aprotic solvents, pharmaceutically acceptable polar protic solvents, and pharmaceutically acceptable nonpolar solvents. However, it is not limited to these. Pharmaceutically acceptable polar aprotic solvents include dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate, acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), It is not limited to these. Pharmaceutically acceptable polar protic solvents include acetic acid, formic acid, ethanol, n-butanol, 1-butanol, 2-butanol, isobutanol, sec-butanol, tert-butanol, n-propanol, isopropanol, 1, Examples include, but are not limited to, 2-propanediol, methanol, glycerol, and water. Pharmaceutically acceptable nonpolar solvents include pentane, cyclopentane, hexane, cyclohexane, benzene, toluene, 1,4-dioxane, chloroform, n-methylpyridone (NMP), and diethyl ether. It is not limited to these.

  The pharmaceutical compositions disclosed herein can include a sufficient amount of solvent to dissolve the therapeutic compound disclosed herein. In other aspects of this embodiment, the pharmaceutical composition disclosed herein comprises a solvent, such as less than about 90% (v / v), less than about 80% (v / v), about 70% ( v / v), less than about 65% (v / v), less than about 60% (v / v), less than about 55% (v / v), less than about 50% (v / v), about 45% ( v / v), less than about 40% (v / v), less than about 35% (v / v), less than about 30% (v / v), less than about 25% (v / v), about 20% ( v / v), less than about 15% (v / v), less than about 10% (v / v), about 5% (v / v), or less than about 1% (v / v). In other aspects of this embodiment, the pharmaceutical compositions disclosed herein may comprise a solvent, such as about 1% (v / v) to 90% (v / v), about 1% (v / v ) To 70% (v / v), about 1% (v / v) to 60% (v / v), about 1% (v / v) to 50% (v / v), about 1% (v / v) v) -40% (v / v), about 1% (v / v) -30% (v / v), about 1% (v / v) -20% (v / v), about 1% (v / V) to 10% (v / v), about 2% (v / v) to 50% (v / v), about 2% (v / v) to 40% (v / v), about 2% ( v / v) to 30% (v / v), about 2% (v / v) to 20% (v / v), about 2% (v / v) to 10% (v / v), about 4% (V / v) to 50% (v / v), about 4% (v / v) to 40% (v / v), about 4% (v / v) to 30% (v / v), about 4 % (V / ) To 20% (v / v), about 4% (v / v) to 10% (v / v), about 6% (v / v) to 50% (v / v), about 6% (v / v) v) -40% (v / v), about 6% (v / v) -30% (v / v), about 6% (v / v) -20% (v / v), about 6% (v / V) to 10% (v / v), about 8% (v / v) to 50% (v / v), about 8% (v / v) to 40% (v / v), about 8% ( v / v) -30% (v / v), about 8% (v / v) -20% (v / v), about 8% (v / v) -15% (v / v), or about 8 % (V / v) to 12% (v / v).

In one embodiment, the solvent can include a pharmaceutically acceptable alcohol. As used herein, the term “alcohol” refers to an organic molecule that contains a hydroxyl functional group (—OH) attached to a carbon atom, where the carbon atom is saturated. In some aspects of this embodiment, the alcohol is, for example, a C _2-4 alcohol, a C _1-4 alcohol, a C _1-5 alcohol, a C _1-7 alcohol, a C _1-10 alcohol, a C _1-15 alcohol. Or a C _1-20 alcohol. In other aspects of this embodiment, the alcohol may be, for example, a primary alcohol, a secondary alcohol, or a tertiary alcohol. In other aspects of this embodiment, the alcohol is, for example, an acyclic alcohol, a monohydric alcohol, a polyhydric alcohol (also known as a polyol or sugar alcohol), an unsaturated aliphatic alcohol, an alicyclic alcohol, or these It may be a combination of Examples of monohydric alcohols include, but are not limited to, methanol, ethanol, propanol, butanol, pentanol, and 1-hexadecanol. Examples of polyhydric alcohols include, but are not limited to, glycol, glycerol, arabitol, erythritol, xylitol, maltitol, sorbitol (glucitol), mannitol, inositol, lactitol, galactitol (iditol), and isomalt. Examples of unsaturated fatty alcohols include prop-2-en-1-ol, 3,7-dimethylocta-2,6-dien-1-ol, and prop-2-yn-1-ol. However, it is not limited to these. Examples of alicyclic alcohols include, but are not limited to, cyclohexane-1,2,3,4,5,6, -hexol and 2- (2-propyl) -5-methylcyclohexane-1-ol. Not.

  In another embodiment, the solvent can comprise a pharmaceutically acceptable alcohol and acid ester. Suitable pharmaceutically acceptable alcohols include those disclosed herein. Suitable acids include, but are not limited to, acetic acid, butyric acid, and formic acid. Examples of alcohol and acid esters include methyl acetate, methyl butyrate, methyl formate, ethyl acetate, ethyl butyrate, ethyl formate, propyl acetate, propyl butyrate, propyl formate, butyl acetate, butyl butyrate, butyl formate, isobutyl acetate, isobutyl butyrate, Examples include, but are not limited to, isobutyl formate, pentyl acetate, pentyl butyrate, pentyl formate, and 1-hexadecyl acetate, 1-hexadecyl butyrate, and 1-hexadecyl formate.

  In another embodiment, the solvent may comprise a pharmaceutically acceptable glycol ether. Glycol ethers belong to the group of alkyl ether-based solvents of ethylene glycol. Non-limiting examples include diethylene glycol monomethyl ether (2- (2-methoxyethoxy) ethanol), diethylene glycol monoethyl ether (2- (2-ethoxyethoxy) ethanol), diethylene glycol monopropyl ether (2- (2-propoxyethoxy) ) Ethanol), diethylene glycol monoisopropyl ether (2- (2-isopropoxyethoxy) ethanol), and diethylene glycol mono-n-butyl ether (2- (2-butoxyethoxy) ethanol). Diethylene glycol monoethyl ether (2- (2-ethoxyethoxy) ethanol) is commercially available as TRANSCUTOL®.

  In another embodiment, the solvent may comprise a pharmaceutically acceptable diol. Diols or double alcohols are chemicals that contain two hydroxyl groups (—OH groups).

In another embodiment, the solvent may comprise pharmaceutically acceptable propylene glycol. Propylene glycol, also called 1,2-propanediol or propane-1,2-diol, is an organic compound of the formula: C ₃ H ₈ O ₂ or HO—CH ₂ —CHOH—CH ₃ .

  In another embodiment, the solvent may comprise pharmaceutically acceptable dipropylene glycol. Dipropylene glycol is composed of three isomeric chemicals, 4-oxa-2,6-heptanediol, 2- (2-hydroxypropoxy) -propan-1-ol, and 2- (2-hydroxy-1-methyl). Ethoxy) -propan-1-ol.

  In another embodiment, the solvent may comprise a pharmaceutically acceptable polypropylene glycol (PPG) polymer. PPG polymers, also known as polypropylene oxide (PPO) polymers or polyoxypropylene (POP) polymers, are prepared by polymerization of propylene oxide and have a wide range of molecular weights from 100 g / mol to 10,000,000 g / mol Is commercially available. Low molecular weight PPG polymers are liquids or low melting point solids, while high molecular weight PPG polymers are solids. As PPG polymers, PPG100, PPG200, PPG300, PPG400, PPG500, PPG600, PPG700, PPG800, PPG900, PPG1000, PPG1100, PPG1200, PPG1300, PPG1400, PPG1500, PPG1600, PPG1700, PPG1800, PPG1900, PPG2000, PPG2 , PPG2400, PPG2500, PPG2600, PPG2700, PPG2800, PPG2900, PPG3000, PPG3250, PPG3350, PPG3500, PPG3750, PPG4000, PPG4250, PPG4500, PPG4750, PPG5000, PPG5500, PPG6000, PP 6500, PPG 7000, PPG 7500, PPG 8000, PPG 8500, PPG 9000, PPG 9500, PPG 10,000, PPG 11,000, PPG 12,000, PPG 13,000, PPG 14,000, PPG 15,000, PPG 16,000, PPG 17,000, PPG 18,000, PPG 19,000 or PPG 20,000 may be mentioned, but is not limited thereto.

  In another embodiment, the solvent may comprise a pharmaceutically acceptable polyethylene glycol (PEG) polymer. PEG polymers, also known as polyethylene oxide (PEO) polymers or polyoxyethylene (POE) polymers, are prepared by polymerization of ethylene oxide and come in a wide range of molecular weights from 100 g / mol to 10,000,000 g / mol. It is commercially available. Low molecular weight PEG polymers are liquid or low melting point solids, while high molecular weight PEG polymers are solids. PEG polymers include PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, PEG700, PEG800, PEG900, PEG1000, PEG1100, PEG1200, PEG1300, PEG1400, PEG1500, PEG1600, PEG1700, PEG1800, PEG1900, PEG2000, PEG2100, PEG2200, PEG2300 , PEG2400, PEG2500, PEG2600, PEG2700, PEG2800, PEG2900, PEG3000, PEG3250, PEG3350, PEG3500, PEG3750, PEG4000, PEG4250, PEG4500, PEG4750, PEG5000, PEG5500, PEG6000, PE 6500, PEG 7000, PEG 7500, PEG 8000, PEG 8500, PEG 9000, PEG 9500, PEG 10,000, PEG 11,000, PEG 12,000, PEG 13,000, PEG 14,000, PEG 15,000, PEG 16,000, PEG 17,000, PEG 18,000, Examples include, but are not limited to, PEG 19,000 or PEG 20,000.

  In another embodiment, the solvent may comprise pharmaceutically acceptable glycerides. Glycerides include substituted glycerols, in which one, two, or all three of the hydroxyl groups of glycerol are each esterified with fatty acids to produce monoglycerides, diglycerides, and triglycerides, respectively. In these compounds, each hydroxyl group of glycerol may be esterified with a different fatty acid. In addition, glycerides may be acetylated to form acetylated monoglycerides, acetylated diglycerides, and acetylated triglycerides.

  In one embodiment, the solvent may comprise a pharmaceutically acceptable solid solvent. Solid solvents will be useful in preparing solid dosage formulations of the pharmaceutical compositions disclosed herein. Typically, the solid solvent is melted to dissolve the therapeutic compound. Pharmaceutically acceptable solid solvents include, but are not limited to, menthol and PEG polymers greater than about 20,000 g / mol.

  Some embodiments herein disclose, in part, pharmaceutically acceptable adjuvants. Adjuvants are agents that improve the action of other agents (eg, therapeutic compounds disclosed herein). In addition, the adjuvants disclosed herein can be used as a solvent to dissolve the therapeutic compounds disclosed herein to form adjuvant solutions. The adjuvants disclosed herein facilitate delivery of therapeutic compounds in a manner that more effectively inhibits pro-inflammatory responses. In one embodiment, the adjuvants disclosed herein facilitate delivery of the therapeutic compounds disclosed herein to macrophages.

  The pharmaceutical composition disclosed herein may comprise a pharmaceutically acceptable adjuvant in an amount sufficient to be mixed with the solution disclosed herein or the emulsion disclosed herein. it can. In other aspects of this embodiment, the pharmaceutical composition disclosed herein has, for example, at least 10% (v / v), at least 20% (v / v), at least 30% (v / v), At least 35% (v / v), at least 40% (v / v), at least 45% (v / v), at least 50% (v / v), at least 55% (v / v), at least 60% (v / V), at least 65% (v / v), at least 70% (v / v), at least 75% (v / v), at least 80% (v / v), at least 85% (v / v), at least An amount of 90% (v / v), at least 95% (v / v), or at least 99% (v / v) can be included. In other aspects of this embodiment, the pharmaceutical compositions disclosed herein can be, for example, from about 30% (v / v) to about 99% (v / v), from about 35% (v / v) to About 99% (v / v), about 40% (v / v) to about 99% (v / v), about 45% (v / v) to about 99% (v / v), about 50% (v / V) to about 99% (v / v), about 30% (v / v) to about 98% (v / v), about 35% (v / v) to about 98% (v / v), about 40% (v / v) to about 98% (v / v), about 45% (v / v) to about 98% (v / v), about 50% (v / v) to about 98% (v / v) v), about 30% (v / v) to about 95% (v / v), about 35% (v / v) to about 95% (v / v), about 40% (v / v) to about 95 % (V / v), about 45% (v / v) to about 95% (v / v), or about 50% (v / v) to about 95% (v v) the range of the amount of adjuvants may include. In yet another aspect of this embodiment, the pharmaceutical composition disclosed herein is, for example, from about 70% (v / v) to about 97% (v / v), about 75% (v / v) To about 97% (v / v), about 80% (v / v) to about 97% (v / v), about 85% (v / v) to about 97% (v / v), about 88% ( v / v) to about 97% (v / v), about 89% (v / v) to about 97% (v / v), about 90% (v / v) to about 97% (v / v), About 75% (v / v) to about 96% (v / v), about 80% (v / v) to about 96% (v / v), about 85% (v / v) to about 96% (v / V), about 88% (v / v) to about 96% (v / v), about 89% (v / v) to about 96% (v / v), about 90% (v / v) to about 96% (v / v), about 75% (v / v) to about 93% (v / v), about 80% (v / v) to about 93% ( / V), about 85% (v / v) to about 93% (v / v), about 88% (v / v) to about 93% (v / v), about 89% (v / v) to about An amount of adjuvant may be included, ranging from 93% (v / v), or from about 90% (v / v) to about 93% (v / v).

  In one embodiment, the adjuvant may be a pharmaceutically acceptable lipid. Lipids can be broadly defined as hydrophobic or amphiphilic small molecules. The amphiphilic nature of some lipids allows the formation of structures such as vesicles, liposomes, or membranes in an aqueous environment. Non-limiting examples of lipids include fatty acids, glycerolipids (eg, monoglycerides, diglycerides, and triglycerides), phospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides. The pharmaceutical compositions disclosed herein include, for example, oils, oil-based liquids, fats, fatty acids, waxes, fatty acid esters, fatty acid salts, fatty alcohols, glycerides (mono, di, or triglycerides), partially hydrolyzed glycerolipids , Lipids such as phospholipids, glycol esters, sucrose esters, glycerol oleate derivatives, medium chain triglycerides, or mixtures thereof. Other examples of pharmaceutically acceptable lipids useful as adjuvants include, for example, US Pat. Nos. 6,923,988, 6,451,339, 6,383,471, 6,294, 192 and 6,267,985. These patents are incorporated herein by reference in their entirety.

  Lipids useful in the pharmaceutical compositions disclosed herein may be pharmaceutically acceptable fatty acids. Fatty acids include carboxylic acids with long unbranched hydrocarbon chains that may be saturated or unsaturated. Such an arrangement forms a fatty acid having a polar hydrophilic end and a nonpolar hydrophobic end insoluble in water. Most natural fatty acids have an even number of carbon atoms, usually have a hydrocarbon chain of 4 to 24 carbons, and may have functional groups including oxygen, halogen, nitrogen, and sulfur bonded thereto. Synthetic or non-natural fatty acids can have any number of hydrocarbon chains from 3 to 40 carbon atoms. If a double bond is present, it can be either cis or trans geometric isomerism, which greatly affects the molecular conformation of the molecule. Cis double bonds cause fatty acid chains to bend, and this effect becomes more pronounced the more double bonds in the chain. Most naturally occurring fatty acids are in the cis configuration, but some natural and partially hydrogenated fats and oils are also in trans form. Examples of fatty acids include caprylic acid (8: 0), pelargonic acid (9: 0), capric acid (10: 0), undecylic acid (11: 0), lauric acid (12: 0), tridecylic acid (13 : 0), myristic acid (14: 0), myristoleic acid (14: 1), pentadecylic acid (15: 0), palmitic acid (16: 0), palmitoleic acid (16: 1), sapienic acid (16: 1) Margaric acid (17: 0), stearic acid (18: 0), oleic acid (18: 1), elaidic acid (18: 1), vaccenic acid (18: 1), linoleic acid (18: 2) , Linoelaidic acid (18: 2), α-linolenic acid (18: 3), γ-linolenic acid (18: 3), stearidonic acid (18: 4), nonadecylic acid (19: 0), arachidic acid (20 : 0), eicosenoic acid (20: 1) ), Dihomo-γ-linolenic acid (20: 3), mead acid (20: 3), arachidonic acid (20: 4), eicosapentaenoic acid (20: 5), heicosyl acid (21: 0), behenic acid ( 22: 0), erucic acid (22: 1), docosahexaenoic acid (22: 6), tricosylic acid (23: 0), lignoceric acid (24: 0), nervonic acid (24: 1), pentacosylic acid (25: 0), serotic acid (26: 0), heptacosylic acid (27: 0), montanic acid (28: 0), nonacosic acid (29: 0), melissic acid (30: 0), hentriacontylic acid (31 : 0), lactelonic acid (32: 0), psylic acid (33: 0), gedaic acid (34: 0), celloplastinic acid (35: 0), and hexatriacontylic acid (36: 0), But not limited to

  Lipids useful in the pharmaceutical compositions disclosed herein may be pharmaceutically acceptable partially hydrogenated lipids. The hydrogenation process adds hydrogen atoms to unsaturated lipids to remove double bonds, resulting in partially or fully saturated lipids. Partial hydrogenation is chemical rather than enzymatic and does not completely hydrogenate, but converts some of the cis isomers to trans unsaturated lipids. In the first reaction step, one hydrogen is added and the remaining carbon of coordination unsaturation is bound to the catalyst. In the second step, hydrogen is added to the remaining carbon to produce saturated fatty acids. The first step is reversible, whereby hydrogen is reabsorbed on the catalyst and double bonds are reformed. Intermediates with only one additional hydrogen do not have a double bond and can rotate freely. Thus, double bonds can be reformed as either cis or trans, of which trans is selected regardless of the starting material.

  In one embodiment, the adjuvant may be a pharmaceutically acceptable saturated or unsaturated fatty acid. In some aspects of this embodiment, the saturated or unsaturated fatty acids are, for example, at least 8, at least 10, at least 12, at least 14, at least 16, at least 18, at least 20, at least 22 At least 24, at least 26, at least 28, or at least 30 carbon atoms. In other aspects of this embodiment, the saturated or unsaturated fatty acid is, for example, 4 to 24 carbon atoms, 6 to 24 carbon atoms, 8 to 24 carbon atoms, 10 to 24 carbon atoms, 12 ˜24 carbon atoms, 14-24 carbon atoms, or 16-24 carbon atoms, 4-22 carbon atoms, 6-22 carbon atoms, 8-22 carbon atoms, 10-10 22 carbon atoms, 12-22 carbon atoms, 14-22 carbon atoms, or 16-22 carbon atoms, 4-20 carbon atoms, 6-20 carbon atoms, 8-20 Carbon atoms, 10-20 carbon atoms, 12-20 carbon atoms, 14-20 carbon atoms, or 16-20 carbon atoms. When unsaturated, the fatty acid can have, for example, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, or 6 or more double bonds.

  In some aspects of this embodiment, the pharmaceutically acceptable saturated or unsaturated fatty acid is a liquid at room temperature. The melting point of the fatty acid is largely determined by the degree of saturation / unsaturation of the hydrocarbon chain. In some aspects of this embodiment, the saturated or unsaturated fatty acid is, for example, 20 ° C. or lower, 15 ° C. or lower, 10 ° C. or lower, 5 ° C. or lower, 0 ° C. or lower, −5 ° C. or lower, −10 ° C. or lower, − It has a melting point of 15 ° C. or lower, or −20 ° C. or lower. In other aspects of this embodiment, the saturated or unsaturated fatty acid is, for example, from about -20 ° C to about 20 ° C, from about -20 ° C to about 18 ° C, from about -20 ° C to about 16 ° C, from about -20 ° C. About 12 ° C, about -20 ° C to about 8 ° C, about -20 ° C to about 4 ° C, about -20 ° C to about 0 ° C, about -15 ° C to about 20 ° C, about -15 ° C to about 18 ° C, about It has a melting point in the range of -15 ° C to about 16 ° C, about -15 ° C to about 12 ° C, about -15 ° C to about 8 ° C, about -15 ° C to about 4 ° C, about -15 ° C to about 0 ° C.

  In another embodiment, the adjuvant can include one pharmaceutically acceptable fatty acid. In some aspects of this embodiment, the adjuvant can include palmitic acid only, stearic acid only, oleic acid only, linoleic acid only, or linolenic acid only.

  In another embodiment, the adjuvant can include a plurality of different pharmaceutically acceptable fatty acids. In some aspects of this embodiment, the adjuvant comprises, for example, two or more different fatty acids, three or more different fatty acids, four or more different fatty acids, five or more different fatty acids, or six or more different fatty acids. Can be included.

  In another aspect of this embodiment, the adjuvant is at least two different pharmaceutically acceptable including at least palmitic acid, stearic acid, oleic acid, linoleic acid, and / or linolenic acid, and any combination thereof. May contain various fatty acids. In other aspects of this embodiment, the adjuvant is, for example, at least 2: 1, at least 3: 1, at least 4: 1, at least 5: 1, at least 6: 1, at least 7: 1, at least 8: 1, at least It may contain palmitic acid and / or stearic acid and / or oleic acid: linolenic acid and / or linoleic acid in a ratio of 9: 1, at least 10: 1, at least 15: 1, or at least 20: 1. In yet another aspect of this embodiment, the adjuvant is, for example, about 1: 1 to about 20: 1, about 2: 1 to about 15: 1, about 4: 1 to about 12: 1, or about 6: 1. Palmitic acid and / or stearic acid and / or oleic acid: linolenic acid and / or linoleic acid in a ratio ranging from about 10: 1 can be included.

  In other aspects of this embodiment, the adjuvant is at least four different pharmaceutically acceptable, including at least palmitic acid, stearic acid, oleic acid, linoleic acid, and / or linolenic acid, and any combination thereof. May contain various fatty acids. In other aspects of this embodiment, the adjuvant is, for example, 10: 10: 1: 1, 9: 9: 1: 1, 8: 8: 1: 1, 7: 7: 1: 1, 6: 6: Palmitic acid in a ratio of 1: 1, 5: 5: 1: 1, 4: 4: 1: 1, 3: 3: 1: 1, 2: 2: 1: 1, or 1: 1: 1: 1 : Stearic acid: linolenic acid: linoleic acid. In other aspects of this embodiment, the adjuvant is, for example, about 10: 10: 1: 1 to about 6: 6: 1: 1, about 8: 8: 1: 1 to about 4: 4: 1: 1, Alternatively, a ratio of palmitic acid: stearic acid: linolenic acid: linoleic acid in the range of about 5: 5: 1: 1 to about 1: 1: 1: 1 can be included.

  The lipids useful in the pharmaceutical compositions disclosed herein may be pharmaceutically acceptable omega fatty acids. Non-limiting examples of omega fatty acids include omega 3, omega 6, omega 7, and omega 9. Omega-3 fatty acids (also known as n-3 fatty acids or omega-3 fatty acids) are a family of essential unsaturated fatty acids that are commonly in the n-3 position, the third counting from the methyl end of the fatty acid. Has the last carbon-carbon double bond at the bond position. Omega 3 fatty acids are “essential” fatty acids because they are essential for normal metabolism and cannot be synthesized by the human body. Examples of omega-3 fatty acids include hexadecatrienoic acid (16: 3), α-linolenic acid (18: 3), stearidonic acid (18: 4), eicosatrienoic acid (20: 3), eicosatetraenoic acid ( 20: 4), eicosapentaenoic acid (20: 5), heneicosapentaenoic acid (21: 5), docosapentaenoic acid (curpanodonic acid) (22: 5), docosahexaenoic acid (22: 6), tetracosapentaene Examples include, but are not limited to, acid (24: 5) and tetracosahexaenoic acid (nisic acid) (24: 6).

  Omega-6 fatty acids (also known as n-6 fatty acids or ω-6 fatty acids) are a family of unsaturated fatty acids that are commonly in the n-6 position, the sixth bond counted from the methyl end of the fatty acid. Has the last carbon-carbon double bond in position. As omega-6 fatty acids, linoleic acid (18: 2), γ-linolenic acid (18: 3), calendic acid (18: 3), eicosadienoic acid (20: 2), dihomo-γ-linolenic acid (20: 3) ), Arachidonic acid (20: 4), docosadienoic acid (22: 2), adrenic acid (22: 4), docosapentaenoic acid (22: 5), tetracosatetraenoic acid (24: 4), and tetracosa Examples include but are not limited to pentaenoic acid (24: 5).

  Omega 7 fatty acids (also known as n-7 fatty acids or ω-7 fatty acids) are a family of unsaturated fatty acids that are commonly in position n-7, the seventh bond counted from the methyl end of the fatty acid. Has the last carbon-carbon double bond in position. Examples of omega-7 fatty acids include 5-dodecenoic acid (12: 1), 7-tetradecenoic acid (14: 1), 9-hexadecenoic acid (palmitoleic acid) (16: 1), 11-decenoic acid (vaccenic acid) (18 1), 9Z, 11E conjugated linoleic acid (lumenic acid) (18: 2), 13-eicosenoic acid (pauric acid) (20: 1), 15-docosenoic acid (22: 1), and 17-tetracosenoic acid ( 24: 1), but is not limited thereto.

  Omega 9 fatty acids (also known as n-9 fatty acids or ω-9 fatty acids) are a family of unsaturated fatty acids, commonly in the 9th position, counting from the methyl end of the fatty acid at the n-9 position Has the last carbon-carbon double bond in position. Omega 9 fatty acids include oleic acid (18: 1), elaidic acid (18: 1), eicosenoic acid (20: 1), mead acid (20: 3), erucic acid (22: 1), nervonic acid (24 1), and ricinoleic acid, but are not limited to these.

  A lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically acceptable fat. As is also known as hard fat or solid fat, fat includes any fatty acid that is solid at normal room temperature, eg, about 20 ° C. Fats are usually composed of a broad group of compounds that are soluble in organic solvents and usually insoluble in water. Fats suitable as lipids useful in the pharmaceutical compositions disclosed herein may be any of triglycerides, triesters of glycerol or some fatty acids.

  A lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically acceptable oil. Oils, also known as liquid fats, include any fatty acid that is liquid at normal room temperature, eg, about 20 ° C. Oils suitable as lipids useful in the pharmaceutical compositions disclosed herein may be any material that is immiscible with natural oils, vegetable oils, or greasy water. Examples of suitable natural oils include, but are not limited to, mineral oil, triacetin, ethyl oleate, hydrogenated natural oil, or mixtures thereof. Examples of suitable vegetable oils include almond oil, peanut oil, avocado oil, canola oil, castor oil, coconut oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, cannabis oil, linseed oil (flax seed oil), Olive oil, palm oil, peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soy bean oil, soya oil, sunflower oil, cocoa butter, walnut oil, wheat germ oil, Or a mixture thereof, but is not limited thereto. Each of these oils is marketed by many vendors familiar to those skilled in the art.

  Oil is typically a mixture of various fatty acids. For example, rapeseed oil obtained from oilseed rape seeds contains both omega-6 and omega-3 fatty acids in a ratio of about 2: 1. As another example, flaxseed oil obtained from flax seed is about 7% palmitic acid, about 3.4 to 4.6% stearic acid, about 18.5 to 22.6% oleic acid, about 14 2 to 17% linoleic acid and about 51.9 to 55.2% α-linolenic acid. As another example, cocoa butter obtained from the seeds of Theobroma cacao contains glycerides derived from palmitic acid, stearic acid, oleic acid, linoleic acid, and arachidonic acid, and has a melting point of 34-38 ° C. In some aspects of this embodiment, the pharmaceutical composition comprises at least 2 different fatty acids, at least 3 different fatty acids, at least 4 different fatty acids, at least 5 different fatty acids, or at least 6 different fatty acids. Containing oil.

  Lipids useful in the pharmaceutical compositions disclosed herein may be pharmaceutically acceptable glycerolipids. Glycerolipids are mainly composed of mono-, di-, and tri-substituted glycerol. One group of glycerolipids are glycerides, which are one, two or all three of the hydroxyl groups of glycerol esterified with the fatty acids disclosed herein, respectively, monoglycerides, Diglyceride and triglyceride are produced. In these compounds, each hydroxyl group of glycerol may be esterified with a different fatty acid. In addition, glycerides may be acetylated to form acetylated monoglycerides, acetylated diglycerides, and acetylated triglycerides. One group of glycerolipids has sugar residues in which one, two, or all three of the hydroxyl groups of glycerol are linked via glycosidic bonds.

  A lipid useful in the pharmaceutical compositions disclosed herein may be a pharmaceutically acceptable partially hydrolyzed glycerolipid. In one aspect of this embodiment, the pharmaceutically acceptable partially hydrolyzed glycerolipid is a triglyceride partially hydrolyzed to a mixture of mono, di, and triglycerides.

  Lipids useful in the pharmaceutical compositions disclosed herein may be pharmaceutically acceptable glycol fatty acid esters. The pharmaceutically acceptable glycol fatty acid ester may be a monoester of glycol, a diester of glycol, or a triester of glycol. Examples of glycol fatty acid esters include, but are not limited to, ethylene glycol fatty acid esters, diethylene glycol fatty acid esters, propylene glycol fatty acid esters, and dipropylene fatty acid esters. Non-limiting examples of glycol fatty acid esters include, for example, ethylene glycol caprylate, ethylene glycol pelargonate, ethylene glycol coupler, ethylene glycol undecylate, ethylene glycol laurate, ethylene glycol tridecylate, ethylene glycol myristate, Ethylene glycol myristolate, ethylene glycol pentadecylate, ethylene glycol palmitate, ethylene glycol palmitate, ethylene glycol saponate, ethylene glycol margarate, ethylene glycol stearate, ethylene glycol palmito stearate, ethylene glycol oleate, ethylene glycol Eridart, ethylene glycol basinate, ethylene glycol REART, ethylene glycol linoleate, ethylene glycol α-linolenate, ethylene glycol γ-linolenate, ethylene glycol stearidonate, ethylene glycol coupling olcaprate, ethylene glycol dicouple olopolate, diethylene glycol caprylate, diethylene glycol pelargonate, diethylene glycol coupler Diethylene glycol undecylate, diethylene glycol laurate, diethylene glycol tridecylate, diethylene glycol myristate, diethylene glycol myristolate, diethylene glycol pentadecylate, diethylene glycol palmitate, diethylene glycol palmitoleate, diethylene glycol saponate, die Lenglycol margarate, diethylene glycol stearate, diethylene glycol palmito stearate, diethylene glycol oleate, diethylene glycol eliate, diethylene glycol basinate, diethylene glycol linoleate, diethylene glycol linoleate, diethylene glycol α-linolenate, diethylene glycol γ-linolenate, diethylene glycol stearidonate, Diethylene glycol coupled oleopalate, diethylene glycol dicoupled olcaprate, propylene glycol caprylate, propylene glycol pelargonate, propylene glycol coupler, propylene glycol undecylate, propylene glycol laurate, propylene glycol Rutridecylate, propylene glycol myristate, propylene glycol myristolate, propylene glycol pentadecylate, propylene glycol palmitate, propylene glycol palmitoleate, propylene glycol saponate, propylene glycol margarate, propylene glycol stearate, propylene glycol palmito stearate, Propylene glycol oleate, propylene glycol elidate, propylene glycol basinate, propylene glycol linoleate, propylene glycol linoleate, propylene glycol α-linolenate, propylene glycol γ-linolenate, propylene glycol stearidonate, propylene glycol stearyl docap Dipropylene glycol caprylate, dipropylene glycol caprylate, dipropylene glycol pelargonate, dipropylene glycol coupler, dipropylene glycol undecylate, dipropylene glycol laurate, dipropylene glycol tridecylate, dipropylene glycol Propylene glycol myristate, dipropylene glycol myristate, dipropylene glycol pentadecylate, dipropylene glycol palmitate, dipropylene glycol palmitoleate, dipropylene glycol saponate, dipropylene glycol margarate, dipropylene glycol stearate, di Propylene glycol palmitostearate, dipropylene glycol oleate, dipropylene glycol Elutriate, dipropylene glycol basinate, dipropylene glycol linoleate, dipropylene glycol linoleate, dipropylene glycol α-linolenate, dipropylene glycol γ-linolenate, dipropylene glycol stearidonate, dipropylene glycol cupryl opalate, And dipropylene glycol dicapryl opalaprate, or any combination thereof.

  Lipids useful in the pharmaceutical compositions disclosed herein may be pharmaceutically acceptable polyether fatty acid esters. The pharmaceutically acceptable polyether fatty acid ester may be a mono-fatty acid ester of a polyether, a di-fatty acid ester of a polyether, or a tri-fatty acid ester of a polyether. Polyether fatty acid esters include, but are not limited to, PEG fatty acid esters, PEG glyceryl fatty acids, PEG fatty acid ester glycerides, PPG fatty acid esters, PPG glyceryl fatty acids, and PPG fatty acid ester glycerides. The molecular weight of PEG or PPG may be, for example, 5 to 20,000. Non-limiting examples of polyether fatty acid esters include, for example, PEG caprylate, PEG pelargonate, PEG coupler, PEG undecylate, PEG laurate, PEG tridecylate, PEG myristate, PEG myristolate, PEG pentadecylate, PEG palmitate, PEG Palmitoleate, PEG sapienate, PEG margarate, PEG stearate, PEG palmitostearate, PEG oleate, PEG elidate, PEG basinate, PEG linoleate, PEG linoleate, PEGα-linolenate, PEGγ-linolenate, PEG stearidnate, PEG caprylocaprate, PEG dicapryllocaprate, PEG glyceryl caprylate, PEG glyceryl pelargonate, PEG glyceryl coupler, PEG glyceryl undecylate, PEG glyceryl laurate, PEG glyceryl tridecylate, PEG glyceryl myristate, PEG glyceryl myristolate, PEG glyceryl pentadecylate, PEG glyceryl palmitate, PEG glyceryl palmitoleate, PEG Glyceryl sapienate, PEG glyceryl margarate, PEG glyceryl stearate, PEG glyceryl palmito stearate, PEG glyceryl oleate, PEG glyceryl elidate, PEG glyceryl basinate, PEG glyceryl linoleate, PEG glyceryl linoleidate, PEG glyceryl α -Linolenate, PEG glyceryl γ-linolenate, PEG glyceryl stearidonate, PE G glyceryl caprylo caprate, PEG glyceryl dicaprylo caprate, capryloyl PEG glyceride, pelargonoyl PEG glyceride, caproyl PEG glyceride, undecyloyl PEG glyceride, lauroyl PEG glyceride, tridecyl PEG glyceride, myristoyl PEG glyceride, myristoyl PEG glyceride, pentadecycloyl PEG Glyceride, palmitoyl PEG glyceride, palmitoleyl PEG glyceride, sapienoyl PEG glyceride, margaroyl PEG glyceride, stearoyl PEG glyceride, palmito stearoyl PEG glyceride, oleoyl PEG glyceride, elidoyl PEG glyceride, bassinoyl PEG glyceride, linoleoyl PEG glyceride, linolee Idoyl PEG glyceride, α-linolenoyl PEG glyceride, γ-linolenoyl PEG glyceride, stearidnoyl PEG glyceride, caprylocaproyl PEG glyceride, dicaprylocaproyl PEG glyceride, PPG caprylate, PPG pelargonate, PPG coupler, PPG undecylate, PPG laurate, PPG tridecylate, PPG myristate, PPG myristolate, PPG pentadecylate, PPG palmitate, PPG palmitoleate, PPG sapienate, PPG margarato, PPG stealthate, PPG palmitostearate, PPG oleate, PPG elidert, PPG basinate, PPG linoleato, PPG linoleilate, PPGα-linolenate, PPGγ-linolena , PPG stearidonate, PPG caprylocaprate, PPG dicapryllocaprate, PPG glyceryl caprylate, PPG glyceryl pelargonate, PPG glyceryl caprate, PPG glyceryl undecylate, PPG glyceryl laurate, PPG glyceryl tridecylate, PPG glyceryl myristate, PPG glyceryl myristolate, PPG glyceryl pentadecylate, PPG glyceryl palmitate, PPG glyceryl palmitate, PPG glyceryl sapinate, PPG glyceryl margarate, PPG glyceryl stearate, PPG glyceryl palmito stearate, PPG glyceryl Oleart, PPG glyceryl elidate, PPG glyceryl basinate, PPG glyceryl linole , PPG glyceryl linoleilate, PPG glyceryl α-linolenate, PPG glyceryl γ-linolenate, PPG glyceryl stearidonate, PPG glyceryl caprylo couplerate, PPG glyceryl dicaprylo couplerate, capryloyl PPG glyceride, pelargonoyl PPG glyceride Undecyloyl PPG glyceride, lauroyl PPG glyceride, tridecyl yl PPG glyceride, myristoyl PPG glyceride, myristoyl PPG glyceride, pentadecycloyl PPG glyceride, palmitoyl PPG glyceride, palmitoleyl oil PPG glyceride, sapienoyl PPG glyceride, margaroyl PPG glyceride, stearoyl PPG glyceride, Palmito Stearo PPG glyceride, oleoyl PPG glyceride, eridoyl PPG glyceride, basinoyl PPG glyceride, linoleoyl PPG glyceride, linoleidoyl PPG glyceride, α-linolenoyl PPG glyceride, γ-linolenoyl PPG glyceride, stearidnoyl PPG glyceride, caprylocaproyl PPG Glycerides, dicaprylocaproyl PPG glycerides, or any combination thereof.

  Commercially available pharmaceutically acceptable polyether fatty acid esters include caprylocaproyl macrogol-8 glyceride (LABRASOL®), propylene glycol monopalmito stearate (MONOSTEOL®), glyceryl dibehenate ( COMPRITOL (registered trademark) 888), glycerin behenate (COMPRITOL (registered trademark) E ATO), behenoyl polyoxyl-8 glyceride (COMPRITAL (registered trademark) HD5 ATO), triglycerin diisostearate (PLLUOL (registered trademark)) Diosostearique), PEG-8 beeswax (APIFIL®), lauroyl macrogol-32 glyceride (GELUCIRE 44/14), stearoyl macrogol-32 Riselide (GELUCIRE 50.13), propylene glycol dicaprylo caprate (LABRAFAC (registered trademark) PG), polyglycerin-3 dioleate (PLLUOL (registered trademark) Oleique CC 497), propylene glycol monolaurate (type I) (LAUROGLYCOL (Registered trademark) FCC), propylene glycol monolaurate (type II) (LAUROGLYCOL (registered trademark) 90), propylene glycol monocaprylate (type I) (CAPRYOL (registered trademark) PGMC), propylene glycol monocaprylate (II) Type) (CAPRYOL® 90), linoleoyl macrogol-6 glyceride (LABRAFIL® M2125CS), oleoyl macrogol-6 glyce (LABRAFIL (registered trademark) M1944CS), Lauroyl macrogol-6 glyceride (LABRAFIL (registered trademark) M2130CS), glycerin dipalmito stearate (Biogapress Vegetal BM297ATO), glycerin distearate (type I) (PRECIROL (registered trademark)) ATO 5), and glycerin monolinoleate (MAISINE® 35-1), but are not limited to these.

  The lipids useful in the pharmaceutical compositions disclosed herein may be a mixture of pharmaceutically acceptable lipids. Examples of mixtures of pharmaceutically acceptable lipids include mixtures of one or more glycerolipids disclosed herein, mixtures of one or more glycol fatty acid esters disclosed herein, Examples include, but are not limited to, mixtures of one or more polyether fatty acid esters disclosed herein, and mixtures of one or more glycerides disclosed herein.

  In some aspects of this embodiment, the mixture of pharmaceutically acceptable lipids is, for example, about 33 ° C, about 34 ° C, about 35 ° C, about 36 ° C, about 37 ° C, about 38 ° C, about 39 ° C. About 40 ° C, about 41 ° C, about 43 ° C, about 43 ° C, about 44 ° C, about 45 ° C, about 45 ° C, about 47 ° C, about 48 ° C, about 49 ° C, about 50 ° C, A mixture of di- and / or triglycerides. In some aspects of this embodiment, the mixture of pharmaceutically acceptable lipids is, for example, about 30 ° C to about 44 ° C, about 30 ° C to about 45 ° C, about 30 ° C to about 46 ° C, about 30 ° C. To about 47 ° C, about 30 ° C to about 48 ° C, about 30 ° C to about 49 ° C, about 30 ° C to about 50 ° C, about 32 ° C to about 44 ° C, about 32 ° C to about 45 ° C, about 32 ° C to about 46 ° C, 32 ° C to 47 ° C, 32 ° C to 48 ° C, 32 ° C to 49 ° C, 32 ° C to 50 ° C, 34 ° C to 44 ° C, 34 ° C to 45 ° C About 34 ° C to about 46 ° C, about 34 ° C to about 47 ° C, about 34 ° C to about 48 ° C, about 34 ° C to about 49 ° C, about 34 ° C to about 50 ° C, about 36 ° C to about 44 ° C, about 36 ° C to about 45 ° C, about 36 ° C to about 46 ° C, about 36 ° C to about 47 ° C, about 36 ° C to about 48 ° C, about 36 ° C to about 49 ° C, about 36 ° C to about 50 ° C, about 38 ° C ~ About 44 ° C, about 38 ° C ~ 45 ° C, about 38 ° C to about 46 ° C, about 38 ° C to about 47 ° C, about 38 ° C to about 48 ° C, about 38 ° C to about 49 ° C, about 38 ° C to about 50 ° C, about 40 ° C to about 44 ° C About 40 ° C to about 45 ° C, about 40 ° C to about 46 ° C, about 40 ° C to about 47 ° C, about 40 ° C to about 48 ° C, about 40 ° C to about 49 ° C, about 40 ° C to about 50 ° C, about 42 ° C to about 44 ° C, about 42 ° C to about 45 ° C, about 42 ° C to about 46 ° C, about 42 ° C to about 47 ° C, about 42 ° C to about 48 ° C, about 42 ° C to about 49 ° C, or about 42 ° C A mixture of mono-, di- and / or triglycerides having a melting point of from about 0C to about 50C.

  In other aspects of this embodiment, the mixture of pharmaceutically acceptable lipids is, for example, about 33 ° C, about 34 ° C, about 35 ° C, about 36 ° C, about 37 ° C, about 38 ° C, about 39 ° C, PEG fatty acid esters having melting points of about 40 ° C, about 41 ° C, about 43 ° C, about 43 ° C, about 44 ° C, about 45 ° C, about 45 ° C, about 47 ° C, about 48 ° C, about 49 ° C, about 50 ° C A mixture of In some aspects of this embodiment, the mixture of pharmaceutically acceptable lipids is, for example, about 30 ° C to about 44 ° C, about 30 ° C to about 45 ° C, about 30 ° C to about 46 ° C, about 30 ° C. To about 47 ° C, about 30 ° C to about 48 ° C, about 30 ° C to about 49 ° C, about 30 ° C to about 50 ° C, about 32 ° C to about 44 ° C, about 32 ° C to about 45 ° C, about 32 ° C to about 46 ° C, 32 ° C to 47 ° C, 32 ° C to 48 ° C, 32 ° C to 49 ° C, 32 ° C to 50 ° C, 34 ° C to 44 ° C, 34 ° C to 45 ° C About 34 ° C to about 46 ° C, about 34 ° C to about 47 ° C, about 34 ° C to about 48 ° C, about 34 ° C to about 49 ° C, about 34 ° C to about 50 ° C, about 36 ° C to about 44 ° C, about 36 ° C to about 45 ° C, about 36 ° C to about 46 ° C, about 36 ° C to about 47 ° C, about 36 ° C to about 48 ° C, about 36 ° C to about 49 ° C, about 36 ° C to about 50 ° C, about 38 ° C ~ About 44 ° C, about 38 ° C ~ 45 ° C, about 38 ° C to about 46 ° C, about 38 ° C to about 47 ° C, about 38 ° C to about 48 ° C, about 38 ° C to about 49 ° C, about 38 ° C to about 50 ° C, about 40 ° C to about 44 ° C About 40 ° C to about 45 ° C, about 40 ° C to about 46 ° C, about 40 ° C to about 47 ° C, about 40 ° C to about 48 ° C, about 40 ° C to about 49 ° C, about 40 ° C to about 50 ° C, about 42 ° C to about 44 ° C, about 42 ° C to about 45 ° C, about 42 ° C to about 46 ° C, about 42 ° C to about 47 ° C, about 42 ° C to about 48 ° C, about 42 ° C to about 49 ° C, or about 42 ° C A mixture of PEG fatty acid esters having a melting point of from about 0C to about 50C.

  In other aspects of this embodiment, the mixture of pharmaceutically acceptable lipids is, for example, about 33 ° C, about 34 ° C, about 35 ° C, about 36 ° C, about 37 ° C, about 38 ° C, about 39 ° C, Mono, di having a melting point of about 40 ° C, about 41 ° C, about 43 ° C, about 43 ° C, about 44 ° C, about 45 ° C, about 45 ° C, about 47 ° C, about 48 ° C, about 49 ° C, about 50 ° C And / or a mixture of triglycerides and PEG fatty acid esters. In some aspects of this embodiment, the mixture of pharmaceutically acceptable lipids is, for example, about 30 ° C to about 44 ° C, about 30 ° C to about 45 ° C, about 30 ° C to about 46 ° C, about 30 ° C. To about 47 ° C, about 30 ° C to about 48 ° C, about 30 ° C to about 49 ° C, about 30 ° C to about 50 ° C, about 32 ° C to about 44 ° C, about 32 ° C to about 45 ° C, about 32 ° C to about 46 ° C, 32 ° C to 47 ° C, 32 ° C to 48 ° C, 32 ° C to 49 ° C, 32 ° C to 50 ° C, 34 ° C to 44 ° C, 34 ° C to 45 ° C About 34 ° C to about 46 ° C, about 34 ° C to about 47 ° C, about 34 ° C to about 48 ° C, about 34 ° C to about 49 ° C, about 34 ° C to about 50 ° C, about 36 ° C to about 44 ° C, about 36 ° C to about 45 ° C, about 36 ° C to about 46 ° C, about 36 ° C to about 47 ° C, about 36 ° C to about 48 ° C, about 36 ° C to about 49 ° C, about 36 ° C to about 50 ° C, about 38 ° C ~ About 44 ° C, about 38 ° C ~ 45 ° C, about 38 ° C to about 46 ° C, about 38 ° C to about 47 ° C, about 38 ° C to about 48 ° C, about 38 ° C to about 49 ° C, about 38 ° C to about 50 ° C, about 40 ° C to about 44 ° C About 40 ° C to about 45 ° C, about 40 ° C to about 46 ° C, about 40 ° C to about 47 ° C, about 40 ° C to about 48 ° C, about 40 ° C to about 49 ° C, about 40 ° C to about 50 ° C, about 42 ° C to about 44 ° C, about 42 ° C to about 45 ° C, about 42 ° C to about 46 ° C, about 42 ° C to about 47 ° C, about 42 ° C to about 48 ° C, about 42 ° C to about 49 ° C, or about 42 ° C Includes mixtures of mono-, di-, and / or triglycerides and PEG fatty acid esters having a melting point of from 0C to about 50C.

Commercially available mixtures of pharmaceutically acceptable lipids include PEG-6 stearate, ethylene glycol palmitostearate and PEG-32 stearate (TEFOSE® 1500; TEFOSE® 63), Triceteales -4 A mixture of phosphate, ethylene glycol palmitostearate and diethylene glycol palmitostearate (SEDEFOS® 75), a mixture of glycerol monostearate and PEG-75 stearate (GELOT®), cetyl alcohol and ethoxylation Mixture of fatty alcohols (ceteth-2-, steareth-20) (EMULCIRE®), saturated C ₁₀ -C ₁₈ triglycerides (GELUCIRE® 33) with a melting point of about 33 ° C. / 01), a mixture of saturated C ₁₀ -C ₁₈ triglycerides having a melting point of about 39 ° C. (GELUCIRE® 39/01), a mixture of saturated C ₁₀ -C ₁₈ triglycerides having a melting point of about 43 ° C. GELUCIRE® 43/01), a mixture of glycerol monostearate 40-55 (type I) and diglyceride (GELEOL® Mono and Digicerides), and a mixture of medium chain triglycerides (LABRAFAC® Lipophile WL1349) ), But are not limited to these.

  Some embodiments herein disclose, in part, pharmaceutically acceptable stabilizers. Stabilizers reduce or eliminate ester formation of therapeutic compounds that may occur as a result of undesired reactions with the particular solvent used. Examples of stabilizers include water, a sacrificial acid containing a fatty acid component and acetic acid, ethyl acetate, sodium acetate / acetic acid (E262), monoglyceride, acetylated monoglyceride, diglyceride, acetylated monoglyceride, acetylated diglyceride, fatty acid, and fatty acid salt. However, it is not limited to these.

  In one embodiment, the pharmaceutically acceptable stabilizer can include a pharmaceutically acceptable emulsifier. An emulsifier (also known as an emulsion) is a substance that stabilizes an emulsion containing a liquid dispersed phase and a liquid continuous phase by increasing its kinetic stability. Accordingly, a homogeneous and stable emulsion using the emulsifier disclosed herein in the situation where the solvent and adjuvant used to make the pharmaceutical composition disclosed herein would not normally mix. Is made. Emulsifiers include, but are not limited to, surfactants, polysaccharides, lectins, and phospholipids.

  In one aspect of this embodiment, the emulsifier can include a surfactant. As used herein, “surfactant” means a natural or synthetic amphiphilic compound. The surfactant may be nonionic, zwitterionic, or ionic. Non-limiting examples of surfactants include polysorbate 20 (TWEEN® 20), polysorbate 40 (TWEEN® 40), polysorbate 60 (TWEEN® 60), polysorbate 61 (TWEEN®). (Trademark) 61), polysorbates such as polysorbate 65 (TWEEN® 65), polysorbate 80 (TWEEN® 80), and polysorbate 81 (TWEEN® 81); Poloxamer 124 (PLURONIC®) L44), poloxamer 181 (PLURONIC® L61), poloxamer 182 (PLURONIC® L62), poloxamer 184 (PLURONIC® L64), poloxamer 188 (PLURON) Poloxamers (polyethylene-polypropylene co-polymers) such as C® F68), Poloxamer 237 (PLURONIC® F87), Poloxamer 338 (PLURONIC® L108), and Poloxamer 407 (PLURONIC® F127) Polyoxyethylene glycol dodecyl ethers such as BRIJ® 30 and BRIJ® 35; 2-dodecoxyethanol (LUBROL®-PX); polyoxyethylene octyl phenyl ether (TRITON ( (Registered trademark) X-100); sodium dodecyl sulfate (SDS); 3-[(3-cholamidopropyl) dimethylammonium) -1-propanesulfonate (CHAPS); Propyl) dimethylammonium) 2-hydroxy-1-propane sulfonate (CHAPSO); contains as sodium alcoholate; sucrose monolaurate. Other non-limiting examples of surfactant excipients include, for example, Ansel (1999) (supra); Gennaro (2000) (supra); Hardman (2001) (supra); and Rowe (2003) (supra). Can be found in Each of these documents is incorporated herein by reference in its entirety.

  In one aspect of this embodiment, the emulsifier can comprise a polysaccharide. Non-limiting examples of polysaccharides include guar gum, agar, alginic acid, cardene, dextran (eg, dextran 1K, dextran 4K, dextran 40K, dextran 60K, and dextran 70K), dextrin, glycogen, inulin, starch, starch derivatives (Eg, hydroxymethyl starch, hydroxyethyl starch, hydroxypropyl starch, hydroxybutyl starch, and hydroxypentyl starch), hetastarch, cellulose, ficoll, methylcellulose (MC), carboxymethylcellulose (CMC), hydroxyethylcellulose (HEC), hydroxypropyl Cellulose (HPC), Hydroxyethylmethylcellulose (HEMC), Hydroxypropylmethylcellulose HPMC); polyvinyl acetate (PVA); polyvinyl pyrrolidone (PVP) (also known as povidone) having a K value of 18 or less, a K value of 18 or 95, or a K value of 95 or more, such as PVP12 (KOLLIDON ( (Registered trademark) 12), PVP17 (KOLLIDON (registered trademark) 17), PVP25 (KOLLIDON (registered trademark) 25), PVP30 (KOLLIDON (registered trademark) 30), PVP90 (KOLLIDON (registered trademark) 90); and polyethyleneimine ( PEI).

  In one aspect of this embodiment, the emulsifier can include a lectin. Lectins are sugar binding proteins and have high specificity for sugar moieties. Lectins can be categorized by the sugar moiety they bind to, mannose binding lectin, galactose / N-acetylgalactosamine binding lectin, N-acetylglucosamine binding lectin, N-acetylneuramin binding lectin, N-acetylneuraminic acid binding lectin , And fucose-binding lectins. Non-limiting examples of surfactants include concanavalin A, lentil lectin, snowdrop lectin, Loin, peanut agglutinin, jacarin, hairy vetch lectin, wheat germ agglutinin, elder collectin, leech agglutinin Element, Inuenju haemagglutinin, Harynica agglutinin, and yellow chawantake lectin.

  In one aspect of this embodiment, the emulsifier can include a phospholipid. The structure of phospholipids usually includes a hydrophobic tail and a hydrophilic head, which are amphiphilic in nature. Most phospholipids contain diglycerides, phosphate groups, and simple organic molecules such as choline, but one exception to this rule is sphingomyelin, which is derived from sphingosine rather than glycerol. is there. Phospholipids include, but are not limited to, diacylglycerides and phosphosphingolipids. Non-limiting examples of diacylglycerides include phosphatidic acid (phosphatidate) (PA), phosphatidylethanolamine (cephalin) (PE), phosphatidylcholine (lecithin) (PC), phosphatidylserine (PS), and phosphatidylinositol. Phosphoinositides including (PI), phosphatidylinositol phosphate (PIP), phosphatidylinositol diphosphate (PIP2), and phosphatidylinositol triphosphate (PIP3) are included. Non-limiting examples of phosphosphingolipids include ceramide phosphorylcholine (sphingomyelin) (SPH), ceramide phosphorylethanolamine (sphingomyelin) (Cer-PE), and ceramide phosphorylglycerol.

  In one embodiment, the pharmaceutically acceptable stabilizer does not contain a pharmaceutically acceptable emulsifier.

  In another embodiment, the pharmaceutical composition does not contain a pharmaceutically acceptable emulsifier.

  The pharmaceutical compositions disclosed herein can be more effectively delivered by a cell type, tissue, organ, or body region such that the therapeutic compounds disclosed herein more effectively inhibit pain responses. Or it acts as a delivery system that allows it to be targeted. This inhibition results in improved treatment of severe pain. For example, the pharmaceutical compositions disclosed herein can facilitate delivery of the therapeutic compounds disclosed herein to macrophages. One possible mechanism for achieving this selective biodistribution is that the pharmaceutical compositions disclosed herein can be designed to take advantage of chylomicron activity. Chylomicrons are relatively large lipoprotein particles and have a diameter of 75 nm to 1,200 nm. Chylomicron contains triglycerides (85 to 92%), phospholipids (6 to 12%), cholesterol (1 to 3%), and apolipoprotein (1 to 2%). Transport to other parts of the body. Chylomicron is one of five major lipoprotein groups, the rest are VLDL, IDL, low density lipoprotein (LDL), high density lipoprotein (HDL), which are fat and cholesterol in the bloodstream It is possible to move in an aqueous solution.

  During digestion, fatty acids and cholesterol are processed in the gastrointestinal tract by the action of pancreatic juice containing lipase and emulsification with bile salts to produce micelles. These micelles allow lipids to be absorbed as free fatty acids by the intestinal absorbing cells (known as intestinal cells). Upon entering the enterocytes, triglycerides and cholesterol are incorporated into the nascent chylomicrons. Neonatal chylomicrons are mainly composed of triglycerides (85%) and contain a small amount of cholesterol and cholesteryl esters. The main apolipoprotein component is apolipoprotein B-48 (APOB48). These new chylomicrons are released by exocytosis from the enterocytes into the milk ducts (lymph vessels from the small intestinal villi) and then secreted into the bloodstream at the junction of the thoracic duct with the left subclavian vein. The

  While circulating in the lymph and blood, chylomicrons exchange constituents for HDL. HDL is converted to mature chylomicron (often referred to simply as “chylomicron”) by conferring apolipoprotein C-II (APOC2) and apolipoprotein E (APOE) to nascent chylomicrons. APOC2 is a cofactor for lipoprotein lipase (LPL) activity. When the stored triglycerides are distributed, chylomicrons return APOC2 to HDL (but APOE maintains), thereby becoming chylomicron remnants (only 30-50 nm at this point). APOB48 and APOE are important in confirming the presence of chylomicron remnants in the liver that degrade into lipoproteins (VLDL, LDL, and HDL) by endocytosis. These lipoproteins are processed and stored by competent cells (including hepatocytes, adipocytes, macrophages, etc.). Thus, without wishing to be bound by theory, the pharmaceutical compositions disclosed herein, upon oral administration, are processed into micelles while present in the gastrointestinal tract and are absorbed by intestinal cells and nascent. It is incorporated into chylomicrons, remains bound to chylomicron remnants taken up by the liver, and is eventually supplied to macrophages present in the tissue undergoing pain.

  As another example, the pharmaceutical compositions disclosed herein can facilitate delivery of the therapeutic compounds disclosed herein to dendritic cells. One possible mechanism for achieving selective biodistribution of the pharmaceutical compositions disclosed herein is to utilize dendritic cell endocytosis / phagocytic activity. Dendritic cells are immune cells that form part of the mammalian immune system. The main function of dendritic cells is to process antigenic substances and present the processed antigenic substances on the surface of dendritic cells to other cells of the immune system. Thus, dendritic cells function as antigen presenting cells and serve as messengers between innate and acquired immunity. Dendritic cells are present in tissues in contact with the external environment, such as the skin (there is a special dendritic cell type called Langerhans cells) and the inner walls of the nose, lungs, stomach, and intestines. These cells can also be seen in the immature state of blood. Once activated, dendritic cells migrate to the lymph nodes where they interact with T cells and B cells to initiate and execute acquired immune responses. Dendritic cells that eat and eat lipid particles are known as part of the dendritic cell environmental monitoring and antigen presentation process. While not wishing to be bound by theory, upon topical or inhalation administration, the pharmaceutical compositions disclosed herein invade the skin or nose, lungs, stomach, and intestinal lining and form dendrites. Cells can be eaten / phagocytosed and eventually inserted into T cells and / or B cells present in the tissue undergoing pain.

  Some aspects of the present specification, in part, disclose methods of preparing the pharmaceutical compositions disclosed herein. The methods disclosed herein comprise a pharmaceutically acceptable adjuvant disclosed herein and a therapeutic compound disclosed herein, wherein the therapeutic compound is a pharmaceutically acceptable adjuvant thereof. Contacting under conditions solubilized therein, thereby forming the pharmaceutical composition disclosed herein.

  Some aspects of the present specification, in part, disclose methods of preparing the pharmaceutical compositions disclosed herein. The methods disclosed herein include: a) a pharmaceutically acceptable solvent disclosed herein and a therapeutic compound disclosed herein, wherein the therapeutic compound is pharmaceutically acceptable. Contacting under conditions that can be dissolved in a suitable solvent, thereby forming a solution; and b) the solution formed in step (a), and a pharmaceutically acceptable adjuvant disclosed herein Is contacted under conditions that allow formation of a pharmaceutical composition. The preparation methods disclosed herein can further comprise a step (c) of removing a pharmaceutically acceptable solvent from the pharmaceutical composition.

  The amount of therapeutic compound that is contacted with the pharmaceutically acceptable solvent in method step (a) may be any desired amount. Factors used to determine the amount of therapeutic compound used include the final amount of therapeutic compound desired in the pharmaceutical composition, the desired concentration of therapeutic compound in solution, the hydrophobicity of the therapeutic compound, These include, but are not limited to, oleophobicity, the temperature at which the contacting step (a) is performed, and the time at which the contacting step (a) is performed, the specific formulation desired, and the specific route of delivery of the pharmaceutical compound. Not.

  The volume of pharmaceutically acceptable solvent used in method step (a) may be any desired volume. Factors used to determine the volume of pharmaceutically acceptable solvent used include the final amount of the desired pharmaceutical composition, the desired concentration of the therapeutic compound in solution, the hydrophobicity of the therapeutic compound, And the oleophobicity of the therapeutic compound, the specific formulation desired, and the specific route of delivery of the pharmaceutical compound.

  In some aspects of this embodiment, the amount of therapeutic compound that is contacted with the solvent in step (a) is, for example, at least 10 mg, at least 20 mg, at least 30 mg, at least 40 mg, at least 50 mg, at least 60 mg, at least 70 mg, at least 80 mg, at least 90 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1,000 mg, at least 1,100 mg, at least 1,200 mg, at least 1, It may be 300 mg, at least 1,400 mg, or at least 1,500 mg. In other aspects of this embodiment, the amount of therapeutic compound contacted with the solvent in step (a) is, for example, from about 10 mg to about 100 mg, from about 50 mg to about 150 mg, from about 100 mg to about 250 mg, from about 150 mg to about 350 mg, About 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1,000 mg, about 850 mg to about 1,200 mg, or about 1,000 mg to about 1,500 mg Range. In other aspects of this embodiment, the amount of therapeutic compound dissolved in the solvent in step (a) is, for example, from about 10 mg to about 250 mg, from about 10 mg to about 500 mg, from about 10 mg to about 750 mg, from about 10 mg to about 1, 000 mg, about 10 mg to about 1,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1,000 mg, about 50 mg to about 1,500 mg, about 100 mg to about 250 mg, About 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1,000 mg, about 100 mg to about 1,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1,000 mg, or about It may range from 200 mg to about 1,500 mg.

  Step (a) can be performed at room temperature to completely dissolve the therapeutic compound in a pharmaceutically acceptable solvent. However, in other embodiments of the method, step (a) can be performed at a temperature higher than room temperature. In some aspects of this embodiment, step (a) comprises, for example, a temperature above 21 ° C., a temperature above 25 ° C., a temperature above 30 ° C., a temperature above 35 ° C., a temperature above 37 ° C., a temperature above 40 ° C. It can be carried out at a high temperature, a temperature higher than 42 ° C, a temperature higher than 45 ° C, a temperature higher than 50 ° C, a temperature higher than 55 ° C, or a temperature higher than 60 ° C. In some aspects of this embodiment, step (a) includes, for example, from about 20 ° C to about 30 ° C, from about 25 ° C to about 35 ° C, from about 30 ° C to about 40 ° C, from about 35 ° C to about 45 ° C, It can be carried out at a temperature of about 40 ° C to about 50 ° C, about 45 ° C to about 55 ° C, or about 50 ° C to about 60 ° C. In some cases, step (a) can be carried out at a temperature below room temperature to completely dissolve the therapeutic compound in a pharmaceutically acceptable solvent. However, in other embodiments of this method, step (a) can be performed at a temperature below room temperature, for example, less than 10 ° C, greater than 5 ° C, greater than 0 ° C, greater than -10 ° C, or greater than -20 ° C. The contacting in step (a) can include mixing the therapeutic compound and a pharmaceutically acceptable solvent, for example, by stirring, inversion, sonication, or vortexing. This mixing may occur until the therapeutic compound is completely dissolved in the solvent, eg, at least 1 second, at least 5 seconds, at least 10 seconds, at least 20 seconds, at least 30 seconds, at least 45 seconds, at least 60 seconds, or longer. It can be carried out.

After contact, the concentration of the therapeutic compound disclosed herein in solution may be any desired concentration. In some aspects of this embodiment, the concentration of the therapeutic compound disclosed herein in solution is, for example, at least 0.00001 mg / mL, at least 0.0001 mg / mL, at least 0.001 mg / mL, at least 0.01 mg / mL, at least 0.1 mg / mL, at least 1 mg / mL, at least 10 mg / mL, at least 25 mg / mL, at least 50 mg / mL, at least 100 mg / mL, at least 200 mg / mL, at least 500 mg / mL, at least 700 mg / ML, at least 1,000 mg / mL, or at least 1,200 mg / mL. In other aspects of this embodiment, the concentration of the therapeutic compound disclosed herein in solution is, for example, up to 1,000 mg / mL, up to 1,100 mg / mL, up to 1,200 mg / mL, up to 1 , 300 mg / mL, up to 1,400 mg / mL, up to 1,500 mg / mL, up to 2,000 mg / mL, up to 2,000 mg / mL, or up to 3,000 mg / mL. In other aspects of this embodiment, the concentration of the therapeutic compound disclosed herein in solution is, for example, from about 0.00001 mg / mL to about 3,000 mg / mL, from about 0.0001 mg / mL to about 3 3,000 mg / mL, about 0.01 mg / mL to about 3,000 mg / mL, about 0.1 mg / mL to about 3,000 mg / mL, about 1 mg / mL to about 3,000 mg / mL, about 250 mg / mL to About 3,000 mg / mL, about 500 mg / mL to about 3,000 mg / mL, about 750 mg / mL to about 3,000 mg / mL, about 1,000 mg / mL to about 3,000 mg / mL, about 100 mg / mL to About 2,000 mg / mL, about 250 mg / mL to about 2,000 mg / mL, about 500 mg / mL to about 2,000 mg / mL, about 750 mg / mL to about 2,000 g / mL, about 1,000 mg / mL to about 2,000 mg / mL, about 100 mg / mL to about 1,500 mg / mL, about 250 mg / mL to about 1,500 mg / mL, about 500 mg / mL to about 1, 500 mg / mL, about 750 mg / mL to about 1,500 mg / mL, about 1,000 mg / mL to about 1,500 mg / mL, about 100 mg / mL to about 1,200 mg / mL, about 250 mg / mL to about 1, 200 mg / mL, about 500 mg / mL to about 1,200 mg / mL, about 750 mg / mL to about 1,200 mg / mL, about 1,000 mg / mL to about 1,200 mg / mL, about 100 mg / mL to about 1, 000 mg / mL, about 250 mg / mL to about 1,000 mg / mL, about 500 mg / mL to about 1,000 mg / mL, about 750 mg / mL to about 1, 00 mg / mL, about 100 mg / mL to about 750 mg / mL, about 250 mg / mL to about 750 mg / mL, about 500 mg / mL to about 750 mg / mL, about 100 mg / mL to about 500 mg / mL, about 250 mg / mL to about 500 mg / mL, about 0.00001 mg / mL to about 0.0001 mg / mL, about 0.00001 mg / mL to about 0.001 mg / mL, about 0.00001 mg / mL to about 0.01 mg / mL, about 0.00001 mg / ML to about 0.1 mg / mL, about 0.00001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 0.01 mg / mL, about 0.001 mg / mL to about 0.1 mg / mL, About 0.001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 10 mg / mL, or about 0.001 mg / mL to about It may be in the range of 100 mg / mL.
The volume of the pharmaceutically acceptable adjuvant used in method step (b) may be any desired volume. Factors used to determine the volume of pharmaceutically acceptable adjuvant used include the desired final amount of the pharmaceutical composition, the desired concentration of the therapeutic compound in the pharmaceutical composition, the solvent used: adjuvant Ratios, and miscibility of the solvent and adjuvant, the particular formulation desired, and the particular delivery route of the pharmaceutical compound.

  In some aspects of this embodiment, the ratio of solution: adjuvant is, for example, at least 5: 1, at least 4: 1, at least 3: 1, at least 2: 1, at least 0: 1, at least 1: 1, at least 1: 2, at least 1: 3, at least 1: 4, at least 1: 5, at least 1: 6, at least 1: 7, at least 1: 8, at least 1: 9, at least 1:10, at least 1:15, at least It may be 1:20, or at least 1:25. In other aspects of this embodiment, the ratio of solution: adjuvant is, for example, about 5: 1 to about 1:25, about 4: 1 to about 1:25, about 3: 1 to about 1:25, about 2. : 1 to about 1:25, about 0: 1 to about 1:25, about 1: 1 to about 1:25, about 1: 2 to about 1:25, about 1: 3 to about 1:25, about 1 : 4 to about 1:25, about 1: 5 to about 1:25, about 5: 1 to about 1:20, about 4: 1 to about 1:20, about 3: 1 to about 1:20, about 2. : 1 to about 1:20, about 0: 1 to about 1:20, about 1: 1 to about 1:20, about 1: 2 to about 1:20, about 1: 3 to about 1:20, about 1 : 4 to about 1:20, about 1: 5 to about 1:20, about 5: 1 to about 1:15, about 4: 1 to about 1:15, about 3: 1 to about 1:15, about 0 : 1 to about 1:15, about 2: 1 to about 1:15, about 1: 1 to about 1:15, about 1: 2 to about 1:15, about 1: 3 1:15, about 1: 4 to about 1:15, about 1: 5 to about 1:15, about 5: 1 to about 1:12, about 4: 1 to about 1:12, about 3: 1 to about 1:12, about 2: 1 to about 1:12, about 0: 1 to about 1:12, about 1: 1 to about 1:12, about 1: 2 to about 1:12, about 1: 3 to about 1:12, about 1: 4 to about 1:12, about 1: 5 to about 1:12, about 1: 6 to about 1:12, about 1: 7 to about 1:12, about 1: 8 to about 1:12, about 5: 1 to about 1:10, about 4: 1 to about 1:10, about 3: 1 to about 1:10, about 2: 1 to about 1:10, about 0: 1 to about 1:10, about 1: 1 to about 1:10, about 1: 2 to about 1:10, about 1: 3 to about 1:10, about 1: 4 to about 1:10, about 1: 5 to about The range may be 1:10, about 1: 6 to about 1:10, about 1: 7 to about 1:10, or about 1: 8 to about 1:10.

  Step (b) can be performed at room temperature to allow a solution containing the therapeutic compound to form a pharmaceutical composition. However, in other embodiments of the method, step (b) can be performed at a temperature higher than room temperature. In some aspects of this embodiment, step (b) includes, for example, a temperature greater than 21 ° C., a temperature greater than 25 ° C., a temperature greater than 30 ° C., a temperature greater than 35 ° C., a temperature greater than 37 ° C., 40 ° C. It can be carried out at higher temperatures, temperatures higher than 42 ° C, temperatures higher than 45 ° C, temperatures higher than 50 ° C, temperatures higher than 55 ° C, or temperatures higher than 60 ° C. In some aspects of this embodiment, step (a) includes, for example, from about 20 ° C to about 30 ° C, from about 25 ° C to about 35 ° C, from about 30 ° C to about 40 ° C, from about 35 ° C to about 45 ° C, It can be carried out at a temperature of about 40 ° C to about 50 ° C, about 45 ° C to about 55 ° C, or about 50 ° C to about 60 ° C. In certain cases, step (b) can be carried out at a temperature below room temperature in order to completely dissolve the therapeutic compound in a pharmaceutically acceptable solvent. However, in other embodiments of the method, step (b) can be performed at a temperature lower than room temperature, for example, less than 10 ° C, greater than 5 ° C, greater than 0 ° C, greater than -10 ° C, or greater than -20 ° C. The contacting in step (b) can include mixing the solution and a pharmaceutically acceptable adjuvant, for example, by stirring, inversion, sonication, or vortexing. This mixing may occur until a pharmaceutical composition is formed, for example, at least 1 second, at least 5 seconds, at least 10 seconds, at least 20 seconds, at least 30 seconds, at least 45 seconds, at least 60 seconds, or longer. it can.

  In certain embodiments, after forming the pharmaceutical composition disclosed herein, a rapid cooling step can be used to lower the temperature of the composition. For example, the rapid cooling step may allow the therapeutic compound to be completely dissolved in a pharmaceutically acceptable solvent using a temperature above room temperature and / or form a pharmaceutical composition in a solution containing the therapeutic compound. Can be used in case of method. In some aspects of this embodiment, the rapid cooling step can be, for example, about 30 ° C./20 minutes, about 25 ° C./20 minutes, about 20 ° C./20 minutes, about 15 ° C./20 minutes, about 30 ° C./15 Minutes, about 25 ° C / 15 minutes, about 20 ° C / 15 minutes, about 15 ° C / 15 minutes, about 30 ° C / 10 minutes, about 25 ° C / 10 minutes, about 20 ° C / 10 minutes, about 15 ° C / 10 minutes About 30 ° C / 5 minutes, about 25 ° C / 5 minutes, about 20 ° C / 5 minutes, about 15 ° C / 5 minutes. In other aspects of this embodiment, the rapid cooling step can be, for example, about 20 ° C. to about 30 ° C./20 minutes, about 20 ° C. to about 30 ° C./15 minutes, about 20 ° C. to about 30 ° C./10 minutes, about 20 ° C to about 30 ° C / 5 minutes, about 15 ° C to about 25 ° C / 20 minutes, about 15 ° C to about 25 ° C / 15 minutes, about 15 ° C to about 25 ° C / 10 minutes, about 15 ° C to about 25 ° C For about 5 minutes, about 10 ° C. to about 20 ° C./20 minutes, about 10 ° C. to about 20 ° C./15 minutes, about 10 ° C. to about 20 ° C./10 minutes, or about 10 ° C. to about 20 ° C./5 minutes Cause a drop.

  In a further aspect of this embodiment, the rapid cooling step can be, for example, about 2.0 ° C./min, about 1.9 ° C./min, about 1.8 ° C./min, about 1.7 ° C./min, about 1. 6 ° C / min, about 1.5 ° C / min, about 1.4 ° C / min, about 1.3 ° C / min, about 1.2 ° C / min, about 1.1 ° C / min, about 1.0 ° C / Min, about 0.9 ° C / min, about 0.8 ° C / min, about 0.7 ° C / min, about 0.6 ° C / min, about 0.5 ° C / min, about 0.4 ° C / min About 0.3 ° C./min, about 0.2 ° C./min, or about 0.1 ° C./min. In a further aspect of this embodiment, the rapid cooling step can be, for example, about 0.1 ° C. to about 0.4 ° C./min, about 0.2 ° C. to about 0.6 ° C./min, about 0.4 ° C. to about 0.8 ° C / min, about 0.6 ° C to about 1.0 ° C / min, about 0.8 ° C to about 1.2 ° C / min, about 1.0 ° C to about 1.4 ° C / min, about 1.2 ° C to about 1.6 ° C / min, about 1.4 ° C to about 1.8 ° C / min, about 1.6 ° C to about 2.0 ° C / min, about 0.1 ° C to about 0. 5 ° C / min, about 0.5 ° C to about 1.0 ° C / min, about 1.0 ° C to about 1.5 ° C / min, about 1.5 ° C to about 2.0 ° C / min, about 0. A temperature decrease of 5 ° C. to about 1.5 ° C./min, or about 1.0 ° C. to about 2.0 ° C./min.

  In some embodiments, temperatures above room temperature used in step (a) or step (b) or both can be used to remove the solvent from the pharmaceutical composition. In other embodiments, removal of the solvent from the pharmaceutical composition requires another step (c). In step (c), removal of the solvent from the pharmaceutical composition can be accomplished using one of various procedures known in the art including evaporation, dialysis, distillation. , Lyophilization, and filtration. These removal procedures can be performed under ambient atmospheric conditions, under low pressure, or under vacuum, and at room temperature or a temperature that requires heating.

  In one embodiment, step (c) can effect complete removal of the pharmaceutically acceptable solvent from the pharmaceutical compositions disclosed herein. In some aspects of this embodiment, step (c) comprises, for example, at least 5%, at least 10%, at least 15% of the pharmaceutically acceptable solvent from the pharmaceutical composition disclosed herein. At least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 93%, at least 95%, at least 97%, or at least 99% removal can be performed.

  Step (c) is performed at a temperature that allows evaporation of the pharmaceutically acceptable solvent disclosed herein, and thus the evaporation temperature is solvent dependent. Factors affecting the evaporation temperature of the solvents disclosed herein include the specific solvent used, the amount of solvent present, the specific therapeutic compound present, the specific adjuvant present, the stability of the therapeutic compound present , The reactivity of the therapeutic compound present, the specific pressure used, the time desired for complete evaporation, but is not limited thereto. In general, when the evaporation step is performed at atmospheric pressure, such as 1 atmosphere, the pharmaceutical composition requires heating. However, under high vacuum conditions, the evaporation step can be performed at a temperature below room temperature, for example, below 22 ° C.

  In one embodiment, removal of the solvent from the pharmaceutical compositions disclosed herein can be performed at atmospheric pressure and above room temperature. In some aspects of this embodiment, removal of the solvent from the pharmaceutical compositions disclosed herein is at atmospheric pressure and, for example, at a temperature above 25 ° C, above 30 ° C, above 35 ° C. High temperature, temperature above 40 ° C, temperature above 45 ° C, temperature above 50 ° C, temperature above 55 ° C, temperature above 60 ° C, temperature above 65 ° C, temperature above 70 ° C, temperature above 80 ° C Or higher than 25 ° C. In other aspects of this embodiment, removal of the solvent from the pharmaceutical compositions disclosed herein is at atmospheric pressure and, for example, from about 25 ° C to about 100 ° C, from about 25 ° C to about 95 ° C, About 25C to about 90C, about 25C to about 85C, about 25C to about 80C, about 25C to about 75C, about 25C to about 70C, about 25C to about 65C, or about It can be carried out at temperatures ranging from 25 ° C to about 60 ° C.

  In another embodiment, removal of the solvent from the pharmaceutical compositions disclosed herein can be performed under vacuum and at a temperature below room temperature. In some aspects of this embodiment, removal of the solvent from the pharmaceutical compositions disclosed herein is under vacuum and, for example, at a temperature lower than 20 ° C, lower than 18 ° C, higher than 16 ° C. Low temperature, temperature below 14 ° C, temperature below 12 ° C, temperature below 10 ° C, temperature below 8 ° C, temperature below 6 ° C, temperature below 4 ° C, temperature below 2 ° C, or below 0 ° C Can be performed at temperature. In other aspects of this embodiment, removal of the solvent from the pharmaceutical compositions disclosed herein is under vacuum and, for example, from about -20 ° C to about 20 ° C, from about -20 ° C to about 18 ° C. ° C, about -20 ° C to about 16 ° C, about -20 ° C to about 14 ° C, about -20 ° C to about 12 ° C, about -20 ° C to about 10 ° C, about -20 ° C to about 8 ° C, about -20 ℃ to about 6 ℃, about -20 ℃ to about 4 ℃, about -20 ℃ to about 2 ℃, about -20 ℃ to about 0 ℃, about -15 ℃ to about 20 ℃, about -10 ℃ to about 20 ℃ About -5C to about 20C, about 0C to about 20C, about -10C to about 20C, about -10C to about 18C, about -10C to about 16C, about -10C About 14 ° C, about -10 ° C to about 12 ° C, about -10 ° C to about 10 ° C, about -10 ° C to about 8 ° C, about -10 ° C to about 6 ° C, about -10 ° C to about 4 ° C, about At temperatures in the range of −10 ° C. to about 2 ° C., or about −10 ° C. to about 0 ° C. It can be.

  The final concentration of the therapeutic compound disclosed herein in the pharmaceutical compositions disclosed herein may be any desired concentration. In one aspect of this embodiment, the final concentration of the therapeutic compound in the pharmaceutical composition may be a therapeutically effective amount. In other aspects of this embodiment, the final concentration of the therapeutic compound in the pharmaceutical composition is, for example, at least 0.00001 mg / mL, at least 0.0001 mg / mL, at least 0.001 mg / mL, at least 0.01 mg / mL. At least 0.1 mg / mL, at least 1 mg / mL, at least 10 mg / mL, at least 25 mg / mL, at least 50 mg / mL, at least 100 mg / mL, at least 200 mg / mL, at least 500 mg / mL, at least 700 mg / mL, at least 1 , 000 mg / mL, or at least 1,200 mg / mL. In other aspects of this embodiment, the concentration of the therapeutic compound disclosed herein in solution is, for example, up to 1,000 mg / mL, up to 1,100 mg / mL, up to 1,200 mg / mL, up to 1 , 300 mg / mL, up to 1,400 mg / mL, up to 1,500 mg / mL, up to 2,000 mg / mL, up to 2,000 mg / mL, or up to 3,000 mg / mL. In other aspects of this embodiment, the final concentration of the therapeutic compound in the pharmaceutical composition is, for example, from about 0.00001 mg / mL to about 3,000 mg / mL, from about 0.0001 mg / mL to about 3,000 mg / mL. About 0.01 mg / mL to about 3,000 mg / mL, about 0.1 mg / mL to about 3,000 mg / mL, about 1 mg / mL to about 3,000 mg / mL, about 250 mg / mL to about 3,000 mg / ML, about 500 mg / mL to about 3,000 mg / mL, about 750 mg / mL to about 3,000 mg / mL, about 1,000 mg / mL to about 3,000 mg / mL, about 100 mg / mL to about 2,000 mg / ML, about 250 mg / mL to about 2,000 mg / mL, about 500 mg / mL to about 2,000 mg / mL, about 750 mg / mL to about 2,000 mg / mL, about 1 000 mg / mL to about 2,000 mg / mL, about 100 mg / mL to about 1,500 mg / mL, about 250 mg / mL to about 1,500 mg / mL, about 500 mg / mL to about 1,500 mg / mL, about 750 mg / mL mL to about 1,500 mg / mL, about 1,000 mg / mL to about 1,500 mg / mL, about 100 mg / mL to about 1,200 mg / mL, about 250 mg / mL to about 1,200 mg / mL, about 500 mg / mL mL to about 1,200 mg / mL, about 750 mg / mL to about 1,200 mg / mL, about 1,000 mg / mL to about 1,200 mg / mL, about 100 mg / mL to about 1,000 mg / mL, about 250 mg / mL mL to about 1,000 mg / mL, about 500 mg / mL to about 1,000 mg / mL, about 750 mg / mL to about 1,000 mg / mL About 100 mg / mL to about 750 mg / mL, about 250 mg / mL to about 750 mg / mL, about 500 mg / mL to about 750 mg / mL, about 100 mg / mL to about 500 mg / mL, about 250 mg / mL to about 500 mg / mL, About 0.00001 mg / mL to about 0.0001 mg / mL, about 0.00001 mg / mL to about 0.001 mg / mL, about 0.00001 mg / mL to about 0.01 mg / mL, about 0.00001 mg / mL to about 0.1 mg / mL, about 0.00001 mg / mL to about 1 mg / mL, about 0.001 mg / mL to about 0.01 mg / mL, about 0.001 mg / mL to about 0.1 mg / mL, about 0.001 mg / ML to about 1 mg / mL, about 0.001 mg / mL to about 10 mg / mL, or about 0.001 mg / mL to about 100 mg / mL Range.

  The pharmaceutical compositions produced using the methods disclosed herein can be formulated for local or systemic delivery using topical, enteral or parenteral routes of administration. Further, the therapeutic compounds disclosed herein can be formulated into pharmaceutical compositions alone or as a single pharmaceutical composition together with one or more other therapeutic compounds disclosed herein. You may prescribe.

  The pharmaceutical composition produced using the methods disclosed herein may be a liquid formulation or a solid or semi-solid formulation. The formulations disclosed herein can be manufactured to form a single phase, such as, for example, an oil or solid phase. Alternatively, the formulations disclosed herein can be manufactured to form two phases, such as, for example, an emulsion. The pharmaceutical compositions disclosed herein intended for such administration can be prepared by any method known in the art for the manufacture of pharmaceutical compositions. Semi-solid preparations suitable for topical administration include, but are not limited to, ointments, creams, salves, and gels.

  Liquid formulations can be formed using various lipids such as oils and other fatty acids that remain liquid within the desired temperature range. In one embodiment, the pharmaceutical compositions disclosed herein are liquid at room temperature. In some aspects of this embodiment, the pharmaceutical compositions disclosed herein can have, for example, a temperature of about 25 ° C or higher, a temperature of about 23 ° C or higher, a temperature of about 21 ° C or higher, a temperature of about 19 ° C or higher. Temperature, temperature above about 17 ° C, temperature above about 15 ° C, temperature above about 12 ° C, temperature above about 10 ° C, temperature above about 8 ° C, temperature above about 6 ° C, temperature above about 4 ° C Or can be formulated to be liquid at temperatures above about 0 ° C.

  For liquid and semi-solid formulations, the concentration of the therapeutic compound disclosed herein may be from about 50 mg / mL to about 1,000 mg / mL. In some aspects of this embodiment, the therapeutically effective amount of a therapeutic compound disclosed herein is, for example, from about 50 mg / mL to about 100 mg / mL, from about 50 mg / mL to about 200 mg / mL, about 50 mg / mL. mL to about 300 mg / mL, about 50 mg / mL to about 400 mg / mL, about 50 mg / mL to about 500 mg / mL, about 50 mg / mL to about 600 mg / mL, about 50 mg / mL to about 700 mg / mL, about 50 mg / mL mL to about 800 mg / mL, about 50 mg / mL to about 900 mg / mL, about 50 mg / mL to about 1,000 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 300 mg / mL, about 100 mg / mL to about 400 mg / mL, about 100 mg / mL to about 500 mg / mL, about 100 mg / mL to about 600 mg / mL L, about 100 mg / mL to about 700 mg / mL, about 100 mg / mL to about 800 mg / mL, about 100 mg / mL to about 900 mg / mL, about 100 mg / mL to about 1,000 mg / mL, about 200 mg / mL to about 300 mg / mL, about 200 mg / mL to about 400 mg / mL, about 200 mg / mL to about 500 mg / mL, about 200 mg / mL to about 600 mg / mL, about 200 mg / mL to about 700 mg / mL, about 200 mg / mL to about 800 mg / mL, about 200 mg / mL to about 900 mg / mL, about 200 mg / mL to about 1,000 mg / mL, about 300 mg / mL to about 400 mg / mL, about 300 mg / mL to about 500 mg / mL, about 300 mg / mL To about 600 mg / mL, about 300 mg / mL to about 700 mg / mL, about 300 mg mL to about 800 mg / mL, about 300 mg / mL to about 900 mg / mL, about 300 mg / mL to about 1,000 mg / mL, about 400 mg / mL to about 500 mg / mL, about 400 mg / mL to about 600 mg / mL, about 400 mg / mL to about 700 mg / mL, about 400 mg / mL to about 800 mg / mL, about 400 mg / mL to about 900 mg / mL, about 400 mg / mL to about 1,000 mg / mL, about 500 mg / mL to about 600 mg / mL About 500 mg / mL to about 700 mg / mL, about 500 mg / mL to about 800 mg / mL, about 500 mg / mL to about 900 mg / mL, about 500 mg / mL to about 1,000 mg / mL, about 600 mg / mL to about 700 mg / ML, about 600 mg / mL to about 800 mg / mL, about 600 mg / mL to about 900 mg / mL, or about 600 mg / mL to about 1,000 mg / mL.

  For semi-solid and solid formulations, the amount of therapeutic compound disclosed herein may typically be from about 0.01% to about 45% by weight. In some aspects of this embodiment, the amount of therapeutic compound disclosed herein is, for example, from about 0.1% to about 45%, from about 0.1% to about 40%, 0.1% to about 35%, about 0.1% to about 30%, about 0.1% to about 25%, about 0.1% to about 20%, about 0. 1% to about 15%, about 0.1% to about 10%, about 0.1% to about 5%, about 1% to about 45%, about 1% to about 40% %, About 1% to about 35%, about 1% to about 30%, about 1% to about 25%, about 1% to about 20%, about 1% to about 15%. %, About 1% to about 10%, about 1% to about 5%, about 5% to about 45%, about 5% to about 40%, about 5% to about 35%. % By weight, about 5% To about 30 wt%, about 5 wt% to about 25 wt%, about 5 wt% to about 20 wt%, about 5 wt% to about 15 wt%, about 5 wt% to about 10 wt%, about 10 wt% To about 45%, about 10% to about 40%, about 10% to about 35%, about 10% to about 30%, about 10% to about 25%, about 10% To about 20 wt%, about 10 wt% to about 15 wt%, about 15 wt% to about 45 wt%, about 15 wt% to about 40 wt%, about 15 wt% to about 35 wt%, about 15 wt% To about 30 wt%, about 15 wt% to about 25 wt%, about 15 wt% to about 20 wt%, about 20 wt% to about 45 wt%, about 20 wt% to about 40 wt%, about 20 wt% To about 35 wt%, about 20 wt% to about 30 wt%, about 20 wt% to about 25 wt%, about 25 wt% to about 45 wt%, about 25 wt% About 40%, about 25 wt% to about 35 wt%, or from about 25% to about 30 wt%, it may be.

  In one embodiment, the liquid formulation comprises a therapeutic compound, glycol ether, partially hydrogenated fat, oil, and alcohol. In one aspect of this embodiment, the liquid formulation comprises about 15 wt% to about 35 wt% therapeutic compound, about 5 wt% to about 25 wt% glycol ether, about 15 wt% to about 40 wt% partial water. Fat, about 15% to about 40% oil, and about 1% to about 15% alcohol. In another aspect of this embodiment, the liquid formulation comprises from about 20% to about 30% therapeutic compound, from about 10% to about 20% glycol ether, from about 20% to about 35% by weight portion. Hydrogenated fat, about 20 wt% to about 35 wt% oil, and about 2 wt% to about 10 wt% alcohol. In yet another aspect of this embodiment, the liquid formulation comprises about 23% to about 27% by weight therapeutic compound, about 13% to about 17% glycol ether, about 25% to about 30% by weight. Partially hydrogenated fat, about 25% to about 30% oil, and about 4% to about 8% alcohol. In yet another aspect of this embodiment, the liquid formulation comprises about 24% to about 26% by weight therapeutic compound, about 14% to about 16% glycol ether, about 26% to about 28% by weight. Contains partially hydrogenated fat, about 26% to about 28% oil, and about 5% to about 7% alcohol. In other aspects of this embodiment, the oil is rapeseed oil or cocoa butter.

  In another embodiment, the liquid formulation comprises a therapeutic compound, glycol ether, glyceryl monolinoleate, oil, and alcohol. In one aspect of this embodiment, the liquid formulation comprises about 15% to about 35% by weight therapeutic compound, about 5% to about 25% glycol ether, about 15% to about 40% glyceryl monolith. Noreate, about 15% to about 40% oil, and about 1% to about 15% alcohol. In another aspect of this embodiment, the liquid formulation comprises about 20% to about 30% by weight therapeutic compound, about 10% to about 20% glycol ether, about 20% to about 35% glyceryl. Monolinoleate, about 20 wt.% To about 35 wt.% Oil, and about 2 wt.% To about 10 wt.% Alcohol. In yet another aspect of this embodiment, the liquid formulation comprises about 23% to about 27% by weight therapeutic compound, about 13% to about 17% glycol ether, about 25% to about 30% by weight. Glyceryl monolinoleate, about 25% to about 30% oil by weight, and about 4% to about 8% alcohol by weight. In yet another aspect of this embodiment, the liquid formulation comprises about 24% to about 26% by weight therapeutic compound, about 14% to about 16% glycol ether, about 26% to about 28% by weight. Glyceryl monolinoleate, about 26 wt.% To about 28 wt.% Oil, and about 5 wt.% To about 7 wt.% Alcohol. In other aspects of this embodiment, the oil is rapeseed oil or cocoa butter.

  In another embodiment, the liquid formulation comprises ibuprofen, diethylene glycol monoethyl ether, glyceryl monolinoleate, oil, and alcohol. In one aspect of this embodiment, the liquid formulation comprises about 15% to about 35% ibuprofen, about 5% to about 25% diethylene glycol monoethyl ether, about 15% to about 40% glyceryl. Monolinoleate, about 15% to about 40% oil by weight, and about 1% to about 15% alcohol by weight. In another aspect of this embodiment, the liquid formulation is about 20% to about 30% ibuprofen, about 10% to about 20% diethylene glycol monoethyl ether, about 20% to about 35% by weight. Glyceryl monolinoleate, about 20% to about 35% oil by weight, and about 2% to about 10% alcohol by weight. In yet another aspect of this embodiment, the liquid formulation comprises about 23% to about 27% ibuprofen, about 13% to about 17% diethylene glycol monoethyl ether, about 25% to about 30% by weight. Glyceryl monolinoleate, about 25% to about 30% oil, and about 4% to about 8% alcohol. In yet another aspect of this embodiment, the liquid formulation is about 24% to about 26% ibuprofen, about 14% to about 16% diethylene glycol monoethyl ether, about 26% to about 28% by weight. Glyceryl monolinoleate, about 26 wt.% To about 28 wt.% Oil, and about 5 wt.% To about 7 wt.% Alcohol. In other aspects of this embodiment, the ibuprofen may be the free acid of the salt of ibuprofen. In other aspects of this embodiment, the oil is rapeseed oil or cocoa butter.

  In one embodiment, the liquid formulation comprises a therapeutic compound, an ester of alcohol, and an oil. In one aspect of this embodiment, the liquid formulation comprises from about 1% to about 10% by weight therapeutic compound, from about 1% to about 10% alcohol ester, and from about 80% to about 98% by weight. Contains oil. In another aspect of this embodiment, the liquid formulation comprises from about 2% to about 8% by weight therapeutic compound, from about 1% to about 7% alcohol ester, and from about 85% to about 97% by weight. Contains oil. In yet another aspect of this embodiment, the liquid formulation comprises from about 3% to about 7% by weight therapeutic compound, from about 2% to about 6% by weight ester of alcohol, and from about 87% to about 95% by weight. Contains% oil. In yet another aspect of this embodiment, the liquid formulation comprises from about 4 wt% to about 6 wt% therapeutic compound, from about 3 wt% to about 5 wt% ester of alcohol, and from about 90 wt% to about 92 wt%. Contains% oil. In other aspects of this embodiment, the oil is rapeseed oil or cocoa butter.

  In another embodiment, the liquid formulation comprises a therapeutic compound, ethyl acetate, and oil. In one aspect of this embodiment, the liquid formulation comprises from about 1% to about 10% therapeutic compound, from about 1% to about 10% ethyl acetate, and from about 80% to about 98% oil by weight. including. In another aspect of this embodiment, the liquid formulation comprises from about 2% to about 8% by weight therapeutic compound, from about 1% to about 7% ethyl acetate, and from about 85% to about 97% by weight. Contains oil. In yet another aspect of this embodiment, the liquid formulation comprises about 3% to about 7% by weight therapeutic compound, about 2% to about 6% ethyl acetate, and about 87% to about 95% by weight. Contains oil. In yet another aspect of this embodiment, the liquid formulation comprises about 4% to about 6% by weight therapeutic compound, about 3% to about 5% ethyl acetate, and about 90% to about 92% by weight. Contains oil. In other aspects of this embodiment, the oil is rapeseed oil or cocoa butter.

  In another embodiment, the liquid formulation comprises ibuprofen, ethyl acetate, and oil. In one aspect of this embodiment, the liquid formulation comprises from about 1% to about 10% ibuprofen, from about 1% to about 10% ethyl acetate, and from about 80% to about 98% oil by weight. Including. In another aspect of this embodiment, the liquid formulation comprises about 2% to about 8% ibuprofen, about 1% to about 7% ethyl acetate, and about 85% to about 97% oil by weight. including. In yet another aspect of this embodiment, the liquid formulation comprises about 3% to about 7% ibuprofen, about 2% to about 6% ethyl acetate, and about 87% to about 95% by weight. Contains oil. In yet another aspect of this embodiment, the liquid formulation comprises about 4% to about 6% ibuprofen, about 3% to about 5% ethyl acetate, and about 90% to about 92% by weight. Contains oil. In other aspects of this embodiment, the ibuprofen may be the free acid of the salt of ibuprofen. In other aspects of this embodiment, the oil is rapeseed oil or cocoa butter.

  In one embodiment, the solid or semi-solid formulations disclosed herein are formulated without a hydrophilic solvent such as water. Such formulations form co-crystals of lipids and therapeutic compounds. In other words, such formulations do not form liposomal emulsions and / or micellar particles that require a hydrophilic solvent.

  In one embodiment, the solid formulation comprises a therapeutic compound, hard fat, partially hydrogenated fat, and polyethylene glycol. In one aspect of this embodiment, the solid dosage form comprises from about 1% to about 30% therapeutic compound, from about 8% to about 70% hard fat, from about 2% to about 65% partial water. Containing fat and about 1% to about 15% polyethylene glycol by weight. In another aspect of this embodiment, the solid dosage form comprises about 10% to about 30% therapeutic compound, about 20% to about 50% hard fat, about 10% to about 30% portion. Hydrogenated fat and from about 5% to about 15% polyethylene glycol by weight. In yet another aspect of this embodiment, the solid formulation comprises about 20% to about 30% therapeutic compound, about 30% to about 50% hard fat, about 10% to about 30% by weight. Partially hydrogenated fat and from about 7% to about 13% polyethylene glycol by weight. In yet another aspect of this embodiment, the solid formulation comprises about 20% to about 30% therapeutic compound, about 35% to about 50% hard fat, about 15% to about 25% by weight. Partially hydrogenated fat and from about 7% to about 13% polyethylene glycol by weight. In a further aspect of this embodiment, the solid formulation comprises from about 23% to about 27% by weight therapeutic compound, from about 41% to about 47% hard fat, from about 18% to about 22% partial water. And about 9% to about 11% polyethylene glycol by weight. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, or PEG700.

  In another embodiment, the solid formulation comprises a therapeutic compound, mono, di, a mixture of triglycerides and PEG fatty acid esters, glyceryl monolinoleate, and polyethylene glycol. In one aspect of this embodiment, the solid dosage form comprises from about 1% to about 30% by weight of therapeutic compound, from about 8% to about 70% by weight of a mixture of mono, di, triglycerides and PEG fatty acid esters, about 2%. % To about 65% by weight glyceryl monolinoleate and about 1% to about 15% by weight polyethylene glycol. In another aspect of this embodiment, the solid dosage form comprises from about 10% to about 30% by weight of the therapeutic compound, from about 20% to about 50% by weight of a mixture of mono-, di-, triglycerides and PEG fatty acid esters, about 10%. % By weight to about 30% by weight glyceryl monolinoleate and about 5% to about 15% by weight polyethylene glycol. In yet another aspect of this embodiment, the solid formulation comprises from about 20% to about 30% by weight of the therapeutic compound, from about 30% to about 50% by weight of a mixture of mono-, di-, triglycerides and PEG fatty acid esters, 10% to about 30% by weight of glyceryl monolinoleate and about 7% to about 13% by weight of polyethylene glycol. In yet another aspect of this embodiment, the solid formulation comprises from about 20% to about 30% by weight of the therapeutic compound, from about 35% to about 50% by weight of a mixture of mono-, di-, triglycerides and PEG fatty acid esters, 15% to about 25% by weight glyceryl monolinoleate, and about 7% to about 13% by weight polyethylene glycol. In a further aspect of this embodiment, the solid dosage form comprises from about 23 wt% to about 27 wt% therapeutic compound, from about 41 wt% to about 47 wt% mono, di, triglyceride and PEG fatty acid ester mixture, about 18 wt%. % To about 22% by weight glyceryl monolinoleate, and about 9% to about 11% polyethylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, or PEG700.

  In another embodiment, the solid formulation comprises ibuprofen, mono, di, a mixture of triglycerides and PEG fatty acid esters, glyceryl monolinoleate, and polyethylene glycol. In one aspect of this embodiment, the solid dosage form comprises from about 1% to about 30% ibuprofen, from about 8% to about 70% by weight of a mixture of mono, di, triglycerides and PEG fatty acid esters, about 2% by weight. About 65% by weight glyceryl monolinoleate, and about 1% to about 15% by weight polyethylene glycol. In another aspect of this embodiment, the solid formulation is about 10% to about 30% by weight ibuprofen, about 20% to about 50% by weight, a mixture of mono-, di-, triglycerides and PEG fatty acid esters, about 10%. % To about 30% by weight glyceryl monolinoleate and about 5% to about 15% by weight polyethylene glycol. In yet another aspect of this embodiment, the solid dosage form comprises about 20% to about 30% ibuprofen, about 30% to about 50% by weight, a mixture of mono-, di-, triglycerides and PEG fatty acid esters, about 10%. % By weight to about 30% by weight glyceryl monolinoleate, and about 7% to about 13% by weight polyethylene glycol. In yet another aspect of this embodiment, the solid dosage form comprises about 20 wt% to about 30 wt% ibuprofen, about 35 wt% to about 50 wt% mono, di, triglyceride and PEG fatty acid ester mixture, about 15 wt% % By weight to about 25% by weight glyceryl monolinoleate, and about 7% to about 13% by weight polyethylene glycol. In a further aspect of this embodiment, the solid dosage form is about 23% to about 27% by weight ibuprofen, about 41% to about 47% by weight, a mixture of mono, di, triglycerides and PEG fatty acid esters, about 18% by weight. About 22% by weight glyceryl monolinoleate, and about 9% to about 11% by weight polyethylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, or PEG700.

  In another embodiment, the solid formulation comprises a therapeutic compound, hard fat, partially hydrogenated fat, polyethylene glycol, and propylene glycol. In one aspect of this embodiment, the solid dosage form comprises from about 1% to about 30% therapeutic compound, from about 8% to about 70% hard fat, from about 2% to about 65% partial water. Fat, about 1% to about 15% polyethylene glycol, and about 1% to about 15% propylene glycol. In another aspect of this embodiment, the solid dosage form comprises about 10% to about 30% therapeutic compound, about 20% to about 50% hard fat, about 10% to about 30% portion. Hydrogenated fat, about 5% to about 15% polyethylene glycol, and about 5% to about 15% propylene glycol. In yet another aspect of this embodiment, the solid formulation comprises about 20% to about 30% therapeutic compound, about 30% to about 50% hard fat, about 10% to about 30% by weight. Partially hydrogenated fat, from about 7% to about 13% polyethylene glycol, and from about 7% to about 13% propylene glycol. In yet another aspect of this embodiment, the solid formulation comprises about 20% to about 30% therapeutic compound, about 35% to about 50% hard fat, about 15% to about 25% by weight. Partially hydrogenated fat, from about 7% to about 13% polyethylene glycol, and from about 7% to about 13% propylene glycol. In a further aspect of this embodiment, the solid formulation comprises from about 23% to about 27% by weight therapeutic compound, from about 41% to about 47% hard fat, from about 18% to about 22% partial water. Fat, 9% to about 11% polyethylene glycol, and about 9% to about 11% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, or PEG700.

  In another embodiment, the solid formulation comprises a therapeutic compound, a mixture of mono, di, triglycerides and PEG fatty acid esters, glyceryl monolinoleate, polyethylene glycol, and propylene glycol. In one aspect of this embodiment, the solid dosage form comprises from about 1% to about 30% by weight of therapeutic compound, from about 8% to about 70% by weight of a mixture of mono, di, triglycerides and PEG fatty acid esters, about 2%. % To about 65% by weight glyceryl monolinoleate, about 1% to about 15% polyethylene glycol, and about 1% to about 15% propylene glycol. In another aspect of this embodiment, the solid dosage form comprises from about 10% to about 30% by weight of the therapeutic compound, from about 20% to about 50% by weight of a mixture of mono-, di-, triglycerides and PEG fatty acid esters, about 10%. From about 5% to about 15% by weight glyceryl monolinoleate, from about 5% to about 15% polyethylene glycol, and from about 5% to about 15% propylene glycol. In yet another aspect of this embodiment, the solid formulation comprises from about 20% to about 30% by weight of the therapeutic compound, from about 30% to about 50% by weight of a mixture of mono-, di-, triglycerides and PEG fatty acid esters, 10% to about 30% by weight glyceryl monolinoleate, about 7% to about 13% polyethylene glycol, and about 7% to about 13% propylene glycol. In yet another aspect of this embodiment, the solid formulation comprises from about 20% to about 30% by weight of the therapeutic compound, from about 35% to about 50% by weight of a mixture of mono-, di-, triglycerides and PEG fatty acid esters, 15 wt% to about 25 wt% glyceryl monolinoleate, 7 wt% to about 13 wt% polyethylene glycol, and about 7 wt% to about 13 wt% propylene glycol. In a further aspect of this embodiment, the solid dosage form comprises from about 23 wt% to about 27 wt% therapeutic compound, from about 41 wt% to about 47 wt% mono, di, triglyceride and PEG fatty acid ester mixture, about 18 wt%. % To about 22% by weight glyceryl monolinoleate, about 9% to about 11% polyethylene glycol, and about 9% to about 11% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, or PEG700.

  In another embodiment, the solid formulation comprises ibuprofen, mono, di, a mixture of triglycerides and PEG fatty acid esters, glyceryl monolinoleate, polyethylene glycol, and propylene glycol. In one aspect of this embodiment, the solid dosage form comprises from about 1% to about 30% ibuprofen, from about 8% to about 70% by weight of a mixture of mono, di, triglycerides and PEG fatty acid esters, about 2% by weight. About 65% by weight glyceryl monolinoleate, about 1% to about 15% polyethylene glycol, and about 1% to about 15% propylene glycol. In another aspect of this embodiment, the solid formulation is about 10% to about 30% by weight ibuprofen, about 20% to about 50% by weight, a mixture of mono-, di-, triglycerides and PEG fatty acid esters, about 10%. % To about 30% by weight glyceryl monolinoleate, about 5% to about 15% polyethylene glycol, and about 5% to about 15% propylene glycol. In yet another aspect of this embodiment, the solid dosage form comprises about 20% to about 30% ibuprofen, about 30% to about 50% by weight, a mixture of mono-, di-, triglycerides and PEG fatty acid esters, about 10%. % To about 30% by weight glyceryl monolinoleate, about 7% to about 13% polyethylene glycol, and about 7% to about 13% propylene glycol. In yet another aspect of this embodiment, the solid dosage form comprises about 20 wt% to about 30 wt% ibuprofen, about 35 wt% to about 50 wt% mono, di, triglyceride and PEG fatty acid ester mixture, about 15 wt% % By weight to about 25% by weight glyceryl monolinoleate, 7% to about 13% by weight polyethylene glycol, and about 7% to about 13% by weight propylene glycol. In a further aspect of this embodiment, the solid dosage form is about 23% to about 27% by weight ibuprofen, about 41% to about 47% by weight, a mixture of mono, di, triglycerides and PEG fatty acid esters, about 18% by weight. To about 22% by weight glyceryl monolinoleate, about 9% to about 11% polyethylene glycol, and about 9% to about 11% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, or PEG700.

  In another embodiment, the semi-solid formulation comprises a therapeutic compound, hard fat, partially hydrogenated fat, polyethylene glycol, and propylene glycol. In one aspect of this embodiment, the semi-solid formulation comprises about 15% to about 55% by weight therapeutic compound, about 7% to about 20% hard fat, about 20% to about 50% by weight portion. Hydrogenated fat, from about 7% to about 20% polyethylene glycol, and from about 1% to about 8% propylene glycol. In one aspect of this embodiment, the semi-solid formulation comprises about 20% to about 50% by weight therapeutic compound, about 8% to about 18% hard fat, about 25% to about 45% by weight portion. Hydrogenated fat, about 8% to about 18% polyethylene glycol, and about 2% to about 6% propylene glycol. In another aspect of this embodiment, the semi-solid formulation comprises about 20% to about 50% therapeutic compound, about 10% to about 16% hard fat, about 25% to about 45% by weight. Partially hydrogenated fat, from about 10% to about 16% polyethylene glycol, and from about 2% to about 6% propylene glycol. In yet another aspect of this embodiment, the semi-solid formulation comprises about 20% to about 50% therapeutic compound, about 11% to about 15% hard fat, about 30% to about 40% by weight. Partly hydrogenated fat, about 11% to about 15% polyethylene glycol, and about 3% to about 5% propylene glycol. In yet another aspect of this embodiment, the semi-solid formulation comprises about 25% to about 44% by weight therapeutic compound, about 12% to about 14% hard fat, about 32% to about 39% by weight. Of partially hydrogenated fat, about 12% to about 14% polyethylene glycol, and about 4% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, or PEG700.

  In another embodiment, the semi-solid formulation comprises a therapeutic compound, a mixture of mono, di, triglycerides and PEG fatty acid esters, glyceryl monolinoleate, polyethylene glycol, and propylene glycol. In one aspect of this embodiment, the semi-solid formulation comprises about 15% to about 55% by weight therapeutic compound, about 7% to about 20% by weight of a mixture of mono-, di-, triglycerides and PEG fatty acid esters, about 20%. % By weight to about 50% by weight glyceryl monolinoleate, about 7% to about 20% polyethylene glycol, and about 1% to about 8% propylene glycol. In another aspect of this embodiment, the semi-solid formulation comprises from about 20% to about 50% by weight therapeutic compound, from about 8% to about 18% by weight of a mixture of mono, di, triglycerides and PEG fatty acid esters, 25% to about 45% by weight glyceryl monolinoleate, about 8% to about 18% polyethylene glycol, and about 2% to about 6% propylene glycol. In another aspect of this embodiment, the semi-solid formulation comprises from about 20% to about 50% by weight therapeutic compound, from about 10% to about 16% by weight of a mixture of mono-, di-, triglycerides and PEG fatty acid esters, 25% to about 45% by weight glyceryl monolinoleate, about 10% to about 16% polyethylene glycol, and about 2% to about 6% propylene glycol. In yet another aspect of this embodiment, the semi-solid formulation comprises about 20% to about 50% by weight therapeutic compound, about 11% to about 15% by weight of a mixture of mono-, di-, triglycerides and PEG fatty acid esters; About 30% to about 40% by weight glyceryl monolinoleate, about 11% to about 15% polyethylene glycol, and about 3% to about 5% propylene glycol. In yet another aspect of this embodiment, the semi-solid formulation comprises from about 25 wt% to about 44 wt% therapeutic compound, from about 12 wt% to about 14 wt% mono, di, triglyceride and PEG fatty acid ester mixture, About 32% to about 39% by weight glyceryl monolinoleate, about 12% to about 14% polyethylene glycol, and about 4% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, or PEG700.

  In another embodiment, the semi-solid formulation comprises ibuprofen, mono, di, a mixture of triglycerides and PEG fatty acid esters, glyceryl monolinoleate, polyethylene glycol, and propylene glycol. In one aspect of this embodiment, the semi-solid formulation comprises about 15% to about 55% by weight ibuprofen, about 7% to about 20% by weight, a mixture of mono, di, triglycerides and PEG fatty acid esters, about 20%. % To about 50% by weight glyceryl monolinoleate, about 7% to about 20% polyethylene glycol, and about 1% to about 8% propylene glycol. In another aspect of this embodiment, the semi-solid formulation comprises from about 20% to about 50% ibuprofen, from about 8% to about 18% by weight of a mixture of mono, di, triglycerides and PEG fatty acid esters, about 25%. % By weight to about 45% by weight glyceryl monolinoleate, about 8% to about 18% polyethylene glycol, and about 2% to about 6% propylene glycol. In another aspect of this embodiment, the semi-solid formulation is about 20% to about 50% by weight ibuprofen, about 10% to about 16% by weight, a mixture of mono-, di-, triglycerides and PEG fatty acid esters, about 25%. % By weight to about 45% by weight glyceryl monolinoleate, about 10% to about 16% polyethylene glycol, and about 2% to about 6% propylene glycol. In yet another aspect of this embodiment, the semi-solid formulation comprises from about 20% to about 50% ibuprofen, from about 11% to about 15% by weight of a mixture of mono, di, triglycerides and PEG fatty acid esters, 30% to about 40% glyceryl monolinoleate, about 11% to about 15% polyethylene glycol, and about 3% to about 5% propylene glycol. In yet another aspect of this embodiment, the semi-solid formulation comprises from about 25% to about 44% by weight ibuprofen, from about 12% to about 14% by weight, a mixture of mono-, di-, triglycerides and PEG fatty acid esters, 32% to about 39% by weight glyceryl monolinoleate, about 12% to about 14% polyethylene glycol, and about 4% propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, or PEG700.

  In another embodiment, the semi-solid formulation comprises a therapeutic compound, hard fat, partially hydrogenated fat, polyethylene glycol, and propylene glycol. In one aspect of this embodiment, the semi-solid formulation comprises from about 10% to about 35% by weight of the therapeutic compound free acid, from about 1% to about 30% by weight of the therapeutic compound salt, from about 7% to about 20% by weight hard fat, about 20% to about 50% partially hydrogenated fat, about 7% to about 20% polyethylene glycol, and about 1% to about 8% propylene glycol . In another aspect of this embodiment, the semi-solid formulation comprises from about 15% to about 30% by weight of the therapeutic compound free acid, from about 1% to about 25% by weight of the therapeutic compound salt, from about 10% to About 16 wt% hard fat, about 25 wt% to about 45 wt% partially hydrogenated fat, about 10 wt% to about 16 wt% polyethylene glycol, and about 2 wt% to about 6 wt% propylene glycol. Including. In yet another aspect of this embodiment, the semi-solid formulation comprises about 15% to about 30% by weight of the therapeutic compound free acid, about 1% to about 25% by weight of the therapeutic compound salt, about 11% by weight. To about 15 wt% hard fat, about 30 wt% to about 40 wt% partially hydrogenated fat, about 11 wt% to about 15 wt% polyethylene glycol, and about 3 wt% to about 5 wt% propylene glycol including. In yet another aspect of this embodiment, the semi-solid formulation comprises from about 20 wt% to about 24 wt% therapeutic compound free acid, from about 5 wt% to about 20 wt% therapeutic compound salt, about 12 wt%. About 14 wt.% Hard fat, about 32 wt.% To about 39 wt.% Partially hydrogenated fat, about 12 wt.% To about 14 wt.% Polyethylene glycol, and about 4 wt.% Propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, or PEG700.

  In another embodiment, the semi-solid formulation comprises a therapeutic compound, a mixture of mono, di, triglycerides and PEG fatty acid esters, glyceryl monolinoleate, polyethylene glycol, and propylene glycol. In one aspect of this embodiment, the semi-solid formulation comprises from about 10% to about 35% by weight of the therapeutic compound free acid, from about 1% to about 30% by weight of the therapeutic compound salt, from about 7% to about 20 wt% mono, di, triglyceride and PEG fatty acid ester mixture, about 20 wt% to about 50 wt% glyceryl monolinoleate, about 7 wt% to about 20 wt% polyethylene glycol, and about 1 wt% to Contains about 8% by weight propylene glycol. In another aspect of this embodiment, the semi-solid formulation comprises from about 15% to about 30% by weight of the therapeutic compound free acid, from about 1% to about 25% by weight of the therapeutic compound salt, from about 10% to About 16% by weight mono-, di-, triglyceride and PEG fatty acid ester mixture, about 25% to about 45% by weight glyceryl monolinoleate, about 10% to about 16% polyethylene glycol, and about 2% by weight Contains about 6% by weight propylene glycol. In yet another aspect of this embodiment, the semi-solid formulation comprises about 15% to about 30% by weight of the therapeutic compound free acid, about 1% to about 25% by weight of the therapeutic compound salt, about 11% by weight. About 15% by weight of a mixture of mono-, di-, triglycerides and PEG fatty acid esters, about 30% to about 40% by weight of glyceryl monolinoleate, about 11% to about 15% by weight of polyethylene glycol, and about 3% % To about 5% by weight of propylene glycol. In yet another aspect of this embodiment, the semi-solid formulation comprises from about 20 wt% to about 24 wt% therapeutic compound free acid, from about 5 wt% to about 20 wt% therapeutic compound salt, about 12 wt%. About 14% by weight of a mixture of mono, di, triglycerides and PEG fatty acid esters, about 32% to about 39% by weight of glyceryl monolinoleate, about 12% to about 14% by weight of polyethylene glycol, and about 4% % Propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, or PEG700.

  In another embodiment, the semi-solid formulation comprises ibuprofen, mono, di, a mixture of triglycerides and PEG fatty acid esters, glyceryl monolinoleate, polyethylene glycol, and propylene glycol. In one aspect of this embodiment, the semi-solid formulation comprises from about 10% to about 35% by weight ibuprofen free acid, from about 1% to about 30% by weight ibuprofen salt, from about 7% to about 20% by weight. % Mono, di, triglyceride and PEG fatty acid ester mixture, about 20% to about 50% glyceryl monolinoleate, about 7% to about 20% polyethylene glycol, and about 1% to about 8% Contains wt% propylene glycol. In another aspect of this embodiment, the semi-solid formulation comprises from about 15% to about 30% ibuprofen free acid, from about 1% to about 25% ibuprofen salt, from about 10% to about 16%. A mixture of about 25% to about 45% glyceryl monolinoleate, about 10% to about 16% polyethylene glycol, and about 2% to about Contains 6% by weight propylene glycol. In yet another aspect of this embodiment, the semi-solid formulation comprises from about 15 wt% to about 30 wt% ibuprofen free acid, from about 1 wt% to about 25 wt% ibuprofen salt, from about 11 wt% to about 30 wt%. 15 wt% mono, di, triglyceride and PEG fatty acid ester mixture, about 30 wt% to about 40 wt% glyceryl monolinoleate, about 11 wt% to about 15 wt% polyethylene glycol, and about 3 wt% to Contains about 5% by weight propylene glycol. In yet another aspect of this embodiment, the semi-solid formulation comprises from about 20% to about 24% by weight ibuprofen free acid, from about 5% to about 20% by weight ibuprofen salt, from about 12% to about 24%. 14 wt% mono, di, triglyceride and PEG fatty acid ester mixture, about 32 wt% to about 39 wt% glyceryl monolinoleate, about 12 wt% to about 14 wt% polyethylene glycol, and about 4 wt% Contains propylene glycol. In other aspects of this embodiment, the polyethylene glycol is, for example, PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, or PEG700.

  The solid or semi-solid formulations disclosed herein take advantage of the different melting points of various adjuvants such as fatty acids. Formation of a solid or semi-solid dosage form is made possible by adjusting the concentration of each fatty acid comprising the pharmaceutical composition disclosed herein. For example, linolenic acid has a melting point (Tm) of about -11 ° C, linoleic acid has a Tm of about -5 ° C, oleic acid has a Tm of about 16 ° C, and palmitic acid has a temperature of about 61-62. The Tm has a Tm of about 67-72C. Increasing the proportion of palmitic acid, stearic acid, or oleic acid increases the melting point of the entire composition, while conversely, increasing the proportion of linoleic acid and linolenic acid decreases the melting point of the composition. Thus, by controlling the type and amount of adjuvant component added, the pharmaceutical composition disclosed herein is substantially solid or semi-solid at room temperature but is ingested and reaches body temperature. Then it can be made to melt. The resulting molten composition readily forms micelles that are absorbed by the intestine, incorporated into chylomicrons, and ultimately absorbed by macrophages. The solid dosage form may be a powder, granule, tablet, capsule or suppository.

In one embodiment, the pharmaceutical compositions disclosed herein are solid at room temperature. In some aspects of this embodiment, the pharmaceutical compositions disclosed herein can have, for example, a temperature of about 35 ° C. or lower, a temperature of about 33 ° C. or lower, a temperature of about 31 ° C. or lower, a temperature of about 29 ° C. or lower. Temperature, temperature below about 27 ° C, temperature below about 25 ° C, temperature below about 23 ° C, temperature below about 21 ° C, temperature below about 19 ° C, temperature below about 17 ° C, temperature below about 15 ° C Formulated to be solid at a temperature of about 12 ° C or lower, a temperature of about 10 ° C or lower, a temperature of about 8 ° C or lower, a temperature of about 6 ° C or lower, a temperature of about 4 ° C or lower, or a temperature of about 0 ° C or lower it can.
In another aspect of this embodiment, the disclosed pharmaceutical composition comprises, for example, 5 ° C or higher, 10 ° C or higher, 15 ° C or higher, 22 ° C or higher, 23 ° C or higher, 24 ° C or higher, 25 ° C or higher, 26 ° C or higher. 27 ° C or higher, 28 ° C or higher, 29 ° C or higher, 30 ° C or higher, 31 ° C or higher, 32 ° C or higher, 33 ° C or higher, 34 ° C or higher, or 35 ° C or higher. In other aspects of this embodiment, the disclosed pharmaceutical compositions can have, for example, about 5 ° C to about 24 ° C, about 10 ° C to about 24 ° C, about 22 ° C to about 24 ° C, about 23 ° C to about 25 ° C. About 24 ° C to about 26 ° C, about 25 ° C to about 27 ° C, about 26 ° C to about 28 ° C, about 27 ° C to about 29 ° C, about 28 ° C to about 30 ° C, about 29 ° C to about 31 ° C, about It has a melting point in the range of 30 ° C to about 32 ° C, about 31 ° C to about 33 ° C, about 32 ° C to about 34 ° C, or about 33 ° C to about 35 ° C. In other aspects of this embodiment, the disclosed pharmaceutical composition can be, for example, from about 22 ° C to about 26 ° C, from about 24 ° C to about 28 ° C, from about 26 ° C to about 30 ° C, from about 28 ° C to about 32 ° C. Or having a melting point in the range of about 30 ° C to about 34 ° C.

  Some aspects herein disclose, in part, a method of treating an individual with severe pain. In one embodiment, the method comprises administering a pharmaceutical composition disclosed herein to an individual in need thereof, wherein the administration reduces symptoms associated with severe pain, thereby treating the individual. To do.

  Some aspects herein disclose, in part, methods for treating an individual suffering from a severe pain condition. As used herein, the term “treating” means reducing or eliminating clinical symptoms of severe pain in an individual, or delaying or preventing the onset of clinical symptoms of severe pain in an individual. . For example, the term “treat” refers to a symptom of a condition characterized by a severe pain state, eg, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, It may mean reducing by at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 95%, or at least 100%. The actual symptoms associated with the severe pain condition are well known and can be determined by one of ordinary skill in the art taking into account various factors, including the site of the severe pain condition, the cause of the severe pain condition, the severe pain condition And / or tissues or organs affected by severe pain conditions. Those skilled in the art will understand the specific symptoms or indicators associated with a particular type of severe pain condition and understand how to determine whether an individual can be the subject of the treatment disclosed herein. Let's go.

  Pain can be measured using one or more pain thresholds. Pain threshold is measured by gradually increasing the intensity of a stimulus such as current or heat applied to the body. The pain sensation threshold is a time point at which an adverse effect starts to occur, and the pain sensation threshold value is a time point when an individual takes action to stop pain.

  Pain can be measured using one or more pain scale questionnaires. Self-reported questionnaires by individuals suffering from severe pain are the most reliable measure, but reports from health professionals can be used as well. Numerous pain measurement scales have been developed, including Alder Hey Triage Pain Score, Behavioral Pain Scale (BPS), Brief Pain Inventory (BPI), Checklist of NonverCalPI Critical Patient Care Observation (Critical-Care Pain Observing Tool (CPOT)), COMFORT scale, Dallas Pain Questionnaire (Delas Pain Questionnaire), Descriptor Differential Scale (DDS), Dispense Dispense Sensitivity (Dolori eter Pain Index (DPI)), revised version-Face Scale (Faces Pain Scale-Revised (FPS-R)), Face Legs Activity Cry Inconductive scale, Lexne algofuncion MPQ)), Multi-dimensional Pain Behavior Evaluation Questionnaire List (Multidimensional Pain Inventory (MPI)), Neck Pain and Disability Scale-NPAD, Numerical 11 point box (BS-11), Quantification Scale (Numerical Numeric Rating) RS-11)), Pediatric Pain Questionnaire (PPQ), Rolland-Morris Back Pain Questionnaire, Visual Analog Scale (VAS), and Won Baker's Face Scale (WongFAcS) However, it is not limited to these. As an example, the NRS-11 scale is an 11-point scale for patient self-reporting, ranking the pain received from 0-10, 0: no pain at all, 1-3: mildly hindering daily living activities No. 4-6: Moderate pain that greatly interferes with daily activities, and 7-10: Extreme pain that completely interferes with daily activities. Quality can be determined by having an individual complete a McGill pain questionnaire that shows which words best describe the person's pain.

  The severe pain symptoms include cold sensation, numbness, pruritus, sensory abnormalities, electric shock sensation, burning sensation, cold hot sensation, sensory failure, allodynia, hyperalgesia, hyperalgesia, somatic sensation, and visceral sensation. Although it is mentioned, it is not limited to these. The actual symptoms associated with the severe pain condition are well known and can be determined by one skilled in the art taking into account various factors, including the site of the severe pain, the cause of the severe pain, and the severity of the severe pain , Affected tissues or organs, and related disorders.

  The pharmaceutical compositions disclosed herein are useful for the treatment of severe pain. Pain is any unpleasant sensation and / or emotion associated with or expressed in connection with actual or potential tissue damage. Pain develops at various severity levels and is usually the result of injury, disease, or emotional disorder, but the underlying cause may or may not be obvious to the health care provider. Severe pain is pain due to a severe pain response that greatly hinders or prevents an individual from performing one or more activities of daily living. Daily living activities (ADL) are activities such as eating, bathing, changing clothes, dressing, work, housework, and leisure that individuals perform daily. ADLs can be categorized based on whether the operation is basic, some means, or occupational. Basic ADL (BADL) includes, for example, personal hygiene and conditioning, clothing and undressing, self-eating, functional mobility (going into and out of beds and wheelchairs, getting on and off toilets, etc.), bowel and bladder management, and , Including self-care tasks such as movement (walking with or without assistive devices (walker, cane, or crutch) or using a wheelchair). Instrumental ADL (IADL) is not necessary for basic functional operation, but is an operation for living independently in a community. IADL includes, for example, performing household chores, taking medications as prescribed, managing money, shopping for groceries or clothing, using communications equipment, using technology, using transport within the community, etc. Can be mentioned. Work ADL (OADL) is usually an optional position and can be delegated to others. OADL includes, for example, care for others (including caregiver selection and supervision), pet care, childcare, communication equipment use, intra-community transfers, financial management and maintenance, meal preparation and cleanup, and safety Procedures and emergency response.

  As used herein, the term “severe pain” includes acute, subacute, chronic nociceptive pathological pain, or psychological distress. In some aspects of this embodiment, the severe pain is not inflammatory pain or the primary origin is not pain due to an inflammatory response.

  The severe pain state can be classified into, for example, acute pain, subacute pain, and chronic pain according to the period and pattern of occurrence. Acute pain is usually a transient, sudden onset organic pain state, only during the period until harmful stimuli are removed and / or the underlying injury or condition is healed continue. Chronic pain is organic pain that persists and prolongs beyond the expected period of healing, and may develop continuously or moderately. Subacute pain is an organic pain state meaning pain located between acute pain and chronic pain. Although somewhat arbitrary, the distinction between acute, subacute, and chronic pain can be determined based on time since onset. Accordingly, acute pain is pain that lasts less than one month, subacute pain is pain that lasts from one month to six months, and chronic pain is pain that lasts six months or more.

  The severe pain state can be classified into 1) nociceptive pain; 2) pathological pain; and 3) inflammatory pain.

  In one embodiment, the severe pain condition comprises nociceptive pain. Nociceptive pain is a severe pain state when an organic pain state is caused by harmful invasion or damage to peripheral nerve fibers (nociceptors) that respond only to stimuli that are close to or beyond harmful intensity, Usually expressed as tingling pain. This type of pain is associated with damage to non-neural tissues such as skin, muscle, viscera, joints, tendons, or bones and is expressed by a normally functioning somatosensory nervous system. Nociceptive pain can be classified based on the type of noxious stimuli such as, for example, thermal pain, mechanical pain, and chemical pain, or based on the site of pain, such as somatic or visceral pain.

  In one embodiment, the severe pain condition includes somatic pain. Somatic pain is nociceptive pain that originates from ligaments, tendons, bones, blood vessels, and also from the nerve itself. Somatic pain is detected by somatic nociceptors. The lack of pain receptors in these areas creates dull, poorly localized pain that lasts longer than cutaneous pain. Non-limiting examples of somatic pain include the following: 1) Excessive muscle tone may be caused by sprains or muscular contusions, for example. 2) Repetitive movement disorders may be caused by overuse of hands, wrists, elbows, shoulders, neck, back, hip joints, feet, legs, or ankle joints. 3) Muscle disorders that cause somatic pain include polymyositis, dermatomyositis, lupus, fibromyalgia, rheumatic polymyalgia, and rhabdomyolysis, and 4) for example, overuse, excessive Examples include muscle pain including elongation, viral infection, metabolic myopathy, nutritional deficiency, or muscle pain caused by chronic fatigue syndrome. 5) For example, abscess, trichinosis, influenza, Lyme disease, malaria, Rocky Mountain spotted fever, avian influenza, cold, community-acquired pneumonia, meningitis, monkey fistula, severe acute respiratory syndrome, toxic shock syndrome Infections such as trichinellosis, typhoid fever, and upper respiratory tract infection, and 6) for example cocaine, cholesterol lowering statins (such as atorvastatin, simvastatin, and lovastatin), and ACE inhibitors for lowering blood pressure (enalapril and Drugs such as captopril also cause somatic pain. Somatic pain can be classified as superficial somatic pain or deep somatic pain. Superficial somatic pain is initiated by the activation of nociceptors in the skin or other superficial tissues and is sharp, well-defined and clearly localized. Examples of injuries that produce superficial somatic pain include mild wounds and mild (one degree) burns. Deep somatic pain is initiated by the stimulation of nociceptors in the ligaments, tendons, bones, blood vessels, fascia and muscles, and is dull, throbbing, unlocalized pain. Examples include sprains and fractures.

  In one embodiment, the severe pain condition includes visceral pain. Visceral pain is nociceptive pain initiated by stimulation of nociceptors in the body's organs and internal cavities, typically due to stretching or ischemia. Visceral pain is diffuse, poorly localized pain that can be expressed as tingling pain, discomfort, dull pain, squeezed pain, and / or deep pain, with nausea and vomiting Sometimes. Visceral pain is extremely difficult to localize, and some damage to visceral tissue may indicate “related” pain, in which case the sensation is confined to an area completely independent of the site of injury. The more deficiency of nociceptors in these areas usually produces tingling, longer lasting pain than somatic pain. Non-limiting examples of somatic pain include 1) eg irritable bowel syndrome and chronic functional abdominal pain (CFAP), functional constipation and functional dyspepsia, non-cardiac chest pain (NCCP), and chronic abdominal pain Functional visceral pain; 2) inflammatory bowel diseases such as gastritis, eg Crohn's disease, ulcerative colitis, microscopic colitis, diverticulitis and gastroenteritis; intestinal ischemia, cholecystitis, appendicitis, Chronic gastroenteritis including gastroesophageal reflux disease, ulcers, nephrolithiasis, urinary tract infections, pancreatitis, and hernias; 3) autoimmune pain including, for example, sarcoidosis and vasculitis; 4) e.g. Organic visceral pain, including pain arising from inflammatory or degenerative lesions, or pain generated by tumors that violate sensory innervation; 5) including, for example, pain associated with chemotherapy or pain associated with radiation therapy Treatment-induced visceral pain

  In one embodiment, the severe pain condition comprises pathological pain. Injury pathological pain is a severe pain state, and an organic pain state is caused by disease or damage to any part of the nervous system, or by abnormal functioning of the nervous system. This type of pain is not a stimulation of pain receptors but is associated with damage to nerve tissue and abnormally functioning somatosensory nervous systems. Non-limiting examples of pathologic pain include neuropathic pain and dysfunctional pain.

  In one embodiment, the severe pain condition comprises neuropathic pain. Injured neuropathic pain is pathological pain, an organic pain state is caused by damage or disease of the somatosensory nervous system, resulting in abnormal sensory excitement from the peripheral nervous system, the central nervous system, or both. Neuropathic pain may be accompanied by spontaneous or induced pain and may include a continuous and / or accidental (seizure) pain component. Neuropathic pain includes, for example, allodynia (a pain response to a stimulus that is not usually painful), hyperalgesia (a worsened response to a painful stimulus that usually produces only mild discomfort), and hyperalgesia ( It may accompany sensory dysfunction (abnormal pain response) such as short-term discomfort becomes long-term severe pain. Pain sensations are expressed as cold sensation, numbness, pruritus, sensory abnormalities (stinging or “numbness”), electric shock, and burning or cold hot pain. Non-limiting examples of neuropathic pain include central neuropathic pain, peripheral neuropathic pain, and afferent blockage pain.

  In one embodiment, the severe pain condition comprises central neuropathic pain. Injuries or diseases that affect the nerves of the central nervous system are called central neuropathic pain. In general, the injury or disease occurs as a cerebral lesion, which occurs primarily in the thalamus region, but may include the hypothalamus and the intrathalamic region. In general, the onset of central neuropathic pain usually occurs late after the occurrence of an initial phenomenon that causes damage to the central nervous system, and the occurrence of pain occurs during the recovery phase from nervous system injury. May happen. Central neuropathic pain includes, for example, thalamic infarction, brainstem infarction, or subarachnoid hemorrhage; cerebral venous thrombosis, brain tumor compressing the thalamus or brainstem; brain abscess compressing the thalamus or brainstem; traumatic brain Injury, pain after brain or spine surgery; complications after brain surgery, such as thalamic destruction for movement disorders, multiple sclerosis, and Parkinson's disease; spinal cord injury; Complications after spinal surgery; may appear during post-stroke conditions, including ischemic lesions such as anterior spinal artery syndrome and Wallenberg syndrome, syringomyelia, radiation myelopathy, HIV myelopathy.

  In one embodiment, the severe pain condition comprises peripheral neuropathic pain. Injuries or diseases that affect the sensory, motor, and / or autonomic nerves of the peripheral nervous system are called peripheral neuropathic pain. Peripheral neuropathic pain occurs when the peripheral nerves fail to communicate to and from the brain and spinal cord, resulting in pain, loss of sensation, or a state of muscle loss. In some cases, failure of the nerves that control blood vessels, intestines, and other organs results in abnormal blood pressure, dyspepsia, and loss of basic biological processes. Symptoms also depend on whether the condition affects the whole body or only one nerve. Risk factors for neuropathy include diabetes, heavy drinking, exposure to certain chemicals and drugs, and long-term pressure on the nerve. Some people have a genetic predisposition to peripheral neuropathy. The four major types of peripheral neuropathic pain are mononeuropathy, multiple mononeuropathy, polyneuropathy, and autonomic neuropathy.

  In one embodiment, the severe pain condition comprises a mononeuropathy. A mononeuropathy is a peripheral neuropathy with impaired function or pathological changes that affect a single nerve or group of nerves. Mononeuropathy is most often caused by damage to local areas resulting from injury or trauma, but in some cases, systemic damage can cause single nerve damage. Common causes are direct trauma, long-term pressure on the nerve, and nerve compression due to swelling or damage to nearby body structures. Injury includes destruction of the myelin sheath (cover) of nerves or nerve cells (axons). This damage delays or prevents action potential conduction through the nerve. Mononeuropathy can involve any part of the body. Mononeuropathic pain includes, for example, sciatic nerve dysfunction, common peroneal nerve dysfunction, peroneal nerve dysfunction, ulnar nerve dysfunction, single brain neuropathy VI, single brain neuropathy VII, single brain neuropathy III (compression type), single Cranial neuropathy III (diabetic type), axillary nerve dysfunction, carpal tunnel syndrome, femoral nerve dysfunction, tibial nerve dysfunction, bell palsy, thoracic outlet syndrome, carpal tunnel syndrome or other local constrictive neuropathy, and Appears in association with sixth (abduction) cranial nerve palsy.

  In one embodiment, the severe pain condition includes multiple mononeuropathy. Multiple mononeuropathy is a peripheral neuropathy with impaired function or pathological changes that affect several non-adjacent nerves sequentially or simultaneously in an asymmetric fashion. Neuropathic pain due to multiple mononeuropathy can progress over days to years and typically indicates a loss of acute or subacute sensory and motor function of individual nerves. The accompanying pattern is asymmetric, but as the disease progresses injuries, it becomes more dense and symmetric, making it difficult to distinguish from multiple neuropathy. Multiple mononeuropathy also causes deep, painful pain, characterized by tingling pain, which worsens at night and often appears in the lower back, hips, or legs. Multiple mononeuropathy can also be characterized as an acute unilateral severe lower limb pain followed by anterior muscle weakness and disappearance of the patella reflex. Multiple mononeuropathic pain is associated with, for example, diabetes mellitus and infections such as leprosy, Lyme disease, HIV, and addiction.

  In one embodiment, the severe pain condition includes polyneuropathy. Polyneuropathy is a peripheral neuropathy with reduced function or pathological changes that affect symmetrically multiple nerves throughout the body. Polyneuropathy can appear suddenly without warning, or it can be chronic and gradually progress over time. Many polyneuropathy involves motor and sensation, and some are also accompanied by dysfunction of the autonomic nervous system. These disorders are often symmetric and usually result from a variety of systematic illnesses and disease processes, all of which affect the peripheral nervous system. Often, polyneuropathy affects the feet and hands, causing weakness, loss of sensation, numbness and burning or burning pain. Polyneuropathy can be categorized in a variety of ways, such as the rate of progression, or by the part of the body involved. Also, the type of polyneuropathy is distinguished by the part of the nerve cell that is mainly affected, such as an axon, myelin sheath, or cell body.

  In one embodiment, the severe pain condition comprises a distal axonal disorder. Distal axonal disorder, or “retrograde death neuropathy”, is the result of some metabolic or toxic neuropathy. They may also be caused by metabolic diseases such as diabetes and renal failure, failure syndromes such as nutritional disorders and alcoholism, or the effects of drugs such as toxins or chemotherapy. The most common cause of distal axonopathy is diabetes, and the most common distal axonopathy is diabetic neuropathy. They can be divided into types containing large diameter fibers, small diameter fibers, or both, depending on the type of axon affected. Usually, the most distal part of the axon is altered first, and axonal atrophy progresses slowly towards the neuronal cell body. When the cause is removed, regeneration is possible, but the prognosis depends on the duration and strength of the stimulus. Persons with distal axon disorders usually exhibit sensorimotor disorders with a symmetrical “glove sock” distribution. In the affected area, deep tendon reflexes and autonomic nervous system function are lost or diminished.

  In one embodiment, the severe pain condition comprises myelinopathy. Myelinopathy or “demyelinating polyneuropathy” results from the disappearance of myelin (or Schwann cells that make and contain myelin). This demyelination leaves the axons intact but delays or completely blocks action potential conduction through the nerve cell axons. The most common cause is acute inflammatory demyelinating polyneuritis (AIDP, the most common form of Guillain-Barre syndrome), while other causes include chronic inflammatory demyelinating polyneuropathy (CIDP) Hereditary metabolic disorders (eg leukodystrophy), and toxins.

  In one embodiment, the severe pain condition comprises a neuronal cell disorder. Nerve cell damage is the result of destruction of peripheral nerves. They are caused by motor neuron disease, sensory neuron disorders (eg shingles), toxins or autonomic neuropathy. Neurotoxins such as the chemotherapy drug vincristine may cause neuronal cell damage. A person with neuropathy may develop various symptoms, depending on the cause, the way the nerve cells are affected, and the type of nerve cells most affected.

  There are a number of conditions that cause polyneuropathy. Peripheral neuropathic pain includes neurological disorders associated with systemic diseases such as diabetic neuropathy, neurological disorders associated with metabolic disorders such as alcoholic neuropathy and burning leg syndrome, shingles and HIV Neurological disorders associated with various viral infections, neurological disorders associated with nutritional disorders, neurological disorders associated with toxins, neurological disorders associated with tumor compression, neurological disorders associated with the remote onset of malignant lesions, drugs such as chemotherapy Neurological disorders associated with radiation, neurological disorders associated with radiation, neurological disorders associated with immune-mediated diseases, and neurological disorders associated with physical trauma to the nerve trunk include, but are not limited to. Multiple neuropathic pain includes post-polio syndrome, post-mastectomy syndrome, diabetic neuropathy, alcoholic neuropathy, amyloid, toxin, AIDS, hypothyroidism, uremia, vitamin deficiency, chemotherapy-induced pain This includes, but is not limited to, 2 ′, 3′-dideoxycytidine (ddC) treatment, Guillain-Barre syndrome or Fabry disease.

  In one embodiment, the severe pain condition includes autonomic neuropathy. Autonomic neuropathy is a peripheral neuropathy with reduced function or pathological changes that involuntarily affect the nonsensory nervous system (ie, the autonomic nervous system). Autonomic neuropathy is a form of polyneuropathy that primarily affects internal organs such as the bladder, muscles, cardiovascular system, gastrointestinal tract, and genitals.

  Peripheral neuropathic pain is a systemic disease, metabolic disorder, nutritional disorder, drug-induced disorder, trauma, trauma and intrusion syndrome, postoperative pain surgery, postoperative complications, HIV sensory neuropathy, demyelinating multiple roots Neuropathy, postherpetic neuralgia, nerve root extraction, cranial neuralgia like trigeminal neuralgia, neuropathic cancer pain; peripheral nerve, plexus, and nerve root compression; paraneoplastic peripheral neuropathy, ganglionopathy ( ganglionopathy); complications of cancer therapy such as chemotherapy, irradiation, and surgery; and complex regional pain syndromes such as type 1 and type 2.

  In one embodiment, the severe pain condition includes neuralgia. Neuralgia is peripheral neuropathic pain that radiates along the nerve tract of one or more specific nerves, usually without any demonstrable pathological changes in the neural structure. Affected nerves are involved in sensing contact, temperature and pressure. A simple stimulus (even a gentle breeze sensation) such as a meal, conversation, face wash, or some light touch or perception may trigger an attack. Attacks may occur in groups or may occur as a single attack. In general, neuralgia develops unbearable pain for a short time, usually less than 2 minutes. However, in the case of atypical neuralgia, the pain may also appear as a symptom from throbbing pain to severe pain and may last for a long time. Symptoms appear everywhere, but usually on or near the surface of the body, each with a sharp tingling or constant burning pain that occurs at the same site; pain along a specific nerve pathway; pain affected Manifested as muscular weakness due to impaired body part function or concomitant motor nerve damage; increased sensitivity of skin or numbness of affected skin area. All contact or compression is also expressed as pain. Movement can also be painful. Neuralgia includes trigeminal neuralgia, glossopharyngeal neuralgia, postherpetic neuralgia (eg, due to herpes virus, syphilis and Lyme disease), carpal tunnel syndrome, abnormal sensory femoral pain, sciatica and atypical facial pain. Although it is mentioned, it is not limited to these.

  In one embodiment, the severe pain condition comprises complex regional pain syndrome (CRPS). CRPS is a neurological disorder resulting from sympathetic dependent pain. Although not yet well understood, the mechanism probably involves abnormal sympathetic somatic neurojunction (ephaps), local inflammatory changes, and spinal cord changes. There are two types of CRPS. CRPS1 (reflex sympathetic dystrophy) is a chronic neuropathy that most commonly occurs in the arms or legs after mild or severe injury. CRPS1 is associated with severe pain; nail, bone, and skin changes; and increased sensitivity to contact with the affected limb. CRPS2 (burning pain) is caused by specific damage to the nerves, resulting in persistent burning pain syndrome, allodynia, and hyperalgesia after traumatic nerve lesions, vasomotor and pro-perspiratory dysfunction and delayed It often accompanies the nutritional changes that appear.

  In one embodiment, the severe pain condition includes associated pain. Related pain results from pain localized in a region away from the site of pain stimulation. Often, associated pain occurs when nerves are compressed or damaged at or near the nerve source. Under this circumstance, the sensation of pain is usually felt in the area where the nerve acts, even if the injury is elsewhere. A common example occurs in disc herniation, where the nerve root arising from the spinal cord is compressed by the adjacent disc material. Pain arises from the damaged disc itself, but pain is also felt in the area (eg, thigh, knee, or foot) affected by the compressed nerve. In the absence of permanent nerve damage, the associated pain can be relieved by reducing pressure on the nerve roots. Myocardial ischemia (reduction of blood flow to a portion of myocardial tissue) is probably the best known example of related pain. The sensation may occur as a limited sensation in the upper chest or as pain in the left shoulder, arm, or hand.

  In one embodiment, the severe pain condition includes afferent block pain. Injuries or diseases that affect peripheral or central afferent nerve activity are called afferent block pain. Afferent blockade pain results from partial or complete disappearance of sensory input from a part of the body and may be caused by blockade from peripheral sensory fibers or nerves from the central nervous system. The underlying mechanism of this type is not known, but may involve a low activation threshold and central nerve sensitization due to the expansion of the receptive field. For afferent block pain syndrome, phantom pain, brain injury, spinal cord injury, lumbar radiculopathy, pain after stroke, paraplegia, brachial plexus detachment, or other types of lesions of the peripheral nerve, central nervous system Examples of the disease state of the system include, but are not limited to.

  In one embodiment, the severe pain condition comprises dysfunctional pain. Dysfunctional pain is pathological pain, in which an organic pain state is caused by abnormal functioning of the somatosensory nervous system, but not initiated by any identifiable lesion of the nervous system. Similar to neuropathic pain, dysfunctional pain is generally expressed as burning pain, cold sensation, electric shock, “numbness and tingling” sensation, numbness and pruritus.

  In one embodiment, the severe pain condition includes a headache. The severe pain state may be a headache (medically known as a cephalgia). Headache is a state of pain from mild to severe pain in the head, and sometimes neck or upper back pain is also interpreted as a headache. A headache may be an indication of the underlying local or systemic disease, or may itself be a disorder. Headaches include muscular / myogenic headache, vascular headache, traction headache, inflammatory headache, chronic sinusitis headache, hormonal headache, rebound headache, organic headache, and epilepsy headache It is not limited to these.

  In one embodiment, the severe pain condition includes a muscular / myogenic headache. A muscular / myogenic headache appears to involve tightening or tensioning of the facial and neck muscles and may spread radially to the frontal region. Tension-type headache is the most common type of myogenic headache. Tension headache is a condition associated with muscle tightening in these areas, usually with pain or discomfort in the head, scalp, or neck. A tension-type headache results from contraction of the neck and scalp muscles. One cause of this muscle contraction is a response to stress, depression, or anxiety. Any movement that keeps the head in one position for a long time without moving can cause headaches. Such actions include typing or using a computer, manual work, and using a microscope. Sleeping in a cool room or sleeping with the neck in an abnormal position can also trigger this type of headache. Tension headaches include, but are not limited to, temporary tension headaches and chronic tension headaches.

  In one embodiment, the severe pain condition comprises a vascular headache. The most common type of vascular headache is migraine. Other types of vascular headaches include cluster headaches that cause repeated onset of severe pain, and headaches arise from high blood pressure.

  In one embodiment, the severe pain condition includes migraine. Migraine is a heterogeneous disorder usually accompanied by recurrent headaches. Migraine is different from other headaches because it occurs with other symptoms such as nausea, vomiting, or sensitivity to light. For most people, pulsatile pain is felt only on one side of the head. Clinical features such as predictive symptoms, presence of prodromal symptoms, or accompanying symptoms such as dizziness may be seen in patient subgroups of different underlying pathophysiological and genetic mechanisms. Migraine includes migraine without aura (ordinary migraine), migraine with aura (classical migraine), menstrual migraine, migraine equivalent (no-headache headache), complex migraine, Examples include, but are not limited to, abdominal migraine, and combined tension / migraine.

  In one embodiment, the severe pain condition includes cluster headache. Cluster headache affects one side of the head (unilateral) and may accompany eye tears and nasal congestion. They occur in groups, occur daily at the same time for several weeks, and then remit.

  In one embodiment, the severe pain condition includes sinusitis headache. Sinusitis is a bacterial, fungal, sinus viral, allergic or autoimmune inflammation. Chronic sinusitis is one of the most common complications of the common cold. Symptoms include nasal congestion, facial pain, headache, fever, general malaise, a dense green or yellow runny nose, and a feeling of worsening swelling of the face when bent forward. In a few cases, chronic maxillary sinusitis may be caused by the spread of bacteria from dental infections. Chronic proliferative eosinophilic sinusitis is a non-infectious form of chronic sinusitis.

  In one embodiment, the severe pain condition includes a traction headache. Traction and inflammatory headaches are symptoms of disorders that are separate from disorders that usually range from stroke to sinus infection.

  In one embodiment, the severe pain condition includes a rebound headache. Recoil headaches, also known as drug abuse headaches, occur when drugs are taken too frequently to relieve headaches. Recoil headaches often occur every day and can cause intense pain.

  In one embodiment, the severe pain condition includes epilepsy headache. Epilepsy headache is associated with seizure activity.

  In one embodiment, the severe pain condition includes psychogenic pain. Psychogenic pain, also called mental distress or somatic pain, is pain caused, increased or prolonged by mental, emotional, or behavioral factors. Headaches, back pain, and stomach pain are sometimes diagnosed as psychogenic. Patients are often accused. This is because healthcare professionals and the general public tend to think that pain from psychological causes is not “real”. However, specialists do not believe it is less realistic or less harmful than pain from any other cause. Individuals affected by long-term pain often show psychological disabilities.

  In one embodiment, the severe pain condition comprises inflammatory pain. Inflammatory pain is a severe pain state in which an organic pain state is caused by the release of a mediator at the site of tissue inflammation, which activates the nociceptive pain pathway and increases sensitivity. This type of pain is associated with some tissue damage caused by a chronic inflammatory response. Inflammatory pain may be associated with joint diseases, autoimmune diseases, connective tissue disorders, injuries, infections, and neuritis.

  In one embodiment, the severe pain condition does not include inflammatory pain.

  In one embodiment, the severe pain condition is not caused by an inflammatory response.

  The pharmaceutical compositions disclosed herein are administered to an individual. The individual is usually a human. In general, all individuals who are candidates for conventional severe pain treatment are candidates for the severe pain treatment disclosed herein. Preoperative assessments typically include routine medical history and physical examination, in addition to careful informed consent that discloses all relevant risks and benefits of the procedure.

  The pharmaceutical compositions disclosed herein can include a therapeutically effective amount of a therapeutic compound. As used herein, the term “effective amount” refers to “therapeutically effective amount”, “effective dose”, or “therapeutically effective effect”. As used in connection with the treatment of severe pain conditions means the minimum dose necessary to achieve the desired therapeutic effect of the therapeutic compound disclosed herein and is associated with the severe pain condition Contains a dose sufficient to reduce symptoms. The effectiveness of the therapeutic compounds disclosed herein in treating severe pain conditions is to observe improvement in an individual based on one or more clinical symptoms and / or physiological indicators associated with the condition. Can be determined. Improvements in severe pain conditions can also be shown by reducing the need for combination therapy.

  A suitable effective amount of a therapeutic compound disclosed herein to be administered to an individual for a particular severe pain condition is the type of pain condition, the site of the pain condition, the cause of the pain condition, the severity of the pain condition, the desired relief Degree, desired duration of relief, specific therapeutic compound used, elimination rate of the therapeutic compound used, pharmacodynamics of the therapeutic compound used, the nature of the other compounds in the composition, specific formulation, specific route of administration Specific characteristics, patient medical history and various factors such as, for example, age, weight, overall health, or any combination thereof, which can be determined by those of ordinary skill in the art. Not. Furthermore, where repeated administrations of the therapeutic compound are to be made, the effective amount of the therapeutic compound will depend on factors such as, but not limited to, the frequency of administration, the half-life of the therapeutic compound, or any combination thereof. It is understood by one of ordinary skill in the art that an effective amount of a therapeutic compound disclosed herein can be estimated from in vitro assays or in vivo administration studies using animal models prior to administration to humans.

  In some aspects of this embodiment, the therapeutically effective amount of a therapeutic compound disclosed herein provides a symptom associated with the severe pain condition, eg, at least 10%, at least 15%, at least 20%, at least 25%. At least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least Reduce by 90%, at least 95%, or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a therapeutic compound disclosed herein provides a symptom associated with the severe pain condition, eg, up to 10%, up to 15%, up to 20%, up to 25%, max 30%, max 35%, max 40%, max 45%, max 50%, max 55%, max 60%, max 65%, max 70%, max 75%, up to 80%, up to 85%, up to 90%, up to 95%, or up to 100%. In yet another aspect of this embodiment, a therapeutically effective amount of a therapeutic compound disclosed herein provides a symptom associated with the severe pain condition, eg, about 10% to about 100%, about 10% to about 90%. About 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% To about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

  In yet another aspect of this embodiment, the therapeutically effective amount of a therapeutic compound disclosed herein typically ranges from about 0.001 mg / kg / day to about 100 mg / kg / day. In some aspects of this embodiment, the effective amount of a therapeutic compound disclosed herein is, for example, at least 0.001 mg / kg / day, at least 0.01 mg / kg / day, at least 0.1 mg / kg. / Day, at least 1.0 mg / kg / day, at least 5.0 mg / kg / day, at least 10 mg / kg / day, at least 15 mg / kg / day, at least 20 mg / kg / day, at least 25 mg / kg / day, at least It may be 30 mg / kg / day, at least 35 mg / kg / day, at least 40 mg / kg / day, at least 45 mg / kg / day, or at least 50 mg / kg / day. In other aspects of this embodiment, the effective amount of a therapeutic compound disclosed herein is, for example, from about 0.001 mg / kg / day to about 10 mg / kg / day, from about 0.001 mg / kg / day to About 15 mg / kg / day, about 0.001 mg / kg / day to about 20 mg / kg / day, about 0.001 mg / kg / day to about 25 mg / kg / day, about 0.001 mg / kg / day to about 30 mg / Kg / day, about 0.001 mg / kg / day to about 35 mg / kg / day, about 0.001 mg / kg / day to about 40 mg / kg / day, about 0.001 mg / kg / day to about 45 mg / kg / Day, from about 0.001 mg / kg / day to about 50 mg / kg / day, from about 0.001 mg / kg / day to about 75 mg / kg / day, or from about 0.001 mg / kg / day to about 100 mg / kg / day It may be a range of days. In yet another aspect of this embodiment, the effective amount of a therapeutic compound disclosed herein is, for example, from about 0.01 mg / kg / day to about 10 mg / kg / day, about 0.01 mg / kg / day. To about 15 mg / kg / day, about 0.01 mg / kg / day to about 20 mg / kg / day, about 0.01 mg / kg / day to about 25 mg / kg / day, about 0.01 mg / kg / day to about 30 mg / kg / day, about 0.01 mg / kg / day to about 35 mg / kg / day, about 0.01 mg / kg / day to about 40 mg / kg / day, about 0.01 mg / kg / day to about 45 mg / day kg / day, about 0.01 mg / kg / day to about 50 mg / kg / day, about 0.01 mg / kg / day to about 75 mg / kg / day, or about 0.01 mg / kg / day to about 100 mg / kg / Day range. In yet another aspect of this embodiment, an effective amount of a therapeutic compound disclosed herein is, for example, from about 0.1 mg / kg / day to about 10 mg / kg / day, about 0.1 mg / kg / day. About 15 mg / kg / day, about 0.1 mg / kg / day to about 20 mg / kg / day, about 0.1 mg / kg / day to about 25 mg / kg / day, about 0.1 mg / kg / day to about 30 mg / kg / day, about 0.1 mg / kg / day to about 35 mg / kg / day, about 0.1 mg / kg / day to about 40 mg / kg / day, about 0.1 mg / kg / day to about 45 mg / day kg / day, about 0.1 mg / kg / day to about 50 mg / kg / day, about 0.1 mg / kg / day to about 75 mg / kg / day, or about 0.1 mg / kg / day to about 100 mg / kg / Day range.

  In other aspects of this embodiment, the effective amount of a therapeutic compound disclosed herein is, for example, from about 1 mg / kg / day to about 10 mg / kg / day, from about 1 mg / kg / day to about 15 mg / kg. / Day, about 1 mg / kg / day to about 20 mg / kg / day, about 1 mg / kg / day to about 25 mg / kg / day, about 1 mg / kg / day to about 30 mg / kg / day, about 1 mg / kg / day Day to about 35 mg / kg / day, about 1 mg / kg / day to about 40 mg / kg / day, about 1 mg / kg / day to about 45 mg / kg / day, about 1 mg / kg / day to about 50 mg / kg / day , About 1 mg / kg / day to about 75 mg / kg / day, or about 1 mg / kg / day to about 100 mg / kg / day. In yet another aspect of this embodiment, an effective amount of a therapeutic compound disclosed herein is, for example, from about 5 mg / kg / day to about 10 mg / kg / day, from about 5 mg / kg / day to about 15 mg / day. kg / day, about 5 mg / kg / day to about 20 mg / kg / day, about 5 mg / kg / day to about 25 mg / kg / day, about 5 mg / kg / day to about 30 mg / kg / day, about 5 mg / kg / Day to about 35 mg / kg / day, about 5 mg / kg / day to about 40 mg / kg / day, about 5 mg / kg / day to about 45 mg / kg / day, about 5 mg / kg / day to about 50 mg / kg / day It may range from about 5 mg / kg / day to about 75 mg / kg / day, or from about 5 mg / kg / day to about 100 mg / kg / day.

  The dose may be a single dose or a cumulative dose (continuous dosing) and can be readily determined by one skilled in the art. For example, treatment of a severe condition can include a single administration of an effective amount of the pharmaceutical composition disclosed herein. Alternatively, for the treatment of severe pain conditions, for example, an effective amount administered over a range of periods such as once a day, twice a day, three times a day, once every few days, or once a week. Multiple administrations of the pharmaceutical composition can be included. The timing of administration may vary from individual to individual depending on factors such as the severity of the individual's symptoms. For example, an effective amount of a pharmaceutical composition disclosed herein can be administered to an individual once a day for an indefinite period of time or until the individual no longer needs treatment. One skilled in the art will recognize that an individual's condition can be monitored throughout the course of treatment and the effective amount of pharmaceutical composition administered can be adjusted accordingly.

  Various routes of administration for administering the therapeutic compounds disclosed herein can be used in accordance with the methods for treating severe pain conditions disclosed herein. For example, depending on the type of severe pain condition being treated, the site of the severe pain condition being treated, the particular therapeutic compound or composition used, or other compounds included in the composition, and the individual's medical history, risk factors and symptoms The pharmaceutical composition can be administered to an individual by any of a variety of means. Accordingly, topical, enteral, or parenteral routes of administration may be suitable for the treatment of severe pain conditions disclosed herein, and such routes are topically applied to the therapeutic compounds or compositions disclosed herein. And systemic delivery. A single therapeutic compound disclosed herein intended for use by inhalation, topical, intranasal, sublingual, injection, instillation, rectal, and / or vaginal routes, or two disclosed herein Compositions comprising more than one therapeutic compound can be prepared by any method known in the art for the manufacture of pharmaceutical compositions.

  In one embodiment, a pharmaceutical composition comprising a therapeutic compound disclosed herein, when administered to an individual, is contained in a pharmaceutical composition that is identical except for the adjuvants disclosed herein. This results in a biodistribution of the therapeutic compound that is different from the biodistribution of the compound.

  In another embodiment, upon administration to an individual, the therapeutic compound of the pharmaceutical composition disclosed herein is delivered to the macrophages. Macrophages are one of the key cell types thought to be involved in the control of inflammatory responses. High levels of therapeutic compounds with anti-pain activity present in the resulting macrophages provide effective treatment of severe pain conditions. In one aspect of this embodiment, upon administration to an individual, a therapeutically effective amount of the therapeutic compound of the pharmaceutical composition disclosed herein is preferentially delivered to the macrophages. In another aspect of this embodiment, the therapeutic compound of the pharmaceutical composition disclosed herein is substantially delivered to the macrophages upon administration to the individual. In yet another aspect of this embodiment, the amount of the therapeutic compound of the pharmaceutical composition disclosed herein that is delivered to the macrophage upon administration to the individual is the amount of therapeutic compound contained in the administered pharmaceutical composition. For example at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55% of the total amount, At least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In yet another aspect of this embodiment, the amount of therapeutic compound of the pharmaceutical composition disclosed herein delivered to the macrophages is the total amount of therapeutic compound contained in the administered pharmaceutical composition, eg, About 5% to about 100%, about 10% to about 100%, about 15% to about 100%, about 20% to about 100%, about 25% to about 100%, about 30% to about 100%, about 35 % To about 100%, about 40% to about 100%, about 45% to about 100%, about 50% to about 100%, about 5% to about 90%, about 10% to about 90%, about 15% to About 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90 %, About 50% to about 90%, about 5% to about 80%, about 10% to about 80%, about 15% to about 80%, about 20% to about 80%, about 2 % To about 80%, about 30% to about 80%, about 35% to about 80%, about 40% to about 80%, about 45% to about 80%, about 50% to about 80%, about 5% to About 70%, about 10% to about 70%, about 15% to about 70%, about 20% to about 70%, about 25% to about 70%, about 30% to about 70%, about 35% to about 70 %, About 40% to about 70%, about 45% to about 70%, or about 50% to about 70%.

  In another embodiment, upon administration to an individual, the therapeutic compound of the pharmaceutical composition disclosed herein is delivered to dendritic cells. Dendritic cells are one of the key cell types that are thought to regulate the interaction between innate and acquired immunity. High levels of therapeutic compounds with anti-pain activity present in the resulting dendritic cells provide effective treatment of severe pain conditions. In one aspect of this embodiment, upon administration to an individual, a therapeutically effective amount of the therapeutic compound of the pharmaceutical composition disclosed herein is preferentially delivered to the dendritic cells. In another aspect of this embodiment, upon administration to an individual, the therapeutic compound of the pharmaceutical composition disclosed herein is substantially delivered to the dendritic cells. In yet another aspect of this embodiment, the amount of therapeutic compound of the pharmaceutical composition disclosed herein that is delivered to the dendritic cell upon administration to the individual is the therapeutic compound included in the administered pharmaceutical composition. For example, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55% , At least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%. In yet another aspect of this embodiment, the amount of therapeutic compound of the pharmaceutical composition disclosed herein delivered to the dendritic cell is the total amount of therapeutic compound contained in the administered pharmaceutical composition, For example, about 5% to about 100%, about 10% to about 100%, about 15% to about 100%, about 20% to about 100%, about 25% to about 100%, about 30% to about 100%, About 35% to about 100%, about 40% to about 100%, about 45% to about 100%, about 50% to about 100%, about 5% to about 90%, about 10% to about 90%, about 15 % To about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90%, about 45% to About 90%, about 50% to about 90%, about 5% to about 80%, about 10% to about 80%, about 15% to about 80%, about 20% to about 80%, about 25% to 80%, about 30% to about 80%, about 35% to about 80%, about 40% to about 80%, about 45% to about 80%, about 50% to about 80%, about 5% to about 70% About 10% to about 70%, about 15% to about 70%, about 20% to about 70%, about 25% to about 70%, about 30% to about 70%, about 35% to about 70%, about It ranges from 40% to about 70%, from about 45% to about 70%, or from about 50% to about 70%.

  In another embodiment, upon administration to an individual, the pharmaceutical composition disclosed herein reduces gastric irritation. In one aspect of this embodiment, the pharmaceutical compositions disclosed herein substantially reduce gastric irritation. In yet another embodiment, the pharmaceutical composition disclosed herein is identical, except that it does not include a pharmaceutically acceptable adjuvant, when administered to an individual. Reduce stomach irritation compared to cases. In one aspect of this embodiment, the pharmaceutical composition disclosed herein is identical to that of the pharmaceutical composition disclosed herein that is identical except that it does not include a pharmaceutically acceptable adjuvant. Substantially reducing gastric irritation. In other aspects of this embodiment, the pharmaceutical compositions disclosed herein provide gastric irritation, eg, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%. At least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least Reduce by 95%, or at least 100%. In yet another aspect of this embodiment, the pharmaceutical compositions disclosed herein provide gastric irritation, eg, from about 5% to about 100%, from about 10% to about 100%, from about 15% to about 100%. About 20% to about 100%, about 25% to about 100%, about 30% to about 100%, about 35% to about 100%, about 40% to about 100%, about 45% to about 100%, about 50% to about 100%, about 5% to about 90%, about 10% to about 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% About 90%, about 35% to about 90%, about 40% to about 90%, about 45% to about 90%, about 50% to about 90%, about 5% to about 80%, about 10% to about 80%, about 15% to about 80%, about 20% to about 80%, about 25% to about 80%, about 30% to about 80%, about 35% to about 80%, about 40% to about 80% About 45% ~ 80%, about 50% to about 80%, about 5% to about 70%, about 10% to about 70%, about 15% to about 70%, about 20% to about 70%, about 25% to about 70% About 30% to about 70%, about 35% to about 70%, about 40% to about 70%, about 45% to about 70%, or about 50% to about 70%.

  In another embodiment, the pharmaceutical compositions disclosed herein reduce intestinal irritation when administered to an individual. In one aspect of this embodiment, the pharmaceutical compositions disclosed herein substantially reduce intestinal irritation. In yet another embodiment, the pharmaceutical composition disclosed herein is identical, except that it does not include a pharmaceutically acceptable adjuvant, when administered to an individual. Intestinal irritation is reduced compared to cases. In one aspect of this embodiment, the pharmaceutical composition disclosed herein is identical to that of the pharmaceutical composition disclosed herein that is identical except that it does not include a pharmaceutically acceptable adjuvant. Substantially reducing intestinal irritation. In another aspect of this embodiment, the pharmaceutical composition disclosed herein exhibits intestinal irritation as compared to a pharmaceutical composition that is identical except that it does not include a pharmaceutically acceptable adjuvant. For example, at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%. In yet another aspect of this embodiment, the pharmaceutical composition disclosed herein is compared to the same pharmaceutical composition disclosed herein except that it does not include a pharmaceutically acceptable adjuvant. Intestinal irritation is, for example, about 5% to about 100%, about 10% to about 100%, about 15% to about 100%, about 20% to about 100%, about 25% to about 100%, about 30 % To about 100%, about 35% to about 100%, about 40% to about 100%, about 45% to about 100%, about 50% to about 100%, about 5% to about 90%, about 10% to About 90%, about 15% to about 90%, about 20% to about 90%, about 25% to about 90%, about 30% to about 90%, about 35% to about 90%, about 40% to about 90 %, About 45% to about 90%, about 50% to about 90%, about 5% to about 80%, about 10% to about 80%, about 15% to about 80%, about 20% to 80%, about 25% to about 80%, about 30% to about 80%, about 35% to about 80%, about 40% to about 80%, about 45% to about 80%, about 50% to about 80% About 5% to about 70%, about 10% to about 70%, about 15% to about 70%, about 20% to about 70%, about 25% to about 70%, about 30% to about 70%, about 35% to about 70%, about 40% to about 70%, about 45% to about 70%, or about 50% to about 70%.

  The pharmaceutical compositions disclosed herein can also be administered to an individual in combination with other therapeutic compounds to enhance the overall therapeutic effect. Using multiple compounds to treat the indication can increase the beneficial effects and reduce the presence of side effects.

Some embodiments of the invention can also be described as follows:
1. A pharmaceutical composition comprising a) a therapeutic compound having anti-pain activity and b) a pharmaceutically acceptable adjuvant.
2. The pharmaceutical composition according to embodiment 1, further comprising a pharmaceutically acceptable solvent.
3. A pharmaceutical composition comprising a) a therapeutic compound having anti-pain activity, b) a pharmaceutically acceptable solvent, and c) a pharmaceutically acceptable adjuvant.
4). a) a therapeutic compound having anti-pain activity; b) a pharmaceutically acceptable solvent; and c) a pharmaceutically acceptable adjuvant, comprising a pharmaceutically acceptable solvent and a pharmaceutically acceptable adjuvant. And a ratio of about 0: 1 to about 1:25.
5). The pharmaceutical composition according to embodiment 2 or 3, wherein the ratio of pharmaceutically acceptable solvent to pharmaceutically acceptable adjuvant ranges from about 0: 1 to about 1:25.
6). The pharmaceutical composition according to embodiments 1-5, wherein the anti-pain activity reduces severe pain response.
7). The pharmaceutical composition according to embodiment 6, wherein the anti-pain activity reduces the acute pain response by at least 10%.
8). The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces the nociceptive pain response.
9. The pharmaceutical composition according to embodiment 8, wherein the anti-pain activity reduces the nociceptive pain response by at least 10%.
10. Embodiment 8. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces pain responses mediated by nociceptors.
11. The pharmaceutical composition according to embodiment 10, wherein the anti-pain activity reduces the pain response mediated by nociceptors by at least 10%.
12 The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces somatic pain response.
13. The pharmaceutical composition according to embodiment 12, wherein the anti-pain activity reduces the somatic pain response by at least 10%.
14 The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces visceral pain response.
15. The pharmaceutical composition according to embodiment 14, wherein the anti-pain activity reduces the visceral pain response by at least 10%.
16. The pharmaceutical composition according to embodiments 1 to 7, wherein the anti-pain activity reduces pathologic pain response.
17. The pharmaceutical composition according to embodiment 16, wherein the anti-pain activity reduces the pathologic pain response by at least 10%.
18. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces the neuropathic pain response.
19. Embodiment 19. The pharmaceutical composition according to embodiment 18, wherein the anti-pain activity reduces the neuropathic pain response by at least 10%.
20. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces central neuropathic pain response.
21. The pharmaceutical composition according to embodiment 20, wherein the anti-pain activity reduces the central neuropathic pain response by at least 10%.
22. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces peripheral neuropathic pain response.
23. The pharmaceutical composition according to embodiment 22, wherein the anti-pain activity reduces the peripheral neuropathic pain response by at least 10%.
24. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces mononeuropathic pain response.
25. The pharmaceutical composition according to embodiment 24, wherein the anti-pain activity reduces the mononeuropathic pain response by at least 10%.
26. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces multiple mononeuropathic pain responses.
27. 27. The pharmaceutical composition according to embodiment 26, wherein the anti-pain activity reduces the multiple mononeuropathic pain response by at least 10%.
28. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces the multiple neuropathic pain response.
29. The pharmaceutical composition according to embodiment 28, wherein the anti-pain activity reduces the polyneuropathic pain response by at least 10%.
30. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces autonomic neuropathic pain response.
31. The pharmaceutical composition according to embodiment 30, wherein the anti-pain activity reduces the autonomic neuropathic pain response by at least 10%.
32. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces the neuralgia response.
33. The pharmaceutical composition according to embodiment 32, wherein the anti-pain activity reduces the neuralgia response by at least 10%.
34. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces complex local pain syndrome pain response.
35. The pharmaceutical composition according to embodiment 34, wherein the anti-pain activity reduces the complex local pain syndrome pain response by at least 10%.
36. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces the associated pain response.
37. The pharmaceutical composition according to embodiment 36, wherein the anti-pain activity reduces the associated pain response by at least 10%.
38. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces afferent blocking pain response.
39. The pharmaceutical composition according to embodiment 38, wherein the anti-pain activity reduces the afferent blocking pain response by at least 10%.
40. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces dysfunctional pain response.
41. The pharmaceutical composition according to embodiment 38, wherein the anti-pain activity reduces the dysfunctional pain response by at least 10%.
42. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces the headache response.
43. The pharmaceutical composition according to embodiment 42, wherein the anti-pain activity reduces the headache response by at least 10%.
44. The pharmaceutical composition according to embodiments 1-7, wherein the anti-pain activity reduces the migraine response.
45. The pharmaceutical composition according to embodiment 44, wherein the anti-pain activity reduces the migraine response by at least 10%.
46. 46. The pharmaceutical composition according to embodiments 1-45, wherein the therapeutic compound has a log P value indicating that it is soluble in an organic solvent.
47. The pharmaceutical composition according to embodiments 1-46, wherein the therapeutic compound has a log P value higher than 1.0.
48. The pharmaceutical composition according to embodiments 1-46, wherein the therapeutic compound has a log P value higher than 2.0.
49. 49. The pharmaceutical composition according to embodiments 1-48, wherein the therapeutic compound has a hydrophobic polar surface area.
50. The therapeutic compound is 8.0 nm ² 50. The pharmaceutical composition according to embodiments 1-49 having a polar surface area of less than.
51. The therapeutic compound is 6.0 nm ² 50. The pharmaceutical composition according to embodiments 1-49 having a polar surface area of less than.
52. The pharmaceutical composition according to embodiments 1-51, wherein the therapeutic compound comprises a non-steroidal anti-pain drug (NSAID).
53. NSAID is salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase 1 (COX1) 53. The pharmaceutical composition of embodiment 52, comprising an inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a combination thereof.
54. The pharmaceutical composition according to embodiments 1-53, wherein the therapeutic compound comprises a PPARγ agonist.
55. PPARγ agonist is monasin, irbesartan, telmisartan, mycophenolic acid, resveratrol, delta (9) -tetrahydrocannabinol, cannabidiol, curcumin, cilostazol, benzbromarone, 6-shogaol, glycyrrhetinic acid, thiazolidinedione, NSAID 56. The pharmaceutical composition according to embodiment 54, comprising, fibrates, or combinations thereof.
56. The pharmaceutical composition according to embodiments 1-55, wherein the therapeutic compound comprises a nuclear receptor binding agent.
57. Embodiments in which the nuclear receptor binding agent comprises a retinoic acid receptor (RAR) binding agent, a retinoid X receptor (RXR) binding agent, a liver X receptor (LXR) binding agent, a vitamin D binding agent, or a combination thereof 56. The pharmaceutical composition according to 56.
58. The pharmaceutical composition according to embodiments 1-57, wherein the therapeutic compound comprises an antihyperlipidemic agent.
59. Embodiment 58 wherein the antihyperlipidemic agent comprises fibrate, statin, tocotrienol, niacin, bile acid sequestrant (bile acid resin), cholesterol absorption inhibitor, pancreatic lipase inhibitor, sympathomimetic amine, or combinations thereof A pharmaceutical composition according to 1.
60. 60. The pharmaceutical composition according to embodiment 59, wherein the fibrate comprises bezafibrate, ciprofibrate, clofibrate, gemfibrozil, fenofibrate, or combinations thereof.
61. The pharmaceutical composition according to embodiment 59, wherein the statin comprises atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, or a combination thereof.
62. 60. The pharmaceutical composition according to embodiment 59, wherein the niacin comprises acipimox, niacin, nicotinamide, vitamin B3, or a combination thereof.
63. 60. The pharmaceutical composition according to embodiment 59, wherein the bile acid sequestrant comprises cholestyramine, colesevelam, colestipol, or a combination thereof.
64. 60. The pharmaceutical composition according to embodiment 59, wherein the cholesterol absorption inhibitor comprises ezetimibe, phytosterol, sterol, stanol, or a combination thereof.
65. 60. The pharmaceutical composition according to embodiment 59, wherein the fat absorption inhibitor comprises orlistat.
66. The sympathomimetic amines are clenbuterol, salbutamol, ephedrine, pseudoephedrine, methamphetamine, amphetamine, phenylephrine, isoproterenol, dobutamine, methylphenidate, risdexamphetamine, kasin, cathinone, methcathinone, cocaine, benzylpiperazine (BZP), methylene 60. The pharmaceutical composition according to embodiment 59 comprising dioxypylovalerone (MDPV), 4-methylaminolex, pemoline, phenmetrazine, propylhexedrine, or a combination thereof.
67. The pharmaceutical composition according to embodiments 1-66, wherein the therapeutic compound comprises an ester of a therapeutic compound.
68. The pharmaceutical composition according to embodiments 1-67, wherein the therapeutic compound comprises an ester of the therapeutic compound according to embodiments 52-66.
69. The pharmaceutical composition according to embodiments 1-68, wherein the pharmaceutically acceptable solvent is less than about 20% (v / v).
70. Embodiments in which the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable polar aprotic solvent, a pharmaceutically acceptable polar protic solvent, a pharmaceutically acceptable apolar solvent, or a combination thereof The pharmaceutical composition according to 1 to 69.
71. 71. The pharmaceutical composition according to embodiments 1-70, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable alcohol.
72. 72. The pharmaceutical composition according to embodiment 71, wherein the pharmaceutically acceptable alcohol comprises an acyclic alcohol, a monohydric alcohol, a polyhydric alcohol, an unsaturated aliphatic alcohol, an alicyclic alcohol, or a combination thereof.
73. The pharmaceutically acceptable alcohol is C _1-20 72. The pharmaceutical composition according to embodiment 71 comprising alcohol.
74. 72. The pharmaceutical composition according to embodiment 71, wherein the pharmaceutically acceptable alcohol comprises methanol, ethanol, propanol, butanol, pentanol, 1-hexadecanol, or a combination thereof.
75. The pharmaceutical composition according to embodiments 1-74, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable ester of a pharmaceutically acceptable alcohol and acid.
76. Pharmaceutically acceptable esters are methyl acetate, methyl butyrate, methyl formate, ethyl acetate, ethyl butyrate, ethyl formate, propyl acetate, propyl butyrate, propyl formate, butyl acetate, butyl butyrate, butyl formate, isobutyl acetate, isobutyl butyrate 76. A pharmaceutical composition according to embodiment 75, comprising: isobutyl formate, pentyl acetate, pentyl butyrate, pentyl formate, and 1-hexadecyl acetate, 1-hexadecyl butyrate, 1-hexadecyl formate, or a combination thereof .
77. Pharmaceutically acceptable solvents include pharmaceutically acceptable glycol ether, pharmaceutically acceptable diol, pharmaceutically acceptable propylene glycol, pharmaceutically acceptable dipropylene glycol, pharmaceutically acceptable The pharmaceutical composition according to embodiments 1-76, comprising any polypropylene glycol (PPG) polymer, pharmaceutically acceptable polyethylene glycol (PEG) polymer, or any combination thereof.
78. Pharmaceutically acceptable glycol ethers include diethylene glycol monomethyl ether (2- (2-methoxyethoxy) ethanol), diethylene glycol monoethyl ether (2- (2-ethoxyethoxy) ethanol), diethylene glycol monopropyl ether (2- (2 -Propoxyethoxy) ethanol), diethylene glycol monoisopropyl ether (2- (2-isopropoxyethoxy) ethanol), diethylene glycol mono-n-butyl ether (2- (2-butoxyethoxy) ethanol), or any combination thereof 78. The pharmaceutical composition according to embodiment 77.
79. The pharmaceutical composition according to embodiment 77, wherein the pharmaceutically acceptable polypropylene glycol (PPG) polymer or the pharmaceutically acceptable polyethylene glycol (PEG) polymer is less than about 2,000 g / mol.
80. 78. The pharmaceutical composition of embodiment 77, wherein the pharmaceutically acceptable polypropylene glycol (PPG) polymer or pharmaceutically acceptable polyethylene glycol (PEG) polymer is greater than about 2,000 g / mol.
81. 52. The pharmaceutical composition according to embodiments 1 to 51, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable glyceride.
82. 82. The pharmaceutical composition according to embodiment 81, wherein the pharmaceutically acceptable glyceride comprises a monoglyceride, diglyceride, triglyceride, acetylated monoglyceride, acetylated diglyceride, acetylated triglyceride, or combinations thereof.
83. The pharmaceutical composition according to embodiments 1-82, wherein the pharmaceutically acceptable solvent is liquid at 20 ° C. or the pharmaceutically acceptable solvent is solid at 20 ° C.
84. 84. The pharmaceutical composition according to embodiment 83, wherein the pharmaceutically acceptable solid solvent comprises menthol.
85. The pharmaceutical composition according to embodiments 1-84, wherein the adjuvant is at least 80% (v / v).
86. The pharmaceutical composition according to embodiments 1-85, wherein the pharmaceutically acceptable adjuvant is liquid at 20 ° C.
87. The pharmaceutical composition according to embodiments 1-86, wherein the pharmaceutically acceptable adjuvant is a solid at 20 ° C.
88. The pharmaceutical composition according to embodiments 1-87, wherein the pharmaceutically acceptable adjuvant comprises a pharmaceutically acceptable lipid.
89. The pharmaceutical composition according to embodiment 88, wherein the pharmaceutically acceptable lipid comprises a saturated fatty acid, an unsaturated fatty acid, or a combination thereof.
90. 90. The pharmaceutical composition according to embodiment 88 or 89, wherein the pharmaceutically acceptable lipid comprises two or more saturated or unsaturated fatty acids.
The pharmaceutical composition according to embodiment 90, wherein the 91.2 or more saturated or unsaturated fatty acids comprise palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or combinations thereof.
92. The pharmaceutical composition according to embodiments 89-91, wherein the unsaturated fatty acid has a melting point of 20 ° C. or lower, or the unsaturated fatty acid is solid at 20 ° C.
93. The pharmaceutical composition according to embodiments 89-91, wherein the unsaturated fatty acid comprises an omega fatty acid.
94. The pharmaceutical composition according to embodiment 88, wherein the pharmaceutically acceptable lipid comprises a pharmaceutically acceptable oil.
95. Pharmaceutically acceptable oils are almond oil, peanut oil, avocado oil, canola oil, castor oil, palm oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, cannabis oil, linseed oil, olive oil, palm oil , Peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soy bean oil, soya oil, sunflower oil, cocoa butter, walnut oil, wheat germ oil, or combinations thereof 94. A pharmaceutical composition according to 94.
96. The pharmaceutically acceptable lipid is a pharmaceutically acceptable glycerolipid, a pharmaceutically acceptable glycol fatty acid ester, a pharmaceutically acceptable polyether fatty acid ester, a mixture of pharmaceutically acceptable lipids, or 90. The pharmaceutical composition according to embodiment 88 comprising any combination thereof.
97. 99. The pharmaceutical composition according to embodiments 1-96, further comprising a pharmaceutically acceptable stabilizer.
98. Pharmaceutically acceptable stabilizers include water, sacrificial acids including fatty acid components and acetic acid, ethyl acetate, sodium acetate / acetic acid, monoglycerides, acetylated monoglycerides, diglycerides, acetylated diglycerides, fatty acids, fatty acid salts, or these 98. The pharmaceutical composition according to embodiment 97 comprising a combination of:
99. 98. The pharmaceutical composition according to embodiment 97, wherein the pharmaceutically acceptable stabilizer comprises a pharmaceutically acceptable emulsifier.
100. 100. The pharmaceutical composition of embodiment 99, wherein the pharmaceutically acceptable emulsifier comprises a surfactant, polysaccharide, lectin, phospholipid, or a combination thereof.
101. The pharmaceutical composition according to embodiments 1 to 100, wherein the pharmaceutical composition does not comprise a pharmaceutically acceptable emulsifier.
102. A method of preparing a pharmaceutical composition comprising contacting a therapeutic compound with a pharmaceutically acceptable adjuvant under conditions that allow formation of the pharmaceutical composition.
103. A method for preparing a pharmaceutical composition comprising: a) contacting a therapeutic compound with a pharmaceutically acceptable solvent under conditions that permit dissolution of the therapeutic compound in a pharmaceutically acceptable solvent. Forming a solution, wherein the therapeutic compound has anti-pain activity and b) the solution formed in step (a) is pharmaceutically acceptable under conditions that allow formation of a pharmaceutical composition. Contacting with a possible adjuvant.
104. A method for preparing a pharmaceutical composition comprising: a) contacting a therapeutic compound with a pharmaceutically acceptable solvent under conditions that permit dissolution of the therapeutic compound in a pharmaceutically acceptable solvent. Wherein the therapeutic compound has anti-pain activity and b) the solution formed in step (a) is pharmaceutically acceptable under conditions that allow formation of a pharmaceutical composition Contacting with an adjuvant, wherein the ratio of pharmaceutically acceptable solvent to pharmaceutically acceptable adjuvant ranges from about 0: 1 to about 1:25.
105. 105. The method of embodiments 102-104, wherein the therapeutic compound has a log P value indicating that it is soluble in an organic solvent.
106. The method of embodiments 102-105, wherein the therapeutic compound has a log P value greater than 1.0.
107. The method of embodiments 102-105, wherein the therapeutic compound has a log P value greater than 2.0.
108. 108. The method of embodiments 102-107, wherein the therapeutic compound has a hydrophobic polar surface area.
109. 109. The method of embodiments 102-108, wherein the therapeutic compound has a polar surface area of less than 8.0 nm2.
110. 109. The method of embodiments 102-108, wherein the therapeutic compound has a polar surface area of less than 6.0 nm2.
111. 111. The method of embodiments 102-110, wherein the therapeutic compound comprises a nonsteroidal anti-pain drug (NSAID).
112. NSAID is salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase 1 (COX1) 112. The method of embodiment 111 comprising an inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a combination thereof.
113. 113. The method of embodiments 102-112, wherein the therapeutic compound comprises a PPARγ agonist.
114. PPARγ agonist is monasin, irbesartan, telmisartan, mycophenolic acid, resveratrol, delta (9) -tetrahydrocannabinol, cannabidiol, curcumin, cilostazol, benzbromarone, 6-shogaol, glycyrrhetinic acid, thiazolidinedione, NSAID 114. The method of embodiment 113, comprising a fibrate, or a combination thereof.
115. 115. The method of embodiments 102-114, wherein the therapeutic compound comprises a nuclear receptor binding agent.
116. Embodiments in which the nuclear receptor binding agent comprises a retinoic acid receptor (RAR) binding agent, a retinoid X receptor (RXR) binding agent, a liver X receptor (LXR) binding agent, a vitamin D binding agent, or a combination thereof 115. The method according to 115.
117. 117. The method of embodiments 102-116, wherein the therapeutic compound comprises an antihyperlipidemic agent.
118. Embodiment 117 wherein the antihyperlipidemic agent comprises fibrate, statin, tocotrienol, niacin, bile acid sequestrant (bile acid resin), cholesterol absorption inhibitor, pancreatic lipase inhibitor, sympathomimetic amine, or combinations thereof The method described in 1.
119. 119. The method of embodiment 118, wherein the fibrate comprises bezafibrate, ciprofibrate, clofibrate, gemfibrozil, fenofibrate, or a combination thereof.
120. 119. The method of embodiment 118 wherein the statin comprises atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, or a combination thereof.
121. 119. The method of embodiment 118 wherein the niacin comprises acipimox, niacin, nicotinamide, vitamin B3, or a combination thereof.
122. 119. The method of embodiment 118, wherein the bile acid sequestrant comprises cholestyramine, colesevelam, colestipol, or a combination thereof.
123. 119. The method of embodiment 118, wherein the cholesterol absorption inhibitor comprises ezetimibe, phytosterol, sterol, stanol, or a combination thereof.
124. 118. The method of embodiment 118, wherein the fat absorption inhibitor comprises orlistat.
125. The sympathomimetic amines are clenbuterol, salbutamol, ephedrine, pseudoephedrine, methamphetamine, amphetamine, phenylephrine, isoproterenol, dobutamine, methylphenidate, risdexamphetamine, kasin, cathinone, methcathinone, cocaine, benzylpiperazine (BZP), methylene 119. The method of embodiment 118 comprising dioxypylovalerone (MDPV), 4-methylaminorex, pemoline, phenmetrazine, propylhexedrine, or a combination thereof.
126. 126. The method of embodiments 102-125, wherein the therapeutic compound comprises an ester of a therapeutic compound.
127. The method of embodiments 102-126, wherein the therapeutic compound comprises an ester of the therapeutic compound described in embodiments 111-126.
128. 128. The method of embodiments 103-127 wherein the pharmaceutically acceptable solvent is less than about 20% (v / v).
129. Embodiments in which the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable polar aprotic solvent, a pharmaceutically acceptable polar protic solvent, a pharmaceutically acceptable apolar solvent, or a combination thereof The method according to 103 to 128.
130. 130. The method of embodiments 103-129, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable alcohol.
131. 130. The method of embodiment 130, wherein the pharmaceutically acceptable alcohol comprises an acyclic alcohol, a monohydric alcohol, a polyhydric alcohol, an unsaturated aliphatic alcohol, an alicyclic alcohol, or a combination thereof.
132. A pharmaceutically acceptable solvent is C _1-20 Embodiment 130. The method of embodiment 130 comprising an alcohol.
133. 130. The method of embodiment 130, wherein the pharmaceutically acceptable alcohol comprises methanol, ethanol, propanol, butanol, pentanol, 1-hexadecanol, or a combination thereof.
134. 130. The method of embodiment 130, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable ester of a pharmaceutically acceptable alcohol and acid.
135. Pharmaceutically acceptable esters are methyl acetate, methyl butyrate, methyl formate, ethyl acetate, ethyl butyrate, ethyl formate, propyl acetate, propyl butyrate, propyl formate, butyl acetate, butyl butyrate, butyl formate, isobutyl acetate, isobutyl butyrate 135. A method according to embodiment 134, comprising: isobutyl formate, pentyl acetate, pentyl butyrate, pentyl formate, and 1-hexadecyl acetate, 1-hexadecyl butyrate, 1-hexadecyl formate, or a combination thereof.
136. 140. The method of embodiments 103-135, wherein the pharmaceutically acceptable solvent is a pharmaceutically acceptable polyethylene glycol (PEG) polymer.
137. The method of embodiment 136, wherein the pharmaceutically acceptable polyethylene glycol (PEG) polymer is less than about 2,000 g / mol.
138. The method of embodiment 136, wherein the pharmaceutically acceptable polyethylene glycol (PEG) polymer is greater than about 2,000 g / mol.
139. 140. The method of embodiments 103-138, wherein the pharmaceutically acceptable solvent comprises a pharmaceutically acceptable glyceride.
140. 140. The method of embodiment 139, wherein the pharmaceutically acceptable glyceride is a monoglyceride, diglyceride, triglyceride, acetylated monoglyceride, acetylated diglyceride, acetylated triglyceride, or combinations thereof.
141. 141. The method of embodiments 103-140, wherein the pharmaceutically acceptable solvent is a liquid at 20 ° C.
142. 142. The method of embodiments 103-141, wherein the pharmaceutically acceptable solvent is a solid at 20 ° C.
143. 142. The method of embodiment 142, wherein the pharmaceutically acceptable solvent is menthol.
144. The method of embodiments 102-143, wherein the pharmaceutically acceptable adjuvant is at least 80% (v / v).
145. The method of embodiment 102-144, wherein the pharmaceutically acceptable adjuvant is a liquid at 20 ° C.
146. The method of embodiment 102-144, wherein the pharmaceutically acceptable adjuvant is a solid at 20 ° C.
147. The method of embodiments 102-146, wherein the pharmaceutically acceptable adjuvant comprises a pharmaceutically acceptable lipid.
148. 148. The method of embodiment 147, wherein the pharmaceutically acceptable lipid comprises a pharmaceutically acceptable saturated fatty acid, an unsaturated fatty acid, or a combination thereof.
149. 148. The method of embodiment 147 or 148, wherein the pharmaceutically acceptable lipid comprises two or more pharmaceutically acceptable saturated or unsaturated fatty acids.
150. The method of embodiment 149, wherein the 150.2 or more saturated or unsaturated fatty acids comprise palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, or combinations thereof.
151. The method according to embodiments 148-150, wherein the pharmaceutically acceptable unsaturated fatty acid has a melting point of 20 ° C. or lower.
152. The method according to embodiments 148-150, wherein the pharmaceutically acceptable unsaturated fatty acid is a solid at 20 ° C.
153. 155. The method of embodiments 148-152 wherein the pharmaceutically acceptable unsaturated fatty acid comprises an omega fatty acid.
154. The method of embodiments 147-153, wherein the pharmaceutically acceptable lipid comprises a pharmaceutically acceptable oil.
155. Pharmaceutically acceptable oils are almond oil, peanut oil, avocado oil, canola oil, castor oil, palm oil, corn oil, cottonseed oil, grape seed oil, hazelnut oil, cannabis oil, linseed oil, olive oil, palm oil 154, comprising peanut oil, rapeseed oil, rice bran oil, safflower oil, sesame oil, soybean oil, soya oil, sunflower oil, walnut oil, wheat germ oil, or combinations thereof the method of.
156. The method of embodiment 103 or 105-155, wherein in step (b), the ratio of pharmaceutically acceptable solvent to pharmaceutically acceptable adjuvant ranges from about 0: 1 to about 1:25.
157. 156. The method of embodiments 102-156, wherein step (a) further comprises contacting a pharmaceutically acceptable stabilizer with a pharmaceutically acceptable solvent and a therapeutic compound.
158. Pharmaceutically acceptable stabilizers are water, sacrificial acid containing fatty acid component and acetic acid, ethyl acetate, sodium acetate / acetic acid, monoglyceride, acetylated monoglyceride, diglyceride, acetylated diglyceride, fatty acid, fatty acid salt, or these 158. The method of embodiment 157 comprising a combination of:
159. The method of embodiment 157 or 158, wherein the pharmaceutically acceptable stabilizer comprises a pharmaceutically acceptable emulsifier.
160. 160. The method of embodiment 159, wherein the pharmaceutically acceptable emulsifier comprises a surfactant, polysaccharide, lectin, phospholipid, or a combination thereof.
161. The method of embodiments 102-158, wherein the pharmaceutical composition does not comprise a pharmaceutically acceptable emulsifier.
162. The method of embodiments 103-161, further comprising the step of removing a pharmaceutically acceptable solvent from the pharmaceutical composition.
163. 163. The method of embodiment 162 wherein at least 5% of the pharmaceutically acceptable solvent is removed from the pharmaceutical composition.
164. 164. The method of embodiment 162 or 163, wherein the removal of the solvent from the pharmaceutical composition disclosed herein is performed at a temperature of less than 20 ° C.
165. The method of embodiments 102-164, wherein the pharmaceutical composition is made according to the description of embodiments 1-101.
166. A method of treating a severely afflicted individual, comprising the step of administering the pharmaceutical composition according to embodiments 1-101 to an individual in need thereof, wherein the administration results in a reduction of symptoms associated with the severely afflicted state. , Thereby treating the individual.
167. 101. Use of the pharmaceutical composition according to embodiments 1-101 in the manufacture of a medicament for the treatment of chronic inflammation.
168. 101. Use of the pharmaceutical composition according to embodiments 1-101 for the treatment of severe pain conditions.
169. The method of embodiment 166 or the use of embodiment 167 or 168, wherein the severe pain condition is acute pain.
170. The method of embodiment 166 or the use of embodiment 167 or 168, wherein the severe pain condition is nociceptive pain.
171. 170. The method or use according to embodiment 170, wherein the nociceptive pain is visceral pain, deep somatic pain, superficial somatic pain or any combination thereof.
172. The method of embodiment 166 or the use of embodiment 167 or 168, wherein the severe pain condition is pathological pain.
173. The method or use according to embodiment 172, wherein the pathological pain is neuropathic pain, dysfunctional pain, or any combination thereof.
174. 178. The method or use of embodiment 173, wherein the neuropathic pain is central neuropathic pain, peripheral neuropathic pain, afferent blockade pain, or any combination thereof.
175. 175. The method or use according to embodiment 174, wherein the peripheral neuropathic pain is mononeuropathy, multiple mononeuropathy, polyneuropathy, or autonomic neuropathy.
176. 178. The method or use of embodiment 175, wherein the polyneuropathy is a distal axonal disorder, a myelinopathy, or a neuronal disorder.
177. The method or use according to embodiment 174, wherein the peripheral neuropathic pain is neuralgia, complex regional pain syndrome.
178. The method of embodiment 166 or the use of embodiment 167 or 168, wherein the severe pain condition is associated pain.
179. The method of embodiment 166 or the use of embodiment 167 or 168, wherein the severe pain condition is a headache.
180. Embodiment 179 wherein the headache is muscular / myogenic headache, vascular headache, traction headache, inflammatory headache, chronic sinusitis headache, hormonal headache, rebound headache, organic headache or epilepsy headache The method or use according to 1.
181. The method of embodiment 166 or the use of embodiment 167 or 168, wherein the severe pain condition is migraine.
182. The body of a therapeutic compound contained in a pharmaceutical composition that is the same except that the pharmaceutical composition comprising the therapeutic compound of embodiments 1-101 does not contain a pharmaceutically acceptable adjuvant when administered to an individual. The method of embodiment 166 or 169-181 or the use of embodiments 167-181 resulting in a biodistribution of the therapeutic compound that is different from the distribution.
183. The amount of therapeutic compound of the pharmaceutical composition according to embodiments 1-101 delivered to macrophages upon administration to an individual is at least 5% of the total amount of therapeutic compound contained in the administered pharmaceutical composition The method of embodiment 166 or 169-182 or the use of embodiments 167-182.
184. Upon administration to an individual, the pharmaceutical composition described in embodiments 1-101 has at least 5% intestinal irritation compared to the pharmaceutical composition described in embodiments 1-101 without a pharmaceutically acceptable adjuvant. The method of embodiment 166 or 169-183 or the use of embodiments 167-183 of reducing.
185. When administered to an individual, the therapeutic compound of the pharmaceutical composition according to embodiments 1-101 causes gastric irritation as compared to the pharmaceutical composition according to embodiments 1-101, which does not include a pharmaceutically acceptable adjuvant. The method of embodiment 166 or 169-184 or the use of embodiments 167-184, reduced by at least 5%.

Examples The following non-limiting examples are provided for illustrative purposes only to facilitate a more complete understanding of the presently contemplated exemplary embodiments. These examples are any of those described herein, including those relating to the compounds, alcohols, lipids, pharmaceutical compositions, methods of preparing the pharmaceutical compositions, or methods of treatment or use for treating severe pain conditions. It should not be construed as limiting the embodiments.

Example 1
Pharmaceutical Composition Liquid Formulation This example illustrates a method of making the pharmaceutical composition disclosed herein as a liquid formulation.

  Initially, 2,400 mg of ibuprofen was contacted directly with 2.0 mL of rapeseed oil to dissolve the therapeutic compound directly into the adjuvant at a concentration of 1,200 mg / mL. However, ibuprofen remained insoluble and practically did not dissolve. Even when the mixture was mixed by vortexing for 20 seconds, it remained insoluble, so it was contacted at 20 ° C. or 37 ° C. and / or incubated at 20 ° C. or 37 ° C. for 24 hours. The insolubility of ibuprofen in rapeseed oil is surprising given that ibuprofen has a log P value of 3.6 and such a high log P value is an indicator that the compound is easily dissolved in an adjuvant such as oil. Was that.

Despite the high log P value of ibuprofen, ibuprofen could not be dissolved directly in the oil, so we next attempted to dissolve the therapeutic agent in a solvent to produce a solution containing the compound first. As a first step, experiments were conducted on the miscibility of solvents in adjuvants such as oils in the absence of therapeutic compounds. In these experiments, 0.5 mL of ethanol was contacted with 10 different volumes of rapeseed oil (Table 1). Each mixture was tested at 22 ° C and 37 ° C. In this case, ethanol and oil were first heated in a water bath before mixing together. Mixing by vortex mixing was attempted for 20 seconds, and the container was allowed to stand immediately or before visual evaluation after 24 hours. Each mixture was evaluated to determine whether ethanol and rapeseed oil form an immiscible layer or a homogeneous mixture. The results are summarized in Table 1. Solvent: adjuvant ratios of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, and 1: 6 form immiscible layers at 22 ° C or 37 ° C immediately after incubation or after 24 hours. It was shown that ethanol and oil did not mix well at these ratios. However, solvent: adjuvant ratios exceeding 1: 7 formed a homogeneous mixture under all test conditions.

Once the alcohol to lipid ratio suitable for the formation of a homogeneous mixture was determined, it was then determined whether the therapeutic compound was first contacted with the solvent prior to contact with the adjuvant. To perform these experiments, 1,000 mg or 1200 mg ibuprofen was dissolved in 0.5 mL ethanol. The resulting alcohol solution was then contacted with rapeseed oil in two different solvent: adjuvant ratios (1: 2 and 1: 9). Each mixture was tested at 20 ° C and 37 ° C. In this case, the ethanol solution and oil were first heated in a water bath before mixing together. Mixing by vortex mixing was attempted for 20 seconds, and the container was allowed to stand immediately or before visual evaluation after 24 hours. Each mixture was evaluated to determine whether the ethanol solution and rapeseed oil form an immiscible layer or a homogeneous mixture. The results are summarized in Table 2. In contrast to the situation where no therapeutic compound is present, when ibuprofen is present in ethanol, ethanol and oil can form a homogeneous mixture under all test conditions for solvent: adjuvant ratios above 1: 2. It was. While not wishing to be bound by theory, the therapeutic compound can have some effect on the way the adjuvant and solvent interact, resulting in a manner that does not occur in the absence of the therapeutic compound. This observation was very surprising because it appeared that a homogeneous mixture was formed. In addition, the results indicate that the therapeutic compound can be formulated at clinically useful concentrations.

Example 2
Pharmaceutical Composition Liquid Formulation This example illustrates a method of making the pharmaceutical composition disclosed herein as a liquid formulation.

  In order to prepare the pharmaceutical compositions disclosed herein using gemfibrozil, the following formulations were investigated. In these experiments, 600 mg of gemfibrozil was contacted with various volumes of ethanol as a solvent and warmed to 37 ° C, after which the resulting solution was contacted with various volumes of linseed oil and warmed to 37 ° C. (Table 3). Each formulation was evaluated to determine whether ethanol and linseed oil form an immiscible layer, or a transparent homogeneous mixture, and further, whether gemfibrozil crystallizes from solution. The results are summarized in Table 3.

As in Example 1 above, gemfibrozil remained insoluble in a single oil and did not dissolve so much as was practically measurable. Formulations containing 0.2 mL of ethanol were not able to completely dissolve gemfibrozil. In addition, the formulation containing 0.3 mL of ethanol was able to dissolve gemfibrozil, but the therapeutic compound began to crystallize out of solution within 3 hours and was completely crystallized within 48 hours. All other formulations tested were able to dissolve gemfibrozil and form the pharmaceutical compositions disclosed herein. However, from the perspective that gemfibrozil remained completely dissolved after 3 weeks, only the formulation containing 0.5 mL of ethanol appeared to be a stable pharmaceutical composition.

Example 3
Pharmaceutical Composition Liquid Formulation This example illustrates a method of making the pharmaceutical composition disclosed herein as a liquid formulation.

  In order to prepare the pharmaceutical composition disclosed herein using ibuprofen, the following method was performed. Approximately 4 g of ibuprofen was contacted with 3.6 mL of ethyl acetate as the solvent, and then the resulting solution was contacted with 76.4 mL of rapeseed oil as an adjuvant. The resulting pharmaceutical composition had a solvent: adjuvant ratio of about 1:21. The pharmaceutical composition was then placed in a round bottom flask and subjected to a rotary evaporator under low pressure. The temperature was kept low and continued to evaporate until a constant weight was reached. The total amount lost was 3.65% of the total weight. The resulting liquid no longer retained the characteristic ethyl acetate odor / taste, indicating that most of the ethyl acetate was removed from the pharmaceutical composition.

  In order to prepare the pharmaceutical composition disclosed herein using ibuprofen, the following method was performed. About 2 g of ibuprofen with 1.2 mL of diethylene glycol monoethyl ether (2- (2-ethoxyethoxy) ethanol) as solvent, 2.2 mL of glyceryl monolinoleate (MAISINE® 35-1 (Gattefosese) as adjuvant )), And 2.2 mL of rapeseed oil, after which the resulting mixture was contacted with 0.46 mL of isopropanol. The mixture was added to the vessel and heated to about 40 ° C. to about 50 ° C., stirred until all components in the mixture were dissolved, and then cooled to 30 ° C. The resulting pharmaceutical composition had a solvent: adjuvant ratio of about 1: 3.67. Next, this pharmaceutical composition was fractionated to prepare 10 liquid capsules each containing about 200 mg of ibuprofen.

Example 4
Pharmaceutical Composition Solid Formulation This example shows a preparation method of the pharmaceutical composition disclosed herein as a solid formulation.

  Since fatty acids can be liquid or solid at room temperature, various fatty acids were investigated to evaluate the potential of each fatty acid in the production of solid formulations. Understanding this will allow the development of a variety of solid formulations by adjusting the relative proportions of each fatty acid. As an initial experiment, linolenic acid, linoleic acid, palmitic acid, and stearic acid were evaluated and using one of these fatty acids, solid or semi-solid at 22 ° C. (simulating room temperature conditions) It was determined whether the pharmaceutical compositions disclosed herein that could be formulated to melt at 37 ° C. (simulating internal body temperature conditions after ingestion) could be prepared.

Four different test formulations were prepared and evaluated for their ability to form a solid dosage formulation at 22 ° C. and melt into a homogeneous solution at 37 ° C. without forming a suspension (Table 4). By dissolving 200 mg ibuprofen in 400 mg menthol, then mixing the resulting solution with 200 mg stearic acid (Tm: about 67-72 ° C.) and heating at 60 ° C. for 30 minutes to form a homogeneous solution. Formulation 1 was prepared. Formulation 1 solidified immediately upon cooling to 22 ° C. Formulation 1 remained solid after overnight incubation at 37 ° C. By dissolving 200 mg ibuprofen in 400 mg menthol, then mixing the resulting solution with 200 mg palmitic acid (Tm: about 61-62 ° C.) and heating at 60 ° C. for 30 minutes to form a homogeneous solution Formulation 2 was prepared. Formulation 2 solidified in about 1 hour after cooling to 22 ° C. Overnight incubation at 37 ° C. completely melted formulation 2 into a clear, homogeneous liquid. However, Formulation 2 solidified again in about 1 hour after cooling to 22 ° C. By dissolving 200 mg ibuprofen in 400 mg menthol and then mixing the resulting solution with 200 mg linoleic acid (Tm: about −5 ° C.) and heating at 37 ° C. for 2 hours to form a homogeneous solution, Formulation 3 was prepared. Formulation 3 remained liquid even after 72 hours of cooling at 22 ° C. By dissolving 200 mg ibuprofen in 400 mg menthol and then mixing the resulting solution with 200 mg linolenic acid (Tm: about -11 ° C) and heating at 37 ° C for 2 hours to form a homogeneous solution, Formulation 4 was prepared. Formulation 4 remained liquid after 72 hours of cooling at 22 ° C.

Based on these data, solid dosage forms of the pharmaceutical compositions disclosed herein can be made. For example, the pharmaceutical composition is solid or semi-solid at 22 ° C. but is formulated to melt into an appropriate clear solution (not suspension) at 37 ° C. (Table 5).

In order to prepare the solid pharmaceutical composition disclosed herein using ibuprofen, the following method was performed. About 15g of ibuprofen, 37 ° C. contain about diethylene glycol monoethyl ether 9.0mL (2- (2- ethoxyethoxy) ethanol), a mixture of saturated _C 10 _{-C 18} triglycerides approximately 33g as an adjuvant as a solvent - Contact was made with a waxy solid having a melting point of 41 ° C. (GELUCIRE® 39/01 (Gattefose)), and about 3.6 mL of isopropanol. The mixture was added to the vessel and heated to about 40 ° C. to about 50 ° C., stirred until all the components of the mixture were dissolved, cooled to about 30 ° C., aliquoted, poured into a mold and cooled to room temperature. The resulting pharmaceutical composition had a solvent: adjuvant ratio of about 1: 3.67. From this pharmaceutical composition, 75 solid tablets each containing about 200 mg ibuprofen were made.

In order to prepare the solid pharmaceutical composition disclosed herein using ibuprofen, the following method was performed. Ibuprofen about 20 g, 41 ° C. contain about diethylene glycol monoethyl ether 12.0mL (2- (2- ethoxyethoxy) ethanol), a mixture of saturated _C 10 _{-C 18} triglycerides approximately 16g as an adjuvant as a solvent - 2. A waxy solid with a melting point of 45 ° C. (GELUCIRE® 43/01 (Gattefose)), and 16 g glyceryl monolinoleate (MAISINE® 35-1 (Gattefose)), and about 3. Contacted with 6 mL isopropanol. The mixture was added to the vessel and heated to about 40 ° C. to about 50 ° C., stirred until all the components of the mixture were dissolved, cooled to about 30 ° C., aliquoted, poured into a mold and cooled to room temperature. The resulting pharmaceutical composition had a solvent: adjuvant ratio of about 1: 2.67. From this pharmaceutical composition, 100 solid tablets each containing about 200 mg ibuprofen were made.

In order to prepare the solid pharmaceutical composition disclosed herein using ibuprofen, the following method was performed. Ibuprofen about 80 g, waxy solid having a saturated _C 10 _{-C 18} melting point of the mixture 41 ° C. to 45 ° C. containing the triglycerides of about 152 g (GELUCIRE (R) 43/01 (Gattefosse),), and about 72mL Of glyceryl monolinoleate (MAISINE® 35-1 (Gattefose)) and about 32 mL of PEG400 are added to the container and heated to about 50 ° C. to about 60 ° C. until all components of the mixture are dissolved Stir. The heated mixture was cooled to about 40 ° C., then aliquoted and poured into a mold and cooled to room temperature. From this pharmaceutical composition, 400 solid tablets, each containing about 200 mg ibuprofen, were made.

In order to prepare the solid pharmaceutical composition disclosed herein using ibuprofen, the following method was performed. A waxy solid having a melting point of 41 ° C. to 45 ° C. (GELUCIRE® 43/01 (Gattefosse) comprising about 1.1 g of ibuprofen sodium salt, about 1.9 g of a mixture of saturated C ₁₀ -C ₁₈ triglycerides ), And about 0.9 mL of glyceryl monolinoleate (MAISINE® 35-1 (Gattefosse)), about 0.4 mL of PEG400, and about 0.3 mL of propylene glycol are added to the container and about 50 ° C. Heat to ˜60 ° C. and stir until all components of the mixture are dissolved. The heated mixture was cooled to about 40 ° C., then aliquoted and poured into a mold and cooled to room temperature. Five solid tablets, each containing about 200 mg ibuprofen, were made from this pharmaceutical composition.

In order to prepare the solid pharmaceutical composition disclosed herein using ibuprofen, the following method was performed. A waxy solid having a melting point of 41 ° C. to 45 ° C. (GELUCIRE® 43 /) comprising a mixture of about 5 g ibuprofen free acid, about 5 g ibuprofen sodium salt, about 3 g saturated C ₁₀ -C ₁₈ triglycerides 01 (Gattefosse)), and about 8 mL of glyceryl monolinoleate (MAISINE® 35-1 (Gattefosse)), about 3 mL of PEG400, and about 1 mL of propylene glycol are added to the container and about 50 ° C. to about Heated to 60 ° C. and stirred until all components of the mixture were dissolved. The heated mixture was cooled to about 40 ° C., then aliquoted and poured into a mold and cooled to room temperature. From this pharmaceutical composition, 50 solid tablets each containing about 200 mg ibuprofen were made.

Example 5
Semisolid Formulation of Pharmaceutical Compositions This example shows how to make a pharmaceutical composition disclosed herein as a semisolid formulation useful for topical administration.

In order to prepare the semi-solid pharmaceutical compositions disclosed herein using ibuprofen, the following method was performed. A waxy solid having a melting point of 41 ° C. to 45 ° C. (GELUCIRE®) comprising a mixture of about 1 g of ibuprofen free acid, about 0.2 g of ibuprofen sodium salt, about 0.6 g of saturated C ₁₀ -C ₁₈ triglycerides ) 43/01 (Gattefose)), and about 1.6 mL of glyceryl monolinoleate (MAISINE® 35-1 (Gattefose)), about 0.6 mL of PEG400, and about 0.15 mL of propylene glycol. In addition to the vessel, it was heated to about 50 ° C. to about 60 ° C. and stirred until all components of the mixture were dissolved. The heated mixture was cooled to room temperature and dispensed into a suitable container. From this pharmaceutical composition, a semi-solid ointment having an ibuprofen concentration of about 400 mg / mL was prepared.

In order to prepare the semi-solid pharmaceutical compositions disclosed herein using ibuprofen, the following method was performed. A waxy solid having a melting point of 41 ° C. to 45 ° C. (GELUCIRE® 43 /) comprising a mixture of about 5 g ibuprofen free acid, about 5 g ibuprofen sodium salt, about 3 g saturated C ₁₀ -C ₁₈ triglycerides 01 (Gattefosse)), and about 8 mL of glyceryl monolinoleate (MAISINE® 35-1 (Gattefosse)), about 3 mL of PEG400, and about 1 mL of propylene glycol are added to the container and about 50 ° C. to about Heated to 60 ° C. and stirred until all components of the mixture were dissolved. The heated mixture was cooled to room temperature and dispensed into a suitable container. From this pharmaceutical composition, a semi-solid ointment having an ibuprofen concentration of about 650 mg / mL was prepared.

Example 6
Intestinal Erosion Animal Model In order to determine whether the pharmaceutical compositions disclosed herein reduce gastric irritation, several experiments were performed using an intestinal erosion mouse model.

  Sprague Dawley rats were divided into 7 experimental groups, each containing 5 animals. After overnight fast, the animals were investigated with one of seven different treatments. Group A was a control and each mouse received oral administration of only 1% methylcellulose / 0.5% polysorbate 80 vehicle only. Group B served as a control, and each mouse was orally administered vehicle / adjuvant vehicle alone (tube feeding of 10% ethanol and 90% linseed oil). Group C served as a control and each mouse received 150 mg / kg of aspirin orally. Group D was a control and each mouse received 100 mg / kg ibuprofen orally suspended in 1% methylcellulose / 0.5% polysorbate 80. Group E is an experimental group where each mouse received a pharmaceutical composition disclosed herein (BC1054-100) containing 100 mg / kg ibuprofen, 10% ethanol and 90% linseed oil. Group F served as a control and each mouse received 100 mg / kg ibuprofen orally suspended in 1% methylcellulose / 0.5% polysorbate 80. Group G is an experimental group where each mouse received a pharmaceutical composition disclosed herein (BC1054-200) containing 200 mg / kg ibuprofen, 10% ethanol and 90% linseed oil. Four hours after treatment, the animals were sacrificed and examined for the extent of gastric bleeding and the severity of erosive lesions of the mucosa. Stomach irritation was scored as follows: 0, no lesion; 1, hyperemia; 2, 1 or 2 mild lesions; 3, 3 or more mild lesions or severe lesions; and 4, very Severe lesion. A score of 50% or higher compared to group C (aspirin-treated control group = 100%) was considered a positive score for gastric irritation.

The results are shown in Table 6. Group D (100 mg / kg ibuprofen-treated control group) and Group F (200 mg / kg ibuprofen-treated control group) were 75% and 95% of severity when induced in group C (aspirin-treated control group), respectively. A gastric lesion was formed. However, Group E (BC1054-100 treated experimental group) and Group G (BC1054-200 treated experimental group) were gastric diseases with 20% and 40% severity of gastric lesions associated with Group C (aspirin treated control group), respectively. Formed a strange. These results indicate that the pharmaceutical compositions disclosed herein reduce the extent to which the therapeutic compound causes mucosal lesions and further causes gastric irritation.

Example 7
A Case Study for Treatment of Intense Pain A 51-year-old man who experienced severe toothache due to nerve exposure after collapse of a tooth filling. The pain was considered too severe to be suppressed with ibuprofen or diclofenac, but the patient disliked the combination of codeine (30 mg) and paracetamol (500 mg) useful for him. The patient contains a 7-day course of 20 mg / kg ibuprofen, 10% ethanol, and 90% rapeseed oil (800 mg twice daily) before going to the dentist to receive a therapeutic cement fill. The pharmaceutical composition (BC1054) disclosed in (1) was taken, thereby effectively suppressing pain. Pain relief occurred within 30 minutes after taking each dose and lasted approximately 12 hours before taking again. The pain control was so good that the patient was no longer aware of the affected tooth pain.

  A 50-year-old man was diagnosed with a masonneuve fracture of an ankle after a sports injury. The patient initially received 500 mg paracetamol and 30 mg codeine in addition to taking 10 mg diclofenac 3 times a day for 8 months to control severe pain. After receiving unacceptable side effects, the patient discontinued the opiate paracetamol and diclofenac therapy and disclosed 20 mg / kg ibuprofen, 10% ethanol, and 90% rapeseed oil (600 mg twice daily). ) Started a 5-day course of a pharmaceutical composition (BC1054). The patient revealed a significant improvement in pain after 2 days and that the pain was completely suppressed after 3 days. Even after 2 months of follow-up, the patient is in a state where there is no severe pain, and thereafter he has resumed an active sports life.

Example 8
Treatment of severe pain After lifting a heavy box the day before, a 62-year-old woman complains of severe back pain. The doctor determines that the back pain is due to acute pain. Women are treated by oral administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, women are treated by oral administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, women are treated by oral administration of a pharmaceutical composition comprising naproxen taken twice a day as disclosed herein. The woman's condition is monitored and after about 3 days of treatment, the woman informs her that the pain has decreased. At 1 week and 3 weeks later, the woman informs that the pain reduction continues. This reduction in acute pain symptoms indicates successful treatment with the pharmaceutical compositions disclosed herein. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 22-year-old man complains of severe pain in his right shoulder that occurred when he lifted a weight one month ago at the gym. The doctor determines that the severe pain is subacute pain. Men are treated by oral administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising naproxen taken twice a day as disclosed herein. The male condition is monitored and after about 3 days of treatment, the male is informed that he has improved to move his arms without shoulder pain. At 1 week, 1 month, and 3 months later, the male informs that shoulder mobility has improved and is painless. This reduction in subacute pain symptoms indicates successful treatment with the pharmaceutical compositions disclosed herein. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 67-year-old man complains of severe ankle pain due to a fall two months ago. The doctor determines that the pain is chronic pain. Men are treated by oral administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising naproxen taken twice a day as disclosed herein. The male condition is monitored and after about 3 days of treatment, the male informs that ankle pain has been reduced and ankle mobility has been improved. At 1 month and 3 months later, the man informs that the mobility of the ankle joint is improved and painless continues. This reduction in chronic pain symptoms indicates successful treatment with the pharmaceutical compositions disclosed herein. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 73-year-old woman complains of severe pain after burning her forearm in a heating oven. The physician determines that the pain is superficial somatic nociceptive pain. Women are treated by oral administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, women are treated by oral administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, women are treated by oral administration of a pharmaceutical composition comprising naproxen as disclosed herein twice daily. The woman's condition is monitored, and after about 3 days of treatment, she is informed that she no longer feels forearm pain. At week 1 and week 3 examinations, the woman informs her that she does not feel pain at that time. This reduction in symptoms of superficial nociceptive pain indicates successful treatment with the pharmaceutical compositions disclosed herein. Similar types of oral administration of the pharmaceutical compositions disclosed herein include, but are not limited to, excessive muscle tone, repetitive movement disorders, myopathy, myalgia, infections, and other drug-induced pain Used to treat patients suffering from severe pain associated with any deep somatic nociceptive pain. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 37-year-old man complains of severe pain from a broken leg while skiing. The physician determines that the pain is due to deep somatic nociceptive pain. Men are treated by oral administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising naproxen taken twice a day as disclosed herein. The man's condition is monitored and after about 3 days of treatment, the man informs that leg pain has decreased. At one month and two months later, the man informs that the pain reduction continues. This reduction in deep somatic nociceptive pain symptoms indicates successful treatment with the pharmaceutical compositions disclosed herein. Similar types of oral administration of the pharmaceutical compositions disclosed herein include, but are not limited to, excessive muscle tone, repetitive movement disorders, myopathy, myalgia, infections, and other drug-induced pain Used to treat patients suffering from severe pain associated with any deep somatic nociceptive pain. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 33-year-old woman complains of chronic abdominal pain. The physician determines that the pain is due to deep visceral nociceptive pain. Women are treated by oral administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, women are treated by oral administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, women are treated by oral administration of a pharmaceutical composition comprising naproxen as disclosed herein twice daily. The woman's condition is monitored and after about 3 days of treatment, the woman informs that her abdominal pain is decreasing. At 1 month and 3 months later, the woman informs that the reduction in abdominal pain continues. This reduction in visceral nociceptive pain symptoms indicates successful treatment with the pharmaceutical compositions disclosed herein. Oral administration of similar types of pharmaceutical compositions disclosed herein includes, but is not limited to, any other including functional visceral pain, chronic gastroenteritis, autoimmune pain, organic visceral pain, and treatment-induced visceral pain It is used to treat patients suffering from severe pain associated with such deep visceral nociceptive pain. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 66-year-old man complains of severe pain after a stroke. The doctor determines that the pain is due to central neuropathic pain. Men are treated by oral administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising naproxen taken twice a day as disclosed herein. The male condition is monitored and after about 3 days of treatment, the male informs that the abdominal pain is decreasing. At 1 month and 3 months later, the man informs that the pain reduction is continuing. This reduction in symptoms of central neuropathic pain indicates successful treatment with the pharmaceutical compositions disclosed herein. Oral administration of similar types of pharmaceutical compositions disclosed herein includes, but is not limited to, cerebral venous thrombosis, cerebral tumors or abscesses compressing the brain, traumatic brain injury or spinal cord injury, brain or spinal cord Postoperative complications, multiple sclerosis, and any other central neuropathic or dysfunctional pain, including Parkinson's disease, ischemic lesions, syringomyelia, radiation myelopathy, and HIV myelopathy Used to treat patients suffering from the severe pain associated with In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 58-year-old man with diabetes complains of severe pain. The doctor determines that the pain is due to peripheral neuropathic pain from diabetic neuropathy. Men are treated by oral administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising naproxen taken twice a day as disclosed herein. The man's condition is monitored and after about 3 days of treatment, the man informs that pain is decreasing. At one month and three months later, the man informs that pain is still decreasing. This reduction in peripheral neuropathic pain indicates successful treatment with the pharmaceutical compositions disclosed herein. Oral administration of similar types of pharmaceutical compositions disclosed herein includes, but is not limited to, systemic diseases, metabolic disorders, nutritional disorders, drug-induced disorders, trauma and intrusion syndrome, postoperative complications, distal axis Chordal disorder, HIV sensory neuropathy, demyelinating polyradiculoneuropathy, postherpetic neuralgia, nerve root extraction, cerebral neuralgia like trigeminal neuralgia, neuropathic cancer pain; peripheral nerve, plexus, and nerve root Paraneoplastic peripheral neuropathy, ganglionopathy; complications of cancer therapy such as chemotherapy, irradiation, and surgery; and complex local pain syndromes such as type 1 and type 2; Is used to treat patients suffering from severe pain associated with any other peripheral neuropathic or dysfunctional pain. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 59-year-old woman complains of severe pain that occurs even with a slight pressure on her forearm. The doctor determines that the pain is due to allodynia. Women are treated by topical administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, women are treated by topical administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, women are treated by topical administration twice daily of a pharmaceutical composition comprising naproxen as disclosed herein. The woman's condition is monitored and after about 3 days of treatment, the woman informs her that the pain has decreased. At one month and three months later, the woman informs that the pain reduction continues. This reduction in allodynia symptoms indicates successful treatment with the pharmaceutical compositions disclosed herein. Similar types of topical administration of the pharmaceutical compositions disclosed herein are used to treat patients suffering from severe pain associated with some sensory dysfunction such as, for example, hyperalgesia or hyperalgesia. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 47-year-old woman complained of severe pain in her left leg when she was crouching and washing dishes. The physician determines that lower limb pain is due to sciatic nerve dysfunction. Women are treated by oral administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, women are treated by oral administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, women are treated by oral administration of a pharmaceutical composition comprising naproxen as disclosed herein twice daily. The woman's condition is monitored and after about 3 days of treatment, the woman informs her that pain is decreasing. At the 1 month and 3 month examinations, the woman informs that the reduction in leg pain continues. This reduction in symptoms of sciatic nerve dysfunction indicates successful treatment with the pharmaceutical compositions disclosed herein. Similar types of oral administration of the pharmaceutical compositions disclosed herein include, for example, total peroneal nerve dysfunction, peroneal nerve dysfunction, ulnar nerve dysfunction, monobrain neuropathy VI, monobrain neuropathy VII, monobrain neuropathy III (Compression type), monocranial neuropathy III (diabetic type), axillary nerve dysfunction, carpal tunnel syndrome, femoral nerve dysfunction, tibial nerve dysfunction, bell palsy, thoracic outlet syndrome, carpal tunnel syndrome or other local Used to treat patients suffering from severe pain associated with any single neuropathy, such as strangulated neuropathy and sixth (abduction) cranial nerve palsy. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 22-year-old man complains of severe pain in his right leg that developed after hiking in the forest. The doctor determines that the severe pain is due to Lyme disease. Men are treated by intravenous injection administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, men are treated by intravenous injection administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, men are treated by intravenous injection administration of a pharmaceutical composition comprising naproxen taken twice a day as disclosed herein. The man's condition is monitored and after about 3 days of treatment, the man informs that pain is decreasing. At 1 week, 1 month, and 3 months later, the man informs that the painless condition continues. This reduction in Lyme disease symptoms indicates successful treatment with the pharmaceutical compositions disclosed herein. Similar types of intravenous administration of the pharmaceutical compositions disclosed herein include, for example, systemic diseases, metabolic disorders, nutritional disorders, drug-induced disorders, trauma and intrusion syndromes, addictions, and infections, etc. Used to treat patients suffering from severe pain associated with some polyneuropathy. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 67-year-old man with chronic alcoholism complains of severe pain. The doctor determines that the pain is polyneuropathy. Men are treated by oral administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising naproxen taken twice a day as disclosed herein. The man's condition is monitored and after about 3 days of treatment, the man informs that pain is decreasing. At one month and three months later, the man informs that the painless condition continues. This reduction in the symptoms of polyneuropathic pain indicates successful treatment with the pharmaceutical compositions disclosed herein. Similar types of oral administration of the pharmaceutical compositions disclosed herein include, but are not limited to, acute inflammatory demyelinating polyneuritis, chronic inflammatory demyelinating polyneuropathy, and genetic metabolic disorders Used to treat patients suffering from severe pain associated with any other polyneuropathy. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 73-year-old woman complains of severe bladder pain. The doctor determines that the pain is due to autonomic disturbance. Women are treated by infusion of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, women are treated by oral administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, women are treated by oral administration of a pharmaceutical composition comprising naproxen as disclosed herein twice daily. The woman's condition is monitored and informs that after about 3 days of treatment, the woman no longer feels pain in the bladder. At the time of the examination after one and three months, the woman informs her that she does not feel pain at that time. This reduction in autonomic neuropathy symptoms indicates successful treatment with the pharmaceutical compositions disclosed herein. Similar types of oral administration of the pharmaceutical compositions disclosed herein are used to treat patients suffering from severe pain associated with any other autonomic neuropathy that affects some other internal organ. The In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 42-year-old man complains of severe pain that occurs whenever he presses the left side of his face. The doctor determines that the pain is due to trigeminal neuralgia. Men are treated by topical administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, men are treated by topical administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, men are treated by topical administration of a pharmaceutical composition comprising naproxen taken twice a day as disclosed herein. The male condition is monitored, and after about 3 days of treatment, the male informs that facial pain is decreasing. At one month and two months later, the man informs that the pain reduction continues. This reduction in the symptoms of trigeminal neuralgia indicates successful treatment with the pharmaceutical compositions disclosed herein. Similar types of topical administration of the pharmaceutical compositions disclosed herein include, but are not limited to, glossopharyngeal neuralgia, postherpetic neuralgia, carpal tunnel syndrome, abnormal sensory femoral pain, sciatica and atypical facial pain, Is used to treat patients suffering from severe pain associated with any other neuralgia. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 54-year-old woman complains of left shoulder pain after suffering a heart attack. The physician determines that the pain is due to related pain from myocardial ischemia. Women are treated by oral administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, women are treated by oral administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, women are treated by oral administration of a pharmaceutical composition comprising naproxen taken twice a day as disclosed herein. The woman's condition is monitored and after about 3 days of treatment, the woman informs her that shoulder pain is decreasing. At one month and three months later, the woman informs that the condition with reduced shoulder pain continues. This reduction in associated pain symptoms indicates successful treatment with the pharmaceutical compositions disclosed herein. Similar types of oral administration of the pharmaceutical compositions disclosed herein are used to treat patients suffering from severe pain associated with any other related pain, including but not limited to disc herniation. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 26-year-old man complains of severe pain in a previously cut arm. The doctor determines that the pain is due to phantom pain. Men are treated by oral administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising naproxen taken twice a day as disclosed herein. The man's condition is monitored and after about 3 days of treatment, the man informs that pain is decreasing. At 1 month and 3 months later, the man informs that the pain reduction is continuing. This reduction in phantom symptoms indicates successful treatment with the pharmaceutical compositions disclosed herein. Similar types of oral administration of the pharmaceutical compositions disclosed herein include, but are not limited to, brain injury, spinal cord injury, lumbar radiculopathy, post-stroke pain, paraplegia, brachial plexus detachment or other types It is used to treat patients suffering from severe pain associated with any other afferent block pain syndrome, including peripheral nerve lesions, pathologies of the central nervous system. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 58-year-old man complains of a headache. Men are treated by oral administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, men are treated by oral administration of a pharmaceutical composition comprising naproxen taken twice a day as disclosed herein. The man's condition is monitored and after about 3 hours of treatment, the man informs that the headache is gone. This disappearance of headache indicates successful treatment with the pharmaceutical compositions disclosed herein. Oral administration of similar types of pharmaceutical compositions disclosed herein includes, but is not limited to, muscular / myogenic headache, vascular headache, traction headache, inflammatory headache, chronic sinusitis headache, hormonal headache It is used to treat patients suffering from severe pain associated with any other headache, including rebound headache, organic headache, and epileptic headache. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  A 59-year-old woman complains of a severe headache. The doctor determines that the pain is due to migraine. Women are treated by oral administration of a pharmaceutical composition comprising ibuprofen taken twice a day as disclosed herein. Alternatively, women are treated by topical administration of a pharmaceutical composition comprising aspirin taken three times a day as disclosed herein. Alternatively, women are treated by topical administration of a pharmaceutical composition comprising naproxen taken twice a day as disclosed herein. The woman's condition is monitored and after about 3 days of treatment, the woman informs her that there is no recurrence of migraine. At the 1 month and 3 month examinations, the woman informs that the state of reduced migraine frequency and intensity continues. This reduction in migraine symptoms indicates successful treatment with the pharmaceutical compositions disclosed herein. Similar types of oral administration of the pharmaceutical compositions disclosed herein include, but are not limited to, migraine without aura (common migraine), migraine with aura (classical migraine), menstrual migraine For the treatment of patients suffering from severe pain associated with any other migraine, including migraine equivalent (migraine headache), complex migraine, abdominal migraine, and mixed migraine used. In a similar manner, for example, salicylic acid derivative NSAID, p-aminophenol derivative NSAID, propionic acid derivative NSAID, acetic acid derivative NSAID, enolic acid derivative NSAID, fenamic acid derivative NSAID, non-selective cyclooxygenase (COX) inhibitor, selective cyclooxygenase Either a 1 (COX1) inhibitor, a selective cyclooxygenase 2 (COX2) inhibitor, or a fibrate is formulated into a pharmaceutical composition and administered to the patient described above.

  Finally, while aspects of the specification have been emphasized by reference to specific embodiments, it is to be understood that these disclosed embodiments are merely illustrative of the principles of the disclosed subject matter. It should be understood that those skilled in the art will readily recognize. Accordingly, it is to be understood that the disclosed subject matter is in no way limited to the specific methods, protocols, and / or reagents described herein. Accordingly, various modifications or changes to the disclosed subject matter or alternative components of the disclosed subject matter can be made in accordance with the teachings herein without departing from the spirit of the specification. Finally, the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the invention. The scope of the invention is defined only by the claims. Accordingly, the present invention is not limited to that precisely as shown and described.

  Particular embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, changes to these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor anticipates that those skilled in the art will adopt such modifications as needed, and that the inventor will do this in a manner other than that specifically described herein. It is contemplated that the invention will be practiced. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments as all possible variations thereof is included in this application unless otherwise indicated herein or otherwise clearly contradicted by context. Is included.

  Alternative groupings of elements, elements or steps of the invention should not be construed as limiting the invention. The members of each group may be billed individually or in any combination with reference to other group members disclosed herein. It is anticipated that one or more members of a group may be included in or removed from the group for convenience and / or patentability reasons. If any such inclusion or removal occurs, the specification will be modified and therefore considered to include groups that meet the description requirements of all Markush groups used in the appended claims.

  Unless otherwise indicated, all numbers representing characteristics, items, quantities, parameters, properties, periods, etc. used in the specification and claims are qualified in all cases with the word “about”. Should be understood as being. As used herein, the term “about” means that a property, item, quantity, parameter, property, period, and so on, of the indicated property, item, quantity, parameter, property, period, is so limited. It is meant to encompass ranges that are plus or minus 10% higher or lower than the value. Accordingly, unless otherwise indicated, the numerical parameters set forth in the specification and appended claims are approximations that may vary. To say the least, nor is it intended to limit the application of the doctrine of equivalents to the scope of the claims, but each numerical representation should at least take into account the number of reported significant digits and It must be interpreted by applying rounding techniques. Although numerical ranges and values describing the broad scope of the invention are approximations, the numerical ranges and values set forth in the specific examples are reported as accurately as possible. Any numerical range and values, however, necessarily arise due to standard deviations and include certain inherent errors that are permitted in their respective testing measurements. The recitation of a range of values herein is intended only to serve as a shorthand notation for individually referring to each distinct value that falls within that range. Unless otherwise indicated herein, each individual value in a numerical range is incorporated into the specification as if it were individually described herein.

  The terms “a”, “an”, “the” used in the context of describing the present invention (particularly in the context of the following claims), unless otherwise indicated, or are clearly inconsistent with the context Unless otherwise, it should be construed to include both the singular and plural forms. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context for another reason. Use of any and all examples or exemplary expressions provided herein (eg, “such as”) is solely for the purpose of clarifying the present application and is separately claimed. There are no restrictions on the scope of the application. No language in the specification should be construed as indicating any non-claimed element essential to the practice of this application.

  The specific embodiments disclosed herein may be further limited in the claims using the phrase “consisting of” or consisting essentially of “consisting essentially of”. When used in a claim, whether it is used at the time of filing or added during amendment, the transitional word “consisting of” is not specified in the claim. Are excluded. The transitional word “consisting essentially of” limits the scope of the claims to those that do not substantially affect the particular material or process and the basic, new features. The embodiments of the invention so claimed have been described essentially or explicitly and can be used herein.

  All patents, patent publications, and other publications mentioned and identified herein are described, for example, in such publications and describe compositions and methods that can be used in connection with the present invention. And are hereby expressly incorporated herein by reference in their entirety for purposes of disclosure. These publications are presented solely because they are disclosed prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are entitled to antedate such disclosure for any prior invention or for any other reason. Dates or representations relating to the content of these documents are based on information available to the applicants and are not an admission regarding the accuracy of the date or content of these documents.

Claims (18)

A pharmaceutical composition comprising:
therapeutic compounds with a) anti-pain activity, and b) a 30 wt% to 95 wt% of a pharmaceutically acceptable adjuvant of the pharmaceutical composition, the pharmaceutically acceptable adjuvant, wherein the pharmaceutical composition and hard fat of at least 30% by weight objects, a hydrophobic lipid containing a monoglyceride, a is an amount of 1 wt% to 50 wt% of a pharmaceutically acceptable adjuvant, and c) the pharmaceutical composition pharmaceutical A pharmaceutically acceptable solvent, which is a pharmaceutically acceptable polypropylene glycol (PPG) polymer, a pharmaceutically acceptable polyethylene glycol (PEG) polymer, or any combination thereof. solvent,
Including
Does not contain emulsifiers or hydrophilic solvents,
Formulated to be solid at a temperature of 15 ° C. or lower and having a melting point of 25 ° C. or higher.
Pharmaceutical composition.   2. The pharmaceutical composition of claim 1, wherein the therapeutic compound comprises a non-steroidal anti-inflammatory drug (NSAID), a PPARγ agonist, a nuclear receptor binding agent, an antihyperlipidemic agent, or any combination thereof.   The pharmaceutical composition according to claim 1 or 2, wherein the hard fat contains triglyceride. The triglycerides comprises a mixture of saturated _C 10 _{-C 18} triglycerides with a melting point of 41 ° C. to 45 ° C., the pharmaceutical composition according to claim 3. The pharmaceutical composition according to any one of claims 1 to 4, wherein the hard fat is in an amount of 30% to 50% by weight of the pharmaceutical composition or 35% to 45% by weight of the pharmaceutical composition. object.   The pharmaceutical composition according to any one of claims 1 to 5, wherein the monoglyceride comprises glyceryl monolinoleate.   7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the pharmaceutically acceptable adjuvant further comprises diglycerides, triglycerides, or any combination thereof.   The pharmaceutical composition of claim 1, wherein the PEG polymer is a liquid PEG polymer.   9. The pharmaceutical composition according to claim 8, wherein the pharmaceutically acceptable PEG polymer is less than 2,000 g / mol.   10. The pharmaceutical composition according to claim 8 or 9, wherein the liquid PEG polymer is PEG100, PEG200, PEG300, PEG400, PEG500, PEG600, PEG700, PEG800, PEG900, PEG1000, or a combination thereof.   The pharmaceutical composition of claim 1, wherein the PPG polymer is a liquid PPG polymer.   12. The pharmaceutical composition according to claim 11, wherein the pharmaceutically acceptable PPG polymer is less than 2,000 g / mol.   13. The pharmaceutical composition according to claim 11 or 12, wherein the liquid PPG polymer is PPG100, PPG200, PPG300, PPG400, PPG500, PPG600, PPG700, PPG800, PPG900, PPG1000, or a combination thereof. The pharmaceutically acceptable solvent is 4% to 30% by weight of the pharmaceutical composition, 6% to 20% by weight of the pharmaceutical composition, 8% to 15% by weight of the pharmaceutical composition, the 7 wt% to 13 wt% of the pharmaceutical composition, 8% to 12% by weight of the pharmaceutical composition, or 9. the amount of weight percent to 11 weight percent of the pharmaceutical composition, more of claims 1 to 13 2. A pharmaceutical composition according to claim 1.   The pharmaceutical composition according to any one of claims 1 to 14, wherein the emulsifier is a surfactant, a polysaccharide, a lectin, and a phospholipid.   16. A pharmaceutical composition according to any one of claims 1 to 15 for use in the treatment of severe pain conditions.   The pharmaceutical composition according to claim 16, wherein the severe pain state is acute pain, subacute pain, or chronic pain.   17. The pharmaceutical composition according to claim 16, wherein the severe pain state is nociceptive pain, pathological pain, related pain, headache, or migraine.