Pharmaceutical composition

Abstract

The present invention relates to a self-emulsifying pharmaceutical composition comprising an unsaturated free fatty acid, at least two emulsifiers, and at least one active pharmaceutical ingredient; the use of said pharmaceutical composition as a medicament; and a process for preparing said composition.

Description

[Technical Field]

[0001] The present invention relates to self-emulsifying pharmaceutical compositions comprising unsaturated free fatty acids, at least two emulsifiers, and at least one active pharmaceutical ingredient (lopinavir); methods for producing the same; and the pharmaceutical use of the said pharmaceutical compositions. In particular, pharmaceutical compositions comprising lopinavir and ritonavir are provided for use in treating and / or inhibiting the progression of diseases and / or disorders, such as HPV-related dysplasia of the cervix. [Background technology]

[0002] Self-emulsifying drug delivery systems (SEDDSs) form emulsions not as a result of mechanical mixing, but rather as a result of the chemical properties of the components of the delivery system. Typically, lipophilic drugs dissolve in oil-based formulations that also contain surfactants. The formulations may be filled into soft or hard capsules for oral administration. After oral administration, if the SEDDS formulation comes into contact with an aqueous environment, such as gastrointestinal fluid, it spontaneously forms an oil-in-water emulsion, which promotes drug absorption.

[0003] Commercially available SEDDS formulations include those containing the orally administered drug cyclosporine, as well as those marketed under the brand names Neoral® and Gengraf®. Norvir® and Fortovase® are marketed as SEDDS formulations containing the HIV protease inhibitors ritonavir and saquinavir, respectively [Gibaud & Attivi, Expert Opinion on Drug Delivery 2012, 937-951].

[0004] Self-emulsifying compositions are isotropic mixtures typically containing oils, surfactants, and optionally auxiliary surfactants and / or cosolvents. Examples of oils used in SEDDSs include long-chain triglycerides, e.g., sesame oil, soybean oil, and castor oil, medium-chain triglycerides, silicone oils, fatty acids, and aliphatic alcohols. Oils are required to dissolve lipophilic or poorly water-soluble drugs. Surfactants or emulsifiers are added to ensure efficient self-dispersion and stability of the formed oil-in-water emulsion. Nonionic surfactants can be classified by their hydrophilic-lipophilic balance (HLB) on a scale of 1 to 20 (where 1 is lipophilic and 20 is hydrophilic) [Griffin, J.Soc. Cosmetic Chem. 1954, 249-256]. Examples of surfactants include polyol and vegetable oil ethers (e.g., polyoxyl 35 castor oil (Cremophor® EL) and polyoxyl 40 hydrogenated castor oil (Cremophor® RH40)), polyol glycerides (e.g., lauroyl macrogol-32 glyceride (Gelucire® 44 / 14) and polyol esters (e.g., polysorbate (e.g., Tween® 20 or Tween® 80) or polyethylene glycol stearate)), as well as more lipophilic surfactants including propylene glycol monoesters (e.g., propylene glycol monolaurate or propylene glycol monocaprylate), glycol monoethers (e.g., Transcutol® or Carbitol®)), and monoglycerides and diglycerides. To provide a stable emulsion, the surfactant content of SEDDS is generally in the range of 30% to 60% by weight [Kovvasu et [al., Asian J. Pharm. 2019, 73-84]. Suitable cosolvents include water, ethanol, glycerin, and polyethylene glycol [Gibaud & Attivi, Expert Opinion on Drug Delivery 2012, 937-951].

[0005] This invention is based on research conducted by the inventors to formulate a self-emulsifying composition containing at least one active pharmaceutical ingredient (lopinavir). The inventors unexpectedly discovered that when at least two emulsifiers having specific properties are used in combination with an unsaturated free fatty acid and at least one active pharmaceutical ingredient (lopinavir), a self-emulsifying drug formulation (SEDDS) with unexpectedly good properties (e.g., drug solubility, and therefore potentially excellent bioavailability) can be obtained, even if the total amount of emulsifiers in the formulation is relatively low.

[0006] The use of unsaturated free fatty acids in a composition is advantageous because it allows control over the quality of the free fatty acids in the composition, such as their identity, quantity, and purity. In contrast, other excipients, such as vegetable oils and polysorbates, may contain low and variable levels of free fatty acids. The composition of free fatty acids in vegetable oils and polysorbates, such as their identity and quantity, may vary from batch to batch and over time. Advantageously, in one embodiment, the active pharmaceutical ingredient is soluble in unsaturated free fatty acids, thus eliminating the need for heating above room temperature to achieve solubilization. This is particularly advantageous when using active pharmaceutical ingredients that are prone to degradation (e.g., lopinavir); especially when the extent and / or rate of degradation, such as degradation by oxidation and / or hydrolysis, increases when the active pharmaceutical ingredient is exposed to heat.

[0007] Preferably, the compositions of the present invention are useful in the treatment of cancer. Many different forms of cancer exist, and it is believed that many different disease causes exist. Although the incidence of cancer varies, in most developed countries, cancer is the second leading cause of death after heart disease.

[0008] Human oncoviruses are recognized as major causes of human cancer, and there is considerable evidence supporting the argument that these viruses cause cancer by inducing genetic instability in infected cells. Indeed, both human T-cell leukemia virus type 1 (HTLV1) Tax and human papillomavirus type 16 (HPV16) E6 oncoprotein are known to induce genetic instability that produces an abnormal number of centrosomes, multinucleation, and nuclear atypia.

[0009] Invasive cervical cancer (ICC) is a type of cancer associated with viral infections that causes >270,000 deaths per year, with over 85% of these occurring in resource-poor countries. Infection with high-risk HPV is established as a major causative agent of ICC. ICC can take 10 to 20 years to develop and is preceded by an HPV-associated pre-invasive condition characterized by either low-grade (CIN1) or high-grade (CIN2 / 3) cervical intraepithelial neoplasia. Lesions can be screened by cervical cytology, in which cells are diagnosed (or graded) as either borderline atypical squamous cell lesions (ASCUS) of undetermined severity, low-grade squamous intraepithelial neoplasia (LSIL), or high-grade squamous intraepithelial neoplasia (HSIL).

[0010] The decline in ICC-related mortality in the developed world relies primarily on organized cytological screening, and similar trends in cervical cancer mortality have been achieved through organized single screening and treatment in other parts of the world. However, a lack of resources and health education in poor countries means that the majority of invasive precervical diseases remain undiagnosed and untreated. Therefore, where resources are limited, low-cost screening and treatment options clearly deserve a higher priority.

[0011] Current treatment options in clinical practice are either destructive or excisional. Histological re-examinations have demonstrated that these treatment methods have similar success rates but differing morbidities. In developed countries worldwide, large loop excision of the transformation zone (LLETZ) (also known as loop electrosurgical excision procedure - LEEP) is used in the majority of clinical velvet and cervical examinations. Over 80% of these procedures are performed locally painlessly, and the entire transformation zone is available for subsequent histological examination. This procedure is associated with the risks of primary / secondary bleeding, prolonged bleeding, infection, and premature birth in subsequent pregnancies. The former side effects can be particularly problematic in resource-poor countries. Destructive procedures in the form of cryotherapy and cryotherapy are often recommended in resource-poor countries because they are low-cost, require minimal infrastructure, and can be performed by trained non-medical healthcare professionals. However, some studies suggest that cryotherapy has a higher failure rate compared to other treatment methods.

[0012] There are various topical and non-surgical approaches being evaluated for the treatment of cervical dysplasia, including photodynamic therapy (PDT); off-licensed use of the anti-cytomegalovirus (CMV) drug cidofovir; topical application of the immunoactivator imiquimod; and direct application of the cytotoxic drug 5-fluorouracil (5-FU). While some of these alternative treatment methods are promising, their outcomes are inferior to the 80–95% success rates reported to be obtained in quality-assured cervical examination units.

[0013] Effective, inexpensive, non-surgical, self-administered treatments for HPV-related cervical dysplasia hold great potential, especially in resource-poor environments. Furthermore, improved compliance with self-administered treatments will be enhanced if side effects are minimized.

[0014] Recent advances in the treatment of viral cancers are disclosed in WO2015 / 059485, which describes the clinical usefulness of protease inhibitors, lopinavir and ritonavir (which have been used as orally administered medicines for the clinical management of retroviral infections, e.g., HIV) for topical administration to tissues for the prevention or treatment of malignancies caused by human papillomavirus. The authors have reported that KALETRA® soft capsules (marketed by Abbott / Abbvie for the treatment of HIV infection by oral administration) can be administered topically (e.g., inserted vaginally for cervical treatment) for the prevention or treatment of cancerous conditions, for the prevention or treatment of oncogenic viral infections, and for the prevention or treatment of benign proliferative conditions.

[0015] KALETRA® is available for oral administration as a solution containing 80 mg of lopinavir and 20 mg of ritonavir per milliliter, or as oral soft capsules containing 133.3 mg of lopinavir and 33.3 mg of ritonavir (lopinavir:ritonavir wt / wt ratio 4:1). The solution further contains alcohol (42% w / w), high fructose corn syrup, propylene glycol, purified water, glycerol, povidone, flavorings, polyoxyl 40 hydrogenated castor oil, acesulfame potassium, sodium saccharin, sodium chloride, peppermint oil, sodium citrate, citric acid, and menthol. The contents of the soft capsules contain lopinavir and ritonavir, along with oleic acid, propylene glycol, polyoxyl 35 castor oil (Cremophor® EL), and purified water (KALETRA® Summary of Product Characteristics, EMA; WO2002 / 096395).

[0016] The compositions of the present invention offer significant advantages compared to previous formulations. Therefore, in one particular embodiment, when a composition comprising lopinavir and ritonavir is administered topically to a mucosal surface (for example, by insertion into the vagina for cervical treatment) or orally, the composition can be used to treat and prevent cancerous conditions, to prevent or treat oncogenic viral infections, and to prevent or treat benign proliferative conditions. [Overview of the project]

[0017] A self-emulsifying pharmaceutical composition comprising an unsaturated free fatty acid, at least two emulsifiers, and at least one active pharmaceutical ingredient (API) (lopinavir and ritonavir) is disclosed herein.

[0018] According to a first aspect of the present invention, a. Unsaturated free fatty acids; b. At least two emulsifiers; and c. At least one active pharmaceutical ingredient (lopinavir); A self-emulsifying pharmaceutical composition is provided, comprising, wherein the at least two emulsifiers include, at least, a first emulsifier having an HLB value greater than about 14, and at least a second emulsifier having an HLB value less than about 6; and the total emulsifier content is less than 30% by weight of the total composition.

[0019] According to the second aspect, a process for producing the self-emulsifying pharmaceutical composition of the first aspect, a) The step of incorporating at least one active pharmaceutical ingredient (lopinavir) into an unsaturated free fatty acid; b) A step of incorporating at least two emulsifiers into the mixture obtained in step a) to obtain a self-emulsifying composition. A process is provided which includes at least two emulsifiers, a first emulsifier having an HLB value of at least about 14 and a second emulsifier having an HLB value of at least less than about 6; and the total emulsifier content is less than 30% by weight of the total composition.

[0020] A third aspect of the present invention provides a pharmaceutical composition according to the first aspect of the present invention for use as a pharmaceutical. In one embodiment, the pharmaceutical composition is used as a pharmacopoeia to treat and / or inhibit the onset or progression of a disease and / or disorder. In one embodiment, the pharmaceutical composition is used as a pharmacopoeia to treat and / or inhibit the onset or progression of cancer and / or benign proliferative disorders. In one embodiment, the pharmaceutical composition comprises an effective amount of at least one active pharmaceutical ingredient (lopinavir). In one embodiment, the pharmaceutical composition comprises an effective amount of at least one active pharmaceutical ingredient (lopinavir) to treat and / or inhibit the onset or progression of a disease or disorder. In one embodiment, the pharmaceutical composition comprises an effective amount of at least one active pharmaceutical ingredient (lopinavir) to treat and / or inhibit the onset or progression of cancer and / or benign proliferative disorders. In a further embodiment, the pharmaceutical composition comprises an effective amount of at least one active pharmaceutical ingredient (lopinavir and / or ritonavir) for treating human papillomavirus (HPV) infection with or without associated abnormal pathology. In one embodiment, the pharmaceutical composition is used as a pharmacopoeia to treat and / or inhibit the development of early-stage neoplasms. In one embodiment, the pharmaceutical composition is used as a pharmacopoeia to treat or prevent the development of HPV-associated neoplasms and / or warts of the cervix, vulva, vagina, penis, anus, mouth, or larynx. In one embodiment, the pharmaceutical composition is intended for use as a pharmacopoeia to treat or prevent the development of cervical neoplasms.

[0021] According to a fourth aspect of the present invention, there is provided a method of treating and / or inhibiting the onset or progression of a disease and / or disorder in a subject that requires such treatment or inhibition, the method comprising administering a therapeutically effective amount of a composition according to the first aspect of the present invention. In one embodiment, there is provided a method of treating and / or inhibiting the onset or progression of cancer and / or a benign proliferative disorder in a subject that requires such treatment or inhibition, the method comprising administering a therapeutically effective amount of a composition according to the first aspect of the present invention. In one embodiment, the cancer or disorder is caused or induced by human papillomavirus (HPV). In a further embodiment, there is provided a method of treating a human papillomavirus (HPV) infection, with or without associated abnormal pathology, in a subject that requires such treatment or inhibition, the method comprising administering a therapeutically effective amount of a pharmaceutical composition according to the first aspect of the present invention. In one embodiment, there is provided a method of treating and / or inhibiting the onset of a neoplasm at an early stage in a subject that requires such treatment or inhibition, the method comprising administering a therapeutically effective amount of a pharmaceutical composition according to the first aspect of the present invention. In one embodiment, there is provided a method of treating or preventing the onset of neoplasms and / or warts in the cervix, vulva, vagina, penis, anus, mouth or larynx associated with HPV in a subject that requires such treatment or inhibition, the method comprising administering a therapeutically effective amount of a pharmaceutical composition according to the first aspect of the present invention. In one embodiment, there is provided a method of treating or preventing the onset of cervical neoplasms in a subject that requires such treatment or inhibition, the method comprising administering a therapeutically effective amount of a pharmaceutical composition according to the first aspect of the present invention.

[0022] Preferably, these cancers or benign proliferative disorders are caused by a viral infection, more preferably an oncogenic virus and particularly a human tumor virus, such as HPV.

[0023] Preferably, the present invention relates to the treatment of a subject having cervical dysplasia associated with HPV, the treatment comprising administering to the subject a therapeutically effective amount of the disclosed pharmaceutical composition.

Best Mode for Carrying Out the Invention

[0024] The disclosed compositions, manufacturing processes, and methods can be more easily understood by referring to the following modes for carrying out the inventions that form part of this disclosure. The disclosed compositions, manufacturing processes, and methods are not limited to the specific compositions, manufacturing processes, and methods described and / or shown herein, and the terms used herein are for the purpose of describing specific embodiments by way of example only and are not intended to limit the claimed compositions, manufacturing processes, and methods. It should be understood that.

[0025] References to specific numerical values include at least the specific value, unless the context clearly indicates otherwise. When a range of values is expressed, other embodiments include from one specific value and / or to another specific value. Further, references to values recited in a range include any and all values within that range. All ranges include the values at both ends and are combinable.

[0026] It should be recognized that certain features of the disclosed compositions, manufacturing processes, and methods described herein in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for the sake of brevity, the various features of the disclosed compositions, manufacturing processes, and methods described in the context of a single embodiment may also be provided separately or in any sub-combination.

[0027] As used herein, the singular forms "a", "an", and "the" include the plural.

[0028] The following abbreviations are used herein: human papillomavirus (HPV); atypical squamous cell carcinoma of undetermined severity (ASC-US); low-grade squamous intraepithelial lesion (LSIL); high-grade squamous intraepithelial lesion (HSIL); cervical intraepithelial neoplasia 1 (CIN1); cervical intraepithelial neoplasia 2 (CIN2); cervical intraepithelial neoplasia 3 (CIN3); carcinoma in situ (CIS); invasive cervical cancer (ICC).

[0029] When values ​​are expressed as approximations using the antecedent “approximately,” it should be understood that a particular value forms a different embodiment. When the term “approximately” is used in relation to a numerical range, truncation, or particular value, it is used to suggest that the enumerated values ​​may vary by up to 10% from the enumerated value. Since many of the numerical values ​​used herein are determined experimentally, it should be understood by those skilled in the art that such determinations may vary between different experiments, and often will vary. The values ​​used herein should not be considered overly restrictive due to this inherent variation. Therefore, the term “approximately” is used to encompass variations of ±10%, ±5%, ±1%, ±0.5%, or ±0.1% from the specified value.

[0030] As used herein, terms such as “treat” mean to reduce the severity and / or frequency of symptoms, to eliminate symptoms and / or the underlying causes thereof, to reduce the frequency or likelihood of symptoms and / or their underlying causes, to delay, prevent and / or slow the progression of a disease and / or disorder, such as cancer or a benign proliferative disorder, and to improve or repair damage caused directly or indirectly by a disease and / or disorder, such as cancer or a benign proliferative disorder.

[0031] As used herein, the phrase “therapeutic dose” means an amount of a composition comprising at least one of the active pharmaceutical ingredients described herein (lopinavir) that is effective in achieving a particular biological or therapeutic outcome, for example, but not limited to, any biological or therapeutic outcome disclosed, described or illustrated herein. The therapeutic dose may vary depending on factors such as the individual’s condition, age, sex, and weight, as well as the ability of the composition to produce a desired response in the subject. Such outcomes include, but not limited to, reduction, remission, and / or regression of a benign or malignant disease, or prevention of the onset of a benign or malignant disease, as determined by any means appropriate to the art.

[0032] As used herein, “subjects” includes vertebrates, mammals, livestock, or preferably humans.

[0033] <Pharmaceutical composition> According to a first aspect of the present invention, a. Unsaturated free fatty acids; b. At least two emulsifiers; and c. At least one active pharmaceutical ingredient (lopinavir); A self-emulsifying pharmaceutical composition is provided, comprising, wherein the at least two emulsifiers include, at least, a first emulsifier having an HLB value greater than about 14, and at least a second emulsifier having an HLB value less than about 6; and the total emulsifier content is less than 30% by weight of the total composition.

[0034] When used herein, a self-emulsifying composition refers to a fat or oil-based composition that, upon introduction into water or an aqueous environment, spontaneously emulsifies to produce an oil-in-water or water-in-oil emulsion. A self-emulsifying pharmaceutical composition refers to a self-emulsifying composition containing pharmaceutically acceptable excipients.

[0035] As used herein, free fatty acids refer to fatty acids that are not bonded to a glycerol backbone, i.e., fatty acids that are not part of a glyceride. One advantage of pharmaceutical compositions containing free fatty acids is that it is possible to control the identity, quantity, and purity of the free fatty acids used in the manufacture of the pharmaceutical composition. Unsaturated free fatty acids are free fatty acids in which at least one double bond exists between carbon atoms within the fatty acid.

[0036] It is understood that commercially available free fatty acid products may contain small amounts of other fatty acids. For example, oleic acid typically contains 7-12% saturated free fatty acids, such as stearic acid and palmitic acid, and other unsaturated free fatty acids, such as linoleic acid (Handbook of Pharmaceutical Excipients, 2 nd (See Edition, entry for Oleic acid) The term unsaturated free fatty acids shall be understood to mean that unsaturated free fatty acids are of pharmacopoeia grade, e.g., United States Pharmacopeia and / or British Pharmacopoeia, and that unsaturated free fatty acids may contain small amounts of other free fatty acids.

[0037] In one embodiment, of the total unsaturated fatty acids (bound and free unsaturated fatty acids) present in the composition, at least 90% by weight, for example, at least 95% by weight, for example, at least 98% by weight, for example, at least 99% by weight, or for example, at least 99.5% by weight, are in free form, that is, neither esterified nor bound to other components, such as glycerol.

[0038] In one embodiment, the unsaturated free fatty acid is not in the form of a triglyceride or polysorbate.

[0039] In one embodiment, the unsaturated free fatty acid has a melting point of less than approximately 25°C. In one embodiment, the unsaturated free fatty acid is selected from oleic acid, linoleic acid, alpha-linoleic acid, palmitoleic acid, gondoiic acid, and ricinoleic acid. In a preferred embodiment, the unsaturated free fatty acid is oleic acid.

[0040] In one embodiment, unsaturated free fatty acids are present in the pharmaceutical composition at a level of at least 25% by weight of the total pharmaceutical composition, for example, at least 35% by weight, at least 45% by weight, at least 50% by weight, at least 55% by weight, at least 60% by weight, at least 65% by weight, or at least 70% by weight of the total pharmaceutical composition.

[0041] In one embodiment, unsaturated free fatty acids are present in the pharmaceutical composition at a level of about 25% to about 85% by weight of the total pharmaceutical composition, for example, at a level of about 40% to about 85% by weight, about 50% to about 85% by weight, about 55% to about 85% by weight, about 60% to about 80% by weight, about 65% to about 80% by weight, about 65% to about 75% by weight, or about 68% to about 72% by weight of the total composition. In a preferred embodiment, unsaturated free fatty acids are present in the pharmaceutical composition at a level of about 65% to about 75% by weight of the total composition. In the most preferred embodiment, unsaturated free fatty acids are present in the pharmaceutical composition at a level of about 68% to about 72% by weight of the total composition. In the most preferred embodiment, unsaturated free fatty acids are present in the pharmaceutical composition at a level of 68% to about 72% by weight of the total composition.

[0042] The composition according to the present invention comprises at least two emulsifiers. In one embodiment, the composition according to the present invention comprises two emulsifiers. The at least two emulsifiers comprise at least a first emulsifier having an HLB value greater than about 14, and at least a second emulsifier having an HLB value less than about 6.

[0043] In one embodiment, at least two emulsifiers are three emulsifiers. In a further embodiment, the three emulsifiers include a first emulsifier having an HLB value greater than about 14, a second emulsifier having an HLB value less than about 6, and a third emulsifier having an HLB value in the range of about 8 to about 15.

[0044] The HLB value is commonly used to define emulsifiers and / or surfactants and refers to the hydrophilic-lipophilic balance of a given compound. The HLB value can be calculated according to Griffin's method as follows [Griffin, J.Soc. Cosmetic Chem. (1949), 311-326; Griffin, J.Soc. Cosmetic Chem. (1954), 249-256]: HLB = 20 × (MW - H / MW - T) (In the formula, MW-H is the molecular weight of the hydrophilic portion of the compound, and MW-T is the molecular weight of the entire compound). For example, for the emulsifier PEG100 stearate, MW-H is the molecular weight of the ethylene glycol portion of the molecule, which is 100 × 44 (MW ethylene monomer oxide = 44 g / mol) = 4400. Since stearic acid has a molecular weight of 284.5 g / mol, MW-T = 4684.5. Therefore, the HLB value for PEG100 stearate is calculated to be 18.8. Glycerol monooleate has an HLB value of 3.5. The HLB values ​​for the constituent components are listed in the table below.

[0045] JPEG0007839091000001.jpg192169

[0046] In one embodiment, the first emulsifier has an HLB value greater than 14, about 15, about 16, about 16.5, about 17, or about 18. In a preferred embodiment, the first emulsifier has an HLB value greater than about 17, for example, 17. In the most preferred embodiment, the first emulsifier has an HLB value greater than about 16.5, for example, 18.

[0047] In one embodiment, the first emulsifier is a polyol ester. As used herein, a polyol ester emulsifier refers to a nonionic emulsifier comprising a polymeric backbone having multiple hydroxyl groups, at least one of which is converted to an ester group. In one embodiment, the polyol ester is an ester of polyethylene glycol (PEG). In one embodiment, PEG has an average molecular weight in the range of 1000 to 9000 g / mol, for example, 3000 to 6000 g / mol, or 4000 to 5000 g / mol. In one embodiment, PEG contains 20 to 200 ethylene glycol monomer units, for example, 50 to 150 units, or 80 to 120 ethylene glycol monomer units. In one embodiment, PEG contains about 100 ethylene glycol monomer units. In one embodiment, the ester is an ester of a fatty acid, such as an ester of capric acid, undecylic acid, lauric acid, tridecanoic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, or arachidic acid. In one embodiment, the ester is an ester of stearic acid. In one embodiment, the first emulsifier is polyol stearate. In one embodiment, the first emulsifier is PEG stearate. In a preferred embodiment, the first emulsifier is PEG 100 stearate.

[0048] In one embodiment, the first emulsifier is a polyethoxylated sorbitan ester. In one embodiment, the ester is a monoester of polyethoxylated sorbitan. In one embodiment, the sorbitan is ethoxylated with 10 to 100 ethylene glycol monomer units, for example, 20 to 100 units, or 20 to 80 units. In one embodiment, the sorbitan is ethoxylated with a total of 20, 60, or 80 ethylene glycol monomer units. In one embodiment, the ester is an ester of a fatty acid, for example, an ester of capric acid, undecylic acid, lauric acid, tridecanoic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, oleic acid, or arachidic acid. In one embodiment, the ester is an ester of lauric acid, stearic acid, or oleic acid. In one embodiment, the first emulsifier is PEG-20 sorbitan monolaurate (polysorbate 20), PEG-60 sorbitan monostearate (polysorbate 20), or PEG-80 sorbitan monooleate (polysorbate 80). In a preferred embodiment, the first emulsifier is PEG-20 sorbitan monolaurate.

[0049] In one embodiment, the second emulsifier has an HLB value of less than about 5.5, for example, less than about 5, less than about 4.5, or less than about 4. In a preferred embodiment, the second emulsifier has an HLB value of less than about 4.5, for example, less than 4.5. In the most preferred embodiment, the second emulsifier has an HLB value of less than about 4, for example, less than 4.

[0050] In one embodiment, the second emulsifier is a monoglyceride. As used herein, a monoglyceride emulsifier refers to a nonionic emulsifier in which a glycerol molecule is bonded to a fatty acid via an ester bond. Monoglyceride emulsifiers include glycerides in which a fatty acid is bonded to either a primary or secondary alcohol site on glycerol. The fatty acid portion of the monoglyceride may be either saturated or unsaturated. In one embodiment, the monoglyceride includes glycerol and an ester of a fatty acid selected from capric acid, undecylic acid, lauric acid, tridecanoic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, behenic acid, myristoleic acid, palmitoleic acid, sapienic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, and erucic acid. In one embodiment, the second emulsifier is selected from glycerol monostearate, glycerol monolaurate, glycerol monooleate, and glycerol monolinoleate, or a mixture thereof. In a preferred embodiment, the second emulsifier is glycerol monooleate.

[0051] In one embodiment, the first emulsifier has an HLB value greater than approximately 15, and the second emulsifier has an HLB value less than approximately 5.5. In one embodiment, the first emulsifier has an HLB value greater than approximately 16, and the second emulsifier has an HLB value less than approximately 5. In one embodiment, the first emulsifier has an HLB value greater than approximately 16.5, and the second emulsifier has an HLB value less than approximately 4.5. In one embodiment, the first emulsifier has an HLB value greater than approximately 18, and the second emulsifier has an HLB value less than approximately 4.5. In one embodiment, the first emulsifier has an HLB value greater than approximately 18, and the second emulsifier has an HLB value less than approximately 4. In one embodiment, the first emulsifier has an HLB value greater than approximately 16.5, and the second emulsifier has an HLB value less than approximately 4.

[0052] Surprisingly, it has been found that solid and / or semi-solid emulsifiers can be incorporated into self-emulsifying compositions to obtain beneficial API solubility profiles. Thus, in one embodiment, the first emulsifier is solid at room temperature. In one embodiment, the second emulsifier is semi-solid at room temperature. In one embodiment, the first emulsifier is solid at room temperature, and the second emulsifier is semi-solid at room temperature. The meanings of the terms “solid” and “semi-solid” will be obvious to those skilled in the field of pharmaceutical formulation. However, it should be understood that a liquid is a material that flows in response to an external force, whereas a solid is a material that does not flow in response to an external force. A semi-solid exhibits to some extent the characteristics of both a solid and a liquid.

[0053] A synergistic interaction exists between the two emulsifiers, resulting in compositions containing at least two emulsifiers providing a superior active pharmaceutical ingredient (API) release profile compared to comparative compositions containing only a single emulsifier. In other words, compositions according to the present invention containing at least two emulsifiers can typically provide a faster API release profile compared to comparative compositions containing only one of the at least two emulsifiers, even if the total emulsifier content of the composition, expressed in weight percent, is the same. In one embodiment, the wt / wt ratio of the second emulsifier to the first emulsifier present in the composition is between about 1:10 and about 10:1, for example, between about 1:5 and about 5:1, between about 1:3 and about 3:1, between about 1:1 and about 5:1, between about 1:1 and about 3:1, between about 1:1 and about 2:1, between about 1:2 and about 2:1, between about 1:1.5 and about 2:1, between about 1:1.3 and about 1:1.1 (for example, about 1:1.2), or between about 1.4:1 and 1.6:1 (for example, about 1.5:1). In preferred embodiments, the wt / wt ratio of the second emulsifier to the first emulsifier in the composition is between about 1:1 and about 2:1, for example, between about 1.2:1 and 1.8:1, between about 1.1:1 and 1.6:1, or between about 1.4:1 and 1.6:1. In most preferred embodiments, the wt / wt ratio of the second emulsifier to the first emulsifier in the composition is about 1.5:1. In most preferred embodiments, the wt / wt ratio of the second emulsifier to the first emulsifier in the composition is about 1.2:1.

[0054] In alternative embodiments, the wt / wt ratio of the second emulsifier to the first emulsifier present in the composition is between about 1:2 and about 1:1, for example, between about 1:1.5 and 1:1, or between about 1:1.3 and 1:1.1. In further embodiments, the wt / wt ratio of the second emulsifier to the first emulsifier present in the composition is about 1:1.2. In yet another embodiment, the wt / wt ratio of the second emulsifier to the first emulsifier present in the composition is 1:1.2.

[0055] In one embodiment, the first emulsifier is present in the pharmaceutical composition at a level of about 1% to about 20% by weight of the total pharmaceutical composition, for example, about 1% to about 10% by weight, about 1% to about 5% by weight, about 3% to about 7% by weight, about 3% to about 6% by weight, about 3% to about 5% by weight (e.g., about 4%), about 4% to about 5% by weight (e.g., about 4.3%), or about 5% to about 6% by weight (e.g., about 5.5%) of the total composition. In a preferred embodiment, the first emulsifier is present in the pharmaceutical composition at a level of about 1% to about 5% by weight of the total composition. In a preferred embodiment, the first emulsifier is present in the pharmaceutical composition at a level of about 2% to about 4% by weight of the total composition. In the most preferred embodiment, the first emulsifier is present in the pharmaceutical composition at a level of about 3% to about 5% by weight of the total composition. In the most preferred embodiment, the first emulsifier is present in the pharmaceutical composition at a level of about 4% by weight of the total composition. In one embodiment, the first emulsifier is present in the pharmaceutical composition at a level of about 5% to about 15% by weight of the total composition (for example, about 7% to about 14% by weight, about 8% to about 13% by weight, or about 9% to about 13% by weight). In one embodiment, the first emulsifier is present in the pharmaceutical composition at a level of about 10% to about 12% by weight of the total composition.

[0056] In alternative embodiments, the first emulsifier is present in the composition at a level of about 4% to about 7% by weight of the total composition. In further embodiments, the first emulsifier is present in the pharmaceutical composition at a level of about 5% to about 6% by weight of the total composition. In yet another embodiment, the first emulsifier is present in the pharmaceutical composition at a level of about 5.5% by weight of the total composition.

[0057] In one embodiment, the second emulsifier is present in the pharmaceutical composition at a level of about 1% to about 20% by weight of the total pharmaceutical composition, for example, about 1% to about 10% by weight, about 2% to about 8% by weight, about 4% to about 7% by weight, about 4% to about 6% by weight (e.g., about 5%), about 5% to about 7% by weight (e.g., about 6%), or about 4% to about 5% by weight (e.g., about 4.5%) of the total composition. In a preferred embodiment, the second emulsifier is present in the pharmaceutical composition at a level of about 1% to about 7% by weight of the total composition. In a preferred embodiment, the second emulsifier is present in the pharmaceutical composition at a level of about 3% to about 6% by weight of the total composition. In the most preferred embodiment, the second emulsifier is present in the pharmaceutical composition at a level of about 5% to about 7% by weight of the total composition. In the most preferred embodiment, the second emulsifier is present in the pharmaceutical composition at a level of about 6% by weight of the total composition. In the most preferred embodiment, the second emulsifier is present in the pharmaceutical composition at a level of about 5% by weight of the total composition.

[0058] In one embodiment, the second emulsifier is present in the pharmaceutical composition at a level of about 5% to about 20% by weight of the total composition (for example, about 7% to about 18% by weight, about 9% to about 16% by weight, or about 10% to about 15% by weight). In one embodiment, the second emulsifier is present in the pharmaceutical composition at a level of about 12% to about 15% by weight of the total composition. In one embodiment, the second emulsifier is present in the pharmaceutical composition at a level of about 13% to about 14% by weight of the total composition.

[0059] In alternative embodiments, the second emulsifier is present in the composition at a level of about 3% to about 6% by weight of the total composition. In further embodiments, the second emulsifier is present in the pharmaceutical composition at a level of about 4% to about 5% by weight of the total composition. In yet another embodiment, the second emulsifier is present in the pharmaceutical composition at a level of about 4.5% by weight of the total composition.

[0060] In certain embodiments of the present invention, it may be desirable or beneficial to have more than two emulsifiers. In one embodiment, the composition according to the present invention comprises three emulsifiers. In further embodiments, the three emulsifiers comprise a first emulsifier having an HLB value greater than about 14, a second emulsifier having an HLB value less than about 6, and a third emulsifier having an HLB value in the range of about 8 to about 15.

[0061] In one embodiment, the third emulsifier has an HLB value in the range of 10 to 15, for example, in the range of 11 to 15, 12 to 15, 13 to 15, 11 to 14, or 12 to 14.

[0062] In one embodiment, the third emulsifier is a polyoxyl castor oil derivative. In one embodiment, the third emulsifier is PEG-30 castor oil, PEG-35 castor oil, PEG-40 castor oil, or PEG-60 castor oil. In a preferred embodiment, the third emulsifier is PEG-35 castor oil.

[0063] In one embodiment, the third emulsifier is present in the pharmaceutical composition in an amount of about 1% to about 10% by weight of the total pharmaceutical composition, for example, about 2% to about 8% by weight, about 3% to about 7% by weight, about 4% to about 6% by weight, or about 5% by weight of the total composition.

[0064] SEDDS formulations typically have a high total emulsifier content (approximately 30% to 60% w / w of the total composition). However, in one aspect of the present invention, it has been surprisingly discovered that, using the combination of unsaturated free fatty acids and emulsifiers disclosed herein, SEDDS with a good API solubility profile but a relatively low total emulsifier content can be obtained. The self-emulsifying pharmaceutical composition of the present invention has a total emulsifier content of less than 30% by weight of the total composition. In one embodiment, the total emulsifier content is less than 25% by weight of the total composition, for example, less than 20% by weight, less than 15% by weight, or less than 12% by weight. In one embodiment, the total emulsifier content is 2% to 20% by weight, 2.5% to 15% by weight, 5% to 15% by weight, 8% to 12% by weight, 10% to 20% by weight, 12% to 20% by weight, 10% to 18% by weight, 12% to 18% by weight, 12% to 16% by weight, 13% to 20% by weight, 14% to 20% by weight, 15% to 20% by weight, 13% to 25% by weight, 14% to 25% by weight, 15% to 25% by weight, 20% to 25% by weight, 20% to 26% by weight, 20% to 27% by weight, 20% to 28% by weight, or 20% to 29% by weight of the total composition. In one embodiment, the total emulsifier content is 8% to 12% by weight of the total composition. In one embodiment, the total emulsifier content is about 10% by weight of the total composition, for example, 10% by weight of the total composition. In one embodiment, the total emulsifier content is about 14% to 15% by weight of the total composition, for example, about 14.3% by weight. In one embodiment, the total emulsifier content is about 28% to 29.9% by weight of the total composition, for example, about 29% to 29.9% by weight, or about 29.5% by weight.

[0065] In one embodiment, the first emulsifier is present in the pharmaceutical composition at a concentration of approximately 3% to approximately 7% by weight (e.g., approximately 4% to approximately 5% by weight) of the total pharmaceutical composition, the second emulsifier is present at a concentration of approximately 4% to approximately 6% by weight of the total pharmaceutical composition, and the third emulsifier is present at a concentration of approximately 4% to approximately 6% by weight of the total pharmaceutical composition. In an alternative embodiment, the first emulsifier is present in the pharmaceutical composition at a concentration of approximately 9% to approximately 13% by weight (e.g., approximately 10% to approximately 12% by weight) of the total pharmaceutical composition, the second emulsifier is present at a concentration of approximately 12% to approximately 15% by weight (e.g., approximately 13% to approximately 14% by weight) of the total pharmaceutical composition, and the third emulsifier is present at a concentration of approximately 4% to approximately 6% by weight of the total pharmaceutical composition, provided that the total emulsifier content is less than 30% by weight of the total composition.

[0066] The compositions according to the present invention are particularly suitable for solubilizing poorly soluble APIs. The compositions according to the present invention are particularly suitable for solubilizing lipophilic APIs that are poorly soluble in an aqueous environment. For example, lopinavir and ritonavir are substantially insoluble in water, with predicted aqueous solubility of 1.9 μg / ml and 1.3 μg / ml, respectively [www.drugbank.ca]. Therefore, in one embodiment, at least one active pharmaceutical ingredient has an aqueous solubility (measured or predicted) of less than 1 mg / ml, for example, less than 0.1 mg / ml, or less than 0.01 mg / ml (less than 10 μg / ml).

[0067] The lipophilicity or hydrophobicity of an API can be determined by predetermined methods known to those skilled in the art. For example, LogP can be determined by distributing the API between octanol and water. LogP values ​​may range from approximately -10 to +10, but most commercially available APIs have LogP values ​​in the range of -2 to +6, particularly 0 to +5, with higher LogP values ​​indicating higher lipophilicity of the API. For example, the lipophilic APIs lopinavir and ritonavir have calculated LogP values ​​[ACD / Labs] of 6.26 and 5.28, respectively.

[0068] In one embodiment, at least one active pharmaceutical ingredient has a LogP value or LogP(clogP) calculation value greater than 4, for example, greater than 4.5, greater than 5.0, or greater than 5.5.

[0069] In one embodiment, at least one active pharmaceutical ingredient is solid at room temperature. In one embodiment, at least one active pharmaceutical ingredient is prepared by synthesis. In one embodiment, at least one active pharmaceutical ingredient is not a fatty acid (either free or bound).

[0070] In one embodiment, at least one active pharmaceutical ingredient (lopinavir) is present in a dissolved state in the pharmaceutical composition. In another embodiment, at least one active pharmaceutical ingredient (lopinavir) is present in a dispersed state in the pharmaceutical composition. In yet another embodiment, a small amount of the minimum active pharmaceutical ingredient (lopinavir) is present in a dispersed state, and a small amount is present in a dissolved state in the pharmaceutical composition. By using techniques such as optical microscopy using polarizing filters, differential scanning calorimetry, or micro-FTIR, it will be apparent to those skilled in the art that the active pharmaceutical ingredient is dissolved or dispersed in the pharmaceutical composition. For example, a crystalline active pharmaceutical ingredient can be added to a placebo pharmaceutical composition (i.e., a composition that does not contain an active pharmaceutical ingredient). When viewed under an optical microscope using a polarizing filter, the crystalline active pharmaceutical ingredient exhibits birefringence. Therefore, the added placebo composition can be used as a comparative standard to confirm the absence of the crystalline active pharmaceutical ingredient in the pharmaceutical composition, and thus demonstrate that the active pharmaceutical ingredient is dissolved in the pharmaceutical composition. Alternatively, and / or further, micro-FTIR can be used to confirm that the active pharmaceutical ingredient (lopinavir) is dissolved in the pharmaceutical composition. In this case, the spectrum obtained from the pharmaceutical composition with the active pharmaceutical ingredient added can be compared with the spectrum obtained from the pharmaceutical composition alone to demonstrate that the active pharmaceutical ingredient (lopinavir) is dissolved in the pharmaceutical composition.

[0071] In one embodiment, at least one active pharmaceutical ingredient (lopinavir and / or ritonavir) is stable within the pharmaceutical composition. The compositions of the present invention are particularly suitable for active pharmaceutical ingredients used in the composition that tend to undergo chemical or physical degradation. In one embodiment, the active pharmaceutical ingredient (lopinavir and / or ritonavir) used in the composition tends to degrade by hydrolysis. In one embodiment, the active pharmaceutical ingredient (lopinavir and / or ritonavir) used in the composition tends to degrade by oxidation. In one embodiment, the active pharmaceutical ingredient (lopinavir) used in the composition tends to degrade with heat. Thanks to the ambient temperature processing used to manufacture the compositions of the present invention, the compositions typically have a lower API (lopinavir) impurity load compared to compositions that require heat (e.g., >40°C) during their preparation. In one embodiment, the pharmaceutical composition contains lopinavir-derived impurities totaling 0.5% by weight or less, for example, less than 0.45% by weight, less than 0.40% by weight, less than 0.35% by weight, less than 0.30% by weight, or less than 0.25% by weight.

[0072] In one embodiment, the pharmaceutical composition contains impurities derived from ritonavir in a total amount of 5% by weight or less, for example, less than 4.5% by weight, less than 4.0% by weight, or less than 3.5% by weight.

[0073] In one embodiment, the pharmaceutical composition contains 0.5% by weight or less of lopinavir-derived impurities in total (e.g., less than 0.45% by weight, less than 0.40% by weight, less than 0.35% by weight, less than 0.30% by weight, or less than 0.25% by weight) and 5% by weight or less of ritonavir-derived impurities in total (e.g., less than 4.5% by weight, less than 4.0% by weight, or less than 3.5% by weight). In another embodiment, the pharmaceutical composition contains less than 0.25% by weight of lopinavir-derived impurities in total and less than 3.5% by weight of ritonavir-derived impurities in total.

[0074] In one embodiment, the active pharmaceutical ingredient used in the composition (e.g., ritonavir) tends to undergo physical morphological changes, such as solid-state polymorphic transitions.

[0075] In one embodiment, at least one active pharmaceutical ingredient (lopinavir) is stable in the pharmaceutical composition for at least 3 months, for example, at least 6 months, for example, at least 9 months, for example, at least 12 months, for example, at least 18 months, for example, at least 24 months, or for example, at least 36 months at a temperature of 5°C.

[0076] In one embodiment, at least one active pharmaceutical ingredient (lopinavir) is stable within the pharmaceutical composition during the process for manufacturing the pharmaceutical composition, and this process is carried out at room temperature.

[0077] In one embodiment, at least one active pharmaceutical ingredient has a solubility measured at ambient temperature of at least 1% w / v in unsaturated free fatty acids, for example, at least 5% w / v in unsaturated free fatty acids, for example, at least 10% w / v in unsaturated free fatty acids, for example, at least 12% w / v in unsaturated free fatty acids, for example, at least 15% w / v in unsaturated free fatty acids, or for example, at least 18% w / v in unsaturated free fatty acids.

[0078] In one embodiment, at least one active pharmaceutical ingredient is present in the pharmaceutical composition at a level between about 0.001% by weight and about 50% by weight of the total composition weight, for example, between about 0.01% by weight and about 50% by weight, between about 0.001% by weight and about 5% by weight, between about 0.1% by weight and about 25% by weight, between about 0.5% by weight and about 15% by weight, between about 0.5% by weight and about 10% by weight, between about 0.5% by weight and about 5% by weight, between about 0.5% by weight and about 2.5% by weight, between about 1.0% by weight and about 2.5% by weight, between about 1.0% by weight and about 2.0% by weight, between about 1.2% by weight and about 1.8% by weight, or between about 1.3% by weight and about 1.7% by weight.

[0079] In one embodiment, at least one active pharmaceutical ingredient is present in the pharmaceutical composition at a level of about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1.0% by weight, about 1.1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.4% by weight, about 1.5% by weight, about 1.6% by weight, about 1.7% by weight, about 1.8% by weight, about 1.9% by weight, or about 2.0% by weight of the total composition weight.

[0080] In one embodiment, at least one active pharmaceutical ingredient (lopinavir) is present in the pharmaceutical composition at a level between about 1% by weight and about 50% by weight of the total composition weight, for example, between about 5% by weight and about 50% by weight, between about 5% by weight and about 25% by weight, between about 5% by weight and about 20% by weight, between about 10% by weight and about 25% by weight, between about 10% by weight and about 20% by weight, between about 11% by weight and about 19% by weight, between about 12% by weight and about 20% by weight, between about 14% by weight and about 20% by weight, between about 15% by weight and about 20% by weight, or between about 15% by weight and about 18% by weight, or between about 16% by weight and about 19% by weight.

[0081] In one embodiment, at least one active pharmaceutical ingredient (lopinavir) is present in the pharmaceutical composition at a level of about 10% by weight, about 10.5% by weight, about 11% by weight, about 11.5% by weight, about 11.5% by weight, about 12% by weight, about 12.5% ​​by weight, about 13% by weight, about 13.5% by weight, about 14% by weight, about 14.5% by weight, about 15% by weight, about 15.5% by weight, about 16% by weight, about 16.5% by weight, about 17% by weight, about 17.5% by weight, about 18% by weight, about 18.5% by weight, about 19% by weight, about 19.5% by weight, or about 20% by weight of the total weight of the composition.

[0082] In one embodiment, the pharmaceutical composition according to the present invention contains two or more active pharmaceutical ingredients. In one embodiment, the pharmaceutical composition according to the present invention contains two active pharmaceutical ingredients. In one embodiment, the two or more active pharmaceutical ingredients are present in the pharmaceutical composition at a total level of about 5% to about 30% by weight, about 5% to about 25% by weight, about 10% to about 30% by weight, about 10% to about 25% by weight, about 15% to about 30% by weight, about 15% to about 25% by weight, about 16% to about 24% by weight, about 17% to about 23% by weight, about 17% to about 21% by weight, about 18% to about 22% by weight, or about 18% to about 20% by weight, or about 18% to about 21% by weight of the total weight of the composition.

[0083] In one embodiment, at least one active pharmaceutical ingredient is classified as a Biopharmaceutical Classification System (BCS) Class II or BCS Class IV active pharmaceutical ingredient. BCS Class II active pharmaceutical ingredients are classified as active ingredients having high osmosis and low solubility. BCS Class IV active pharmaceutical ingredients are classified as active ingredients having low osmosis and low solubility. In accordance with the ICH guideline (ICH guideline M9 on biopharmaceutical classification system based biowaivers; August 6, 2018), the active pharmaceutical ingredient is classified as highly soluble if the highest single therapeutic dose is completely dissolved in 250 ml or less of an aqueous medium at 37 ± 1°C over a pH range of 1.2 to 6.8. The evaluation of osmosis should preferentially be based on human pharmacokinetic experiments, e.g., the absorption range derived from absolute bioavailability or mass balance. If the absolute bioavailability is ≥ 85%, it can be concluded that the osmosis is high.

[0084] In one embodiment, at least one active pharmaceutical ingredient is selected from protease inhibitors, retinoids, vitamin D analogs, anti-leprosy active pharmaceutical ingredients, calcineurin inhibitors, cannabinoids, 5-alpha reductase inhibitors, androgen receptor inhibitors, peroxisome proliferator-responsive receptor activators, antihistamines, chloride channel activators, tyrosine kinase inhibitors, hormones, protease inhibitors, and mTOR kinase inhibitors.

[0085] In one embodiment, at least one active pharmaceutical ingredient is abacavir, acitretin, alitretinoin, efavirenz, enfuvirtide, estradiol, nevirapine, ritonavir, lopinavir, tenofovir, adefovir, entecavir, ribavirin, acyclovir, famciclovir, penciclovir, valacyclovir, cidofovir, ganciclovir, valganciclovir, oseltamivir, zanamivir, amprenavir, bexarotene, or carbohydrate. The following are selected: cifediol, calcitriol, clofazimine, cyclosporine A, doxelcalciferol, dronabinol, dutasteride, enzalutamide, fenofibrate, isotretinoin, loratadine, lubiprostone, nintedanib, paricalcitol, progesterone, saquinavir, sirolimus, tipranavir, tretinoin, atorvastatin, carvedilol, itraconazole, ketoprofen, and simvastatin.

[0086] In one embodiment, at least one active pharmaceutical ingredient is selected from abacavir, efavirenz, enfuvirtide, estradiol, nevirapine, ritonavir, lopinavir, tenofovir, adefovir, entecavir, ribavirin, acyclovir, famciclovir, penciclovir, valacyclovir, cidofovir, ganciclovir, valganciclovir, oseltamivir, and zanamivir.

[0087] In one embodiment, the pharmaceutical composition further comprises an active pharmaceutical ingredient synergistic agent. In one embodiment, the active pharmaceutical ingredient synergistic agent is an HIV protease enzyme inhibitor.

[0088] In one embodiment, at least one active pharmaceutical ingredient is an HIV protease enzyme inhibitor. In one embodiment, the HIV protease enzyme inhibitor is selected from lopinavir and ritonavir.

[0089] Lopinavir (CAS#192725-17-0) is a protease inhibitor chemically named [1S-[1R*(R*),3R*,4R*]]-N-[4[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-α-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide (IUPAC name=(2S)-N-[(2S,4S,5S)-5-[[2-(2,6-dimethylphenoxy)acetyl]amino]-4-hydroxy-1,6-diphenyl-hexane-2-yl]-3-methyl-2-(2-oxo-1,3-diadinan-1-yl)butanamide). Lopinavir has the molecular formula C 37 H 48 It is composed of N4O5 and has a molecular weight of 628.80.

[0090] Ritonavir (CAS #155213-67-5) is derived from 2,4,7,12-tetraazatridecane-13-euic acid, 10-hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-5-thiazolylmethyl ester [5S-(5R*,8R*,10R*,11R*)](I Ritonavir is a protease inhibitor chemically named as 1,3-thiazole-5-ylmethyl N-[(2S,3S,5S)-3-hydroxy-5-[[(2S)-3-methyl-2-[[methyl-[(2-propan-2-yl-1,3-thiazole-4-yl)methyl]carbamoyl]amino]butanoyl]amino]-1,6-diphenylhexane-2-yl]carbamate). Ritonavir has the molecular formula C 37 H 48 It has the compound N6O5S2 and a molecular weight of 720.94.

[0091] In one embodiment, the pharmaceutical composition comprises lopinavir and ritonavir.

[0092] In one embodiment, the molar ratio of lopinavir to ritonavir present in the composition is between approximately 1:10 and approximately 18:1, for example between approximately 1:10 and approximately 15:1, for example between approximately 1:5 and approximately 15:1, for example between approximately 1:1 and approximately 15:1, for example between approximately 2:1 and approximately 15:1, for example between approximately 4:1 and approximately 15:1, for example between approximately 8:1 and approximately 14:1, for example between approximately 9:1 and approximately 14:1, for example between approximately 10:1 and approximately 14:1, for example between approximately 10.5:1 and approximately 18:1, for example between 10.5:1 and approximately 18:1, for example between approximately 10.5:1 and approximately 14:1, for example between approximately 11:1 and approximately 13:1, for example between approximately 11.5 and approximately 17:1, for example between approximately 11.5: Between 1 and approximately 16.0:1, for example, between approximately 11.5:1 and approximately 15:1, for example, approximately 14.5:1, for example, 14.5:1, for example, approximately 14:1, for example, 14:1, for example, approximately 13.8:1, for example, 13.8:1, for example, approximately 13.75:1, for example, 13.75:1, for example, approximately 13.5:1, for example, 13.5:1, for example, approximately 13:1, for example, 13:1, for example, approximately 12.5:1, for example, 12.5:1, for example, approximately 12:1, for example, 12:1, for example, approximately 11.75:1, for example, 11.75:1, for example, approximately 9:1, for example, 9:1, for example, approximately 5:1, for example, 5:1, for example, approximately 4.6:1, or for example, 4.6:1. In preferred embodiments, the molar ratio of lopinavir to ritonavir in the composition is approximately 13.8:1, for example, 13.8:1.

[0093] In one embodiment, the wt / wt ratio of lopinavir to ritonavir present in the composition is between approximately 1:10 and approximately 18:1, for example between approximately 1:10 and approximately 15:1, for example between approximately 1:5 and approximately 15:1, for example between approximately 1:1 and approximately 15:1, for example between approximately 2:1 and approximately 15:1, for example between approximately 4:1 and approximately 15:1, for example between approximately 8:1 and approximately 14:1, for example between approximately 9:1 and approximately 14:1, for example between approximately 10:1 and approximately 14:1, for example between approximately 10.5:1 and approximately 18:1, for example between 10.5:1 and approximately 18:1, for example between approximately 10.5:1 and approximately 14:1, for example between approximately 11:1 and approximately 13:1, for example between approximately 11.5 and approximately 17:1, for example between approximately 11.5:1 and approximately 16 Between 0:1, for example, between approximately 11.5:1 and approximately 15:1, for example, approximately 14.5:1, for example, 14.5:1, for example, approximately 14:1, for example, 14:1, for example, approximately 13.8:1, for example, 13.8:1, for example, approximately 13.75:1, for example, 13.75:1, for example, approximately 13.5:1, for example, 13.5:1, for example, approximately 13:1, for example, 13:1, for example, approximately 12.5:1, for example, 12.5:1, for example, approximately 12:1, for example, 12:1, for example, approximately 11.75:1, for example, 11.75:1, for example, approximately 11.5:1, for example, 11.5:1, for example, approximately 11.25:1, for example, 11.25:1, or for example, approximately 11:1, for example, 11:1. In a preferred embodiment, the wt / wt ratio of lopinavir to ritonavir present in the composition is approximately 12:1, for example, 12:1.

[0094] In one embodiment, lopinavir is present in the pharmaceutical composition at a level between about 1% by weight and about 50% by weight of the total composition weight, for example, between about 5% by weight and about 50% by weight, between about 5% by weight and about 25% by weight, between about 5% by weight and about 20% by weight, between about 10% by weight and about 25% by weight, between about 10% by weight and about 20% by weight, between about 11% by weight and about 19% by weight, between about 12% by weight and about 20% by weight, between about 14% by weight and about 20% by weight, between about 15% by weight and about 20% by weight, or between about 16% by weight and about 19% by weight.

[0095] In one embodiment, lopinavir is present in the pharmaceutical composition at a level of about 10% by weight, about 10.5% by weight, about 11% by weight, about 11.5% by weight, about 11.5% by weight, about 12% by weight, about 12.5% ​​by weight, about 13% by weight, about 13.5% by weight, about 14% by weight, about 14.5% by weight, about 15% by weight, about 15.5% by weight, about 16% by weight, about 16.5% by weight, about 17% by weight, about 17.5% by weight, about 18% by weight, about 18.5% by weight, about 19% by weight, about 19.5% by weight, or about 20% by weight of the total weight of the composition.

[0096] In one embodiment, ritonavir is present in the pharmaceutical composition at a level between about 0.001% by weight and about 50% by weight of the total composition weight, for example, between about 0.01% by weight and about 50% by weight, between about 0.001% by weight and about 5% by weight, between about 0.1% by weight and about 25% by weight, between about 0.5% by weight and about 15% by weight, between about 0.5% by weight and about 10% by weight, between about 0.5% by weight and about 5% by weight, between about 0.5% by weight and about 2.5% by weight, between about 1.0% by weight and about 2.5% by weight, between about 1.0% by weight and about 2.0% by weight, between about 1.2% by weight and about 1.8% by weight, or between about 1.3% by weight and about 1.7% by weight.

[0097] In one embodiment, ritonavir is present in the pharmaceutical composition at a level of about 0.5% by weight, about 0.6% by weight, about 0.7% by weight, about 0.8% by weight, about 0.9% by weight, about 1.0% by weight, about 1.1% by weight, about 1.2% by weight, about 1.3% by weight, about 1.4% by weight, about 1.5% by weight, about 1.6% by weight, about 1.7% by weight, about 1.8% by weight, about 1.9% by weight, or about 2.0% by weight of the total weight of the composition.

[0098] Additional excipients may be optionally included in the composition according to the present invention, provided that the inclusion of such excipients does not unacceptably affect the self-emulsifying ability of the composition.

[0099] In one embodiment, the pharmaceutical composition further comprises an antioxidant. In one embodiment, the antioxidant is butylated hydroxyanisole (BHA), tert-butylhydroquinone (TBHQ), or butylated hydroxytoluene (BHT). In a preferred embodiment, the antioxidant is butylated hydroxytoluene. In one embodiment, the antioxidant is present in the pharmaceutical composition at about 0.05 wt% to about 0.5 wt% of the total weight of the pharmaceutical composition, such as about 0.05 wt% to about 0.15 wt%, such as about 0.1 wt% to about 0.3 wt%, such as about 0.2 wt%, such as 0.2 wt%, such as about 0.1 wt%, or such as 0.1 wt%.

[0100] In one embodiment, the pharmaceutical composition is an anhydrous pharmaceutical composition. In one embodiment, the pharmaceutical composition comprises less than 5 wt% water, such as less than 1 wt%, less than 0.5 wt%, less than 0.1 wt%, or less than 0.05 wt% water of the total weight of the pharmaceutical composition. In one embodiment, the pharmaceutical composition is substantially free of water. In one embodiment, the pharmaceutical composition is completely free of water.

[0101] In one embodiment, the pharmaceutical composition according to the present invention further comprises a thickening agent. In an alternative embodiment, the pharmaceutical composition according to the present invention does not comprise a thickening agent. A thickening agent is an excipient that increases the viscosity of a mixture when added to the mixture. In one embodiment, the thickening agent is selected from mono / diglycerides, ceresine wax, and hydrogenated vegetable oil or combinations thereof. In one embodiment, the pharmaceutical composition according to the present invention does not comprise mono / diglycerides, ceresine wax, or hydrogenated vegetable oil.

[0102] In one embodiment, the pharmaceutical composition according to the present invention further comprises a stiffening agent. In an alternative embodiment, the pharmaceutical composition according to the present invention does not comprise a stiffening agent. A stiffening agent is an excipient used to stiffen a composition such that the anhydrous composition is semi-solid at room temperature. Usually, the stiffening agent is a saturated free fatty acid, such as C 10 ~C 38 saturated free fatty acids, such as C 16 ~C 22It may be a saturated free fatty acid. A saturated free fatty acid is a free fatty acid in which there are no double bonds between carbon atoms in the fatty acid (i.e., the fatty acid is not bonded to another molecule, such as glycerol). In one embodiment, the stiffening agent is selected from capric acid, undecylic acid, lauric acid, tridecanoic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, henicosyl acid, behenic acid, tricosylic acid, lignoceric acid, pentacosylic acid, cerotic acid, heptacosyl acid, montanic acid, nonacosyl acid, melisic acid, henatriconcylic acid, laxeronic acid, phylic acid, gedaic acid, ceroplastic acid, hexatriaconcylic acid, heptatriacontanoic acid, and octatricontanoic acid. In one embodiment, the pharmaceutical composition according to the present invention does not contain stearic acid.

[0103] In one embodiment, the pharmaceutical composition according to the present invention is liquid or semi-solid at room temperature. Preferably, the pharmaceutical composition according to the present invention is liquid at room temperature. The viscosity of the composition can be determined mainly by measuring the kinematic viscosity coefficient for liquid compositions, or by measuring the complex viscosity for compositions having more semi-solid properties.

[0104] The kinematic viscosity coefficient can be determined according to the method described in Example 3. In one embodiment, the pharmaceutical composition according to the present invention has a kinematic viscosity coefficient of less than 500 cP.s. at 25°C, for example, less than 400 cP.s., less than 300 cP.s., or less than 200 cP.s. In one embodiment, the pharmaceutical composition according to the present invention has a kinematic viscosity coefficient of 10 to 500 cP.s. at 25°C, for example, 25 to 400 cP.s., 50 to 300 cP.s., or 100 to 200 cP.s.

[0105] Complex viscosity is defined as a function of frequency-dependent viscosity for a viscoelastic fluid, determined by subjecting it to vibrational shear stress. Complex viscosity can be determined according to the method described in Example 4. In one embodiment, the pharmaceutical composition according to the present invention has a complex viscosity of less than 1000 cP.s., for example, less than 800 cP.s., less than 600 cP.s., less than 400 cP.s., or less than 200 cP.s., when the complex viscosity is measured at an angular frequency of 0.1 rad / s.

[0106] In one embodiment, the pharmaceutical composition according to the present invention includes a mucosal adhesive. In an alternative embodiment, the pharmaceutical composition according to the present invention does not include a mucosal adhesive. The mucosal adhesive attracts water / moisture at the application site of the composition, altering the physical properties of the composition. The resulting mucosal adhesive composition exhibits greater adhesion and / or tackiness. Typically, the mucosal adhesive is a cellulose ether, such as methylcellulose, ethylcellulose, or hydroxypropylmethylcellulose (also known as hypromellose). In one embodiment, the pharmaceutical composition according to the present invention does not include hydroxypropylmethylcellulose.

[0107] In one embodiment, the pharmaceutical composition according to the present invention does not contain one or more of the following: thickeners, stiffeners, or mucosal adhesives.

[0108] In one embodiment, the pharmaceutical composition according to the present invention does not contain an alcohol solvent, such as ethanol or glycol (e.g., propylene glycol). In another embodiment, the pharmaceutical composition according to the present invention does not contain propylene glycol.

[0109] In one embodiment, a. Unsaturated free fatty acids; b. A first emulsifier having an HLB value greater than approximately 14; c. A second emulsifier having an HLB value of less than approximately 6; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0110] In one embodiment, a. Unsaturated free fatty acids; b. A first emulsifier having an HLB value greater than approximately 14; c. A second emulsifier having an HLB value of less than approximately 6; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains a total emulsifier content of less than 30% by weight of the total composition, and the composition is liquid at room temperature.

[0111] In one embodiment, a. Unsaturated free fatty acids; b. A first emulsifier having an HLB value greater than approximately 14; c. A second emulsifier having an HLB value of less than approximately 6; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains a total emulsifier content of less than 30% by weight of the total composition, and the composition does not contain thickeners (e.g., mono / diglycerides, white ceresin wax, or hydrogenated vegetable oil) or stiffeners (e.g., stearic acid).

[0112] In one embodiment, a. Unsaturated free fatty acids; b. A first emulsifier having an HLB value greater than approximately 14; c. A second emulsifier having an HLB value of less than approximately 6; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains a total emulsifier content of less than 30% by weight of the total composition, and the composition does not contain a mucosal adhesive (e.g., hypromellose).

[0113] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value greater than approximately 14; c. A second emulsifier having an HLB value of less than approximately 6; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0114] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value greater than approximately 16; c. A second emulsifier having an HLB value of less than approximately 5; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0115] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value greater than approximately 17; c. A second emulsifier having an HLB value of less than approximately 4; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0116] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value greater than approximately 16; c. A second emulsifier having an HLB value of less than approximately 5; and d. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0117] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value greater than approximately 17; c. A second emulsifier having an HLB value of less than approximately 4; and d. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 20% by weight of the total composition.

[0118] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value greater than approximately 17; c. A second emulsifier having an HLB value of less than approximately 4; and d. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 15% by weight of the total composition.

[0119] In one embodiment, a. Unsaturated free fatty acids; b. Polyol ester emulsifiers having an HLB value greater than approximately 15 (e.g., polyol stearate, e.g., PEG-100 stearate); c. A second emulsifier having an HLB value of less than approximately 5; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0120] In one embodiment, a. Unsaturated free fatty acids; b. Polyol ester emulsifiers having an HLB value greater than approximately 15 (e.g., polyol stearate, e.g., PEG-100 stearate); c. A second emulsifier having an HLB value of less than approximately 5; and d. Lopinavir; It contains and has a total emulsifier content of less than 20% by weight of the total composition.

[0121] In one embodiment, a. Unsaturated free fatty acids; b. Polysorbate emulsifiers having an HLB value greater than approximately 15 (e.g., Polysorbate 20); c.; d. A second emulsifier having an HLB value of less than approximately 5; and e. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0122] In one embodiment, a. Unsaturated free fatty acids; b. A first emulsifier having an HLB value greater than approximately 15; c. Monoglyceride emulsifiers (e.g., glycerol monooleate) having an HLB value of less than approximately 5; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0123] In one embodiment, a. Unsaturated free fatty acids; b. A first emulsifier having an HLB value of approximately 15 or higher; c. Monoglyceride emulsifiers (e.g., glycerol monooleate) having an HLB value of less than approximately 5; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 20% by weight of the total composition.

[0124] In one embodiment, a. Unsaturated free fatty acids; b. A first emulsifier having an HLB value of approximately 15 or higher; c. Monoglyceride emulsifiers (e.g., glycerol monooleate) having an HLB value of less than approximately 5; d. A third emulsifier; and e. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0125] In one embodiment, a. Unsaturated free fatty acids; b. A first emulsifier having an HLB value of approximately 15 or higher; c. Monoglyceride emulsifiers (e.g., glycerol monooleate) having an HLB value of less than approximately 5; d. A third emulsifier having an HLB value between approximately 8 and approximately 15 (for example, between approximately 10 and approximately 15, or between approximately 12 and approximately 14); and e. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0126] In one embodiment, a. Oleic acid; b. Polyol ester emulsifiers having an HLB value greater than approximately 15 (e.g., polyol stearate, e.g., PEG-100 stearate); c. A second emulsifier having an HLB value of less than approximately 5; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0127] In one embodiment, a. Oleic acid; b. Polyol ester emulsifiers having an HLB value greater than approximately 15 (e.g., polyol stearate, e.g., PEG-100 stearate); c. A second emulsifier having an HLB value of less than approximately 5; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 20% by weight of the total composition.

[0128] In one embodiment, a. Oleic acid; b. Polyol ester emulsifiers having an HLB value greater than approximately 15 (e.g., polyol stearate, e.g., PEG-100 stearate); c. A second emulsifier having an HLB value of less than approximately 5; and d. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0129] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value of approximately 15 or higher; c. Monoglyceride emulsifiers (e.g., glycerol monooleate) having an HLB value of less than approximately 5; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0130] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value greater than approximately 15; c. Monoglyceride emulsifiers (e.g., glycerol monooleate) having an HLB value of less than approximately 5; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 20% by weight of the total composition.

[0131] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value greater than approximately 15; c. Monoglyceride emulsifiers (e.g., glycerol monooleate) having an HLB value of less than approximately 5; and d. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0132] In one embodiment, a. Oleic acid; b. Polyol ester emulsifiers having an HLB value greater than approximately 15 (e.g., polyol stearate, e.g., PEG-100 stearate); c. Monoglyceride emulsifiers (e.g., glycerol monooleate) having an HLB value of less than approximately 5; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0133] In one embodiment, a. Oleic acid; b. Polyol ester emulsifiers having an HLB value greater than approximately 15 (e.g., polyol stearate, e.g., PEG-100 stearate); c. Monoglyceride emulsifiers (e.g., glycerol monooleate) having an HLB value of less than approximately 5; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 20% by weight of the total composition.

[0134] In one embodiment, a. Oleic acid; b. Polyol ester emulsifiers having an HLB value greater than approximately 15 (e.g., polyol stearate, e.g., PEG-100 stearate); c. Monoglyceride emulsifiers (e.g., glycerol monooleate) having an HLB value of less than approximately 5; and d. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0135] In one embodiment, a. Oleic acid; b. PEG-100 stearate; c. Glycerol monooleate; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition (for example, less than 15% by weight).

[0136] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value greater than approximately 15; c. Monoglyceride emulsifiers (e.g., glycerol monooleate) having an HLB value of less than approximately 5; d. A third emulsifier having an HLB value between approximately 8 and approximately 15 (for example, between approximately 10 and approximately 15, or between approximately 12 and approximately 14); and e. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0137] In one embodiment, a. Oleic acid; b. Polysorbate emulsifiers having an HLB value greater than approximately 15 (e.g., Polysorbate 20); c. Monoglyceride emulsifiers (e.g., glycerol monooleate) having an HLB value of less than approximately 5; d. A third emulsifier having an HLB value between approximately 8 and approximately 15 (for example, between approximately 10 and approximately 15, or between approximately 12 and approximately 14); and e. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0138] In one embodiment, a. Oleic acid; b. Polysorbate emulsifiers having an HLB value greater than approximately 15 (e.g., Polysorbate 20); c. Monoglyceride emulsifiers (e.g., glycerol monooleate) having an HLB value of less than approximately 5; d. Polyoxyl castor oil derivatives (e.g., PEG35 castor oil) emulsifiers having an HLB value between approximately 10 and 15; and e. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0139] In one embodiment, a. Oleic acid; b. PEG-100 stearate; c. Glycerol monooleate; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition (for example, less than 15% by weight).

[0140] In one embodiment, a. Oleic acid; b. PEG-100 stearate; c. Glycerol monooleate; and d. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition (for example, less than 15% by weight).

[0141] In one embodiment, a. Oleic acid; b. Polysorbate 20; c. Glycerol monooleate; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition (for example, less than 15% by weight).

[0142] In one embodiment, a. Oleic acid; b. Polysorbate 20; c. Glycerol monooleate; and d. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition (for example, less than 15% by weight).

[0143] In one embodiment, a. Oleic acid; b. Polysorbate 20; c. Glycerol monooleate; d. PEG35 castor oil; and e. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition (for example, less than 15% by weight).

[0144] In one embodiment, a. Oleic acid; b. Polysorbate 20; c. Glycerol monooleate; d. PEG35 castor oil; and e. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition (for example, less than 15% by weight).

[0145] In one embodiment, a. Approximately 50% to 80% by weight (for example, approximately 65% ​​to 75% by weight) of unsaturated free fatty acids; b. A first emulsifier having an HLB value of approximately 14 or more, in an amount of approximately 3% to 6% by weight; c. A second emulsifier having an HLB value of less than 6, in an amount of approximately 4% to 7% by weight; and d. Lopinavir in an amount of approximately 10% to 20% by weight; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0146] In one embodiment, a. Approximately 65% ​​to 75% by weight of unsaturated free fatty acids; b. A first emulsifier having an HLB value of approximately 14 or more, ranging from approximately 3% to approximately 5% by weight; c. A second emulsifier having an HLB value of less than 6, in an amount of approximately 5% to 7% by weight; and d. Approximately 15% to 20% by weight of lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition (for example, less than 15% by weight).

[0147] In one embodiment, a. Approximately 65% ​​to 75% by weight of unsaturated free fatty acids; b. A first emulsifier having an HLB value of approximately 14 or more, in an amount of approximately 3% to 6% by weight; c. A second emulsifier having an HLB value of less than 6, in an amount of approximately 4% to 7% by weight; and d. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition (for example, less than 15% by weight).

[0148] In one embodiment, a. Approximately 65% ​​to 75% by weight of oleic acid; b. A first emulsifier having an HLB value of approximately 14 or more, in an amount of approximately 3% to 6% by weight; c. Approximately 4% to 7% by weight of glycerol monooleate; and d. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 15% by weight of the total composition.

[0149] In one embodiment, a. Approximately 65% ​​to 75% by weight of oleic acid; b. Approximately 3% to 6% by weight of PEG-100 stearate or polysorbate 20; c. Approximately 4% to 7% by weight of glycerol monooleate; and d. Lopinavir and optionally ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 15% by weight of the total composition.

[0150] In one embodiment, a. Approximately 65% ​​to 75% by weight of oleic acid; b. Approximately 3% to 6% by weight of PEG-100 stearate or polysorbate 20; c. Approximately 4% to 7% by weight of glycerol monooleate; and d. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains a total emulsifier content of less than 15% by weight of the total composition, and the wt / wt ratio of lopinavir to ritonavir present in the composition is between approximately 11:1 and approximately 13:1 (for example, approximately 12:1).

[0151] In one embodiment, a. Oleic acid in an amount of approximately 68% to 72% by weight; b. Approximately 3% to 6% by weight of PEG-100 stearate; c. Approximately 4% to 7% by weight of glycerol monooleate; d. Approximately 15% to 20% by weight of lopinavir; and e. Approximately 1.3% to 1.7% by weight of ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains, has a total emulsifier content of about 10% by weight of the total composition, and has a wt / wt ratio of lopinavir to ritonavir present in the composition of about 12:1.

[0152] In one embodiment, a. Oleic acid in an amount of approximately 60% to 75% by weight; b. A first emulsifier having an HLB value of approximately 14 or more, in an amount of approximately 3% to 6% by weight; c. Approximately 4% to 7% by weight of glycerol monooleate; d. A third emulsifier having an HLB value between approximately 8 and 15, in an amount of approximately 4% to 6% by weight; and e. Lopinavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0153] In one embodiment, a. Oleic acid in an amount of approximately 60% to 75% by weight; b. Approximately 3% to 6% by weight of PEG-100 stearate or polysorbate 20; c. Approximately 4% to 7% by weight of glycerol monooleate; d. A third emulsifier containing approximately 4% to 6% by weight, having an HLB value between approximately 8 and 15; and e. Lopinavir and optionally ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains and has a total emulsifier content of less than 30% by weight of the total composition.

[0154] In one embodiment, a. Oleic acid in an amount of approximately 60% to 75% by weight; b. Approximately 3% to 6% by weight of PEG-100 stearate or polysorbate 20; c. Approximately 4% to 7% by weight of glycerol monooleate; d. Approximately 4% to 6% by weight of PEG35 castor oil; and e. Lopinavir and ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains a total emulsifier content of less than 30% by weight of the total composition, and the wt / wt ratio of lopinavir to ritonavir present in the composition is between approximately 11:1 and approximately 13:1 (for example, approximately 12:1).

[0155] In one embodiment, a. Oleic acid in an amount of approximately 60% to 72% by weight; b. Approximately 3% to 6% by weight of PEG-100 stearate or polysorbate 20; c. Approximately 4% to 7% by weight of glycerol monooleate; d. Approximately 4% to 6% by weight of PEG35 castor oil; e. Approximately 15% to 20% by weight of lopinavir; and f. Approximately 1.3% to 1.7% by weight of ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains a total emulsifier content of less than 30% by weight of the total composition, and the wt / wt ratio of lopinavir to ritonavir present in the composition is approximately 12:1.

[0156] In one embodiment, a. Approximately 60% to 65% by weight of oleic acid; b. Approximately 3% to 5% by weight of polysorbate 20; c. Glycerol monooleate, approximately 4% to 6% by weight; d. Approximately 4% to 6% by weight of PEG35 castor oil; e. Approximately 17% to 23% by weight of lopinavir; and f. Approximately 1.5% to 1.9% by weight of ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains a total emulsifier content of less than 30% by weight of the total composition, and the wt / wt ratio of lopinavir to ritonavir present in the composition is approximately 12:1.

[0157] In one embodiment, a. Oleic acid in an amount of approximately 50% to 55% by weight; b. Approximately 15% to 20% by weight of polysorbate 20; c. Approximately 4% to 7% by weight of glycerol monooleate; d. Approximately 4% to 6% by weight of PEG35 castor oil; e. Approximately 15% to 19% by weight of lopinavir; and f. Approximately 1.2% to 1.5% by weight of ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains a total emulsifier content of less than 30% by weight of the total composition, and the wt / wt ratio of lopinavir to ritonavir present in the composition is approximately 12:1.

[0158] In one embodiment, a. Oleic acid in an amount of approximately 45% to 55% by weight; b. Approximately 10% to 14% by weight of polysorbate 20; c. Approximately 12% to 16% by weight of glycerol monooleate; d. Approximately 3% to 6% by weight of PEG35 castor oil; e. Approximately 15% to 23% by weight of lopinavir; and f. Approximately 1.2% to 1.9% by weight of ritonavir; A self-emulsifying pharmaceutical composition is provided, which contains a total emulsifier content of less than 30% by weight of the total composition, and the wt / wt ratio of lopinavir to ritonavir present in the composition is approximately 12:1.

[0159] In one embodiment, a. Unsaturated free fatty acids; b. A first emulsifier having an HLB value greater than approximately 14; c. A second emulsifier having an HLB value of less than approximately 6; d. Antioxidants; e. Lopinavir; and f. ritonavir; A self-emulsifying pharmaceutical composition is provided, comprising the above, wherein the total emulsifier content is less than 30% by weight of the total composition.

[0160] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value greater than approximately 14; c. A second emulsifier having an HLB value of less than approximately 6; d. Antioxidants; e. Lopinavir; and f. ritonavir; A self-emulsifying pharmaceutical composition is provided, comprising the above, wherein the total emulsifier content is less than 30% by weight of the total composition.

[0161] In one embodiment, a. Unsaturated free fatty acids; b. Polyol ester emulsifiers having an HLB value greater than approximately 14 (e.g., PEG-100 stearate); c. A second emulsifier having an HLB value of less than approximately 6; d. Antioxidants; e. Lopinavir; and f. ritonavir; A self-emulsifying pharmaceutical composition is provided, comprising the above, wherein the total emulsifier content is less than 30% by weight of the total composition.

[0162] In one embodiment, a. Unsaturated free fatty acids; b. A first emulsifier having an HLB value greater than approximately 14; c. Monoglyceride emulsifiers having an HLB value of less than approximately 6 (e.g., glycerol monooleate); d. Antioxidants; e. Lopinavir; and f. ritonavir; A self-emulsifying pharmaceutical composition is provided, comprising the above, wherein the total emulsifier content is less than 30% by weight of the total composition.

[0163] In one embodiment, a. Unsaturated free fatty acids; b. Polysorbate emulsifiers having an HLB value greater than approximately 14 (e.g., Polysorbate 20); c. Monoglyceride emulsifiers having an HLB value of less than approximately 6 (e.g., glycerol monooleate); d. Antioxidants; e. Lopinavir; and f. ritonavir; A self-emulsifying pharmaceutical composition is provided, comprising the above, wherein the total emulsifier content is less than 30% by weight of the total composition.

[0164] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value greater than 14; c. Monoglyceride emulsifiers having an HLB value of less than approximately 6 (e.g., glycerol monooleate); d. Antioxidants; e. Lopinavir; and f. ritonavir; A self-emulsifying pharmaceutical composition is provided, comprising the above, wherein the total emulsifier content is less than 20% by weight of the total composition.

[0165] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value greater than 14; c. Monoglyceride emulsifiers having an HLB value of less than approximately 6 (e.g., glycerol monooleate); d. Antioxidants; e. Lopinavir; and f. ritonavir; A self-emulsifying pharmaceutical composition is provided, comprising the above, wherein the total emulsifier content is approximately 8% to 12% by weight of the total composition, and the wt / wt ratio of the monoglyceride emulsifier present in the composition to the first emulsifier is between approximately 1.1:1 and 1.6:1 (for example, between approximately 1.4:1 and 1.6:1).

[0166] In one embodiment, a. Oleic acid; b. Polyol ester emulsifiers having an HLB value greater than approximately 14 (e.g., PEG-100 stearate or polysorbate 20); c. Monoglyceride emulsifiers having an HLB value of less than approximately 6 (e.g., glycerol monooleate); d. Antioxidants; e. Lopinavir; and f. ritonavir; A self-emulsifying pharmaceutical composition is provided, comprising the above, wherein the total emulsifier content is approximately 8% to 12% by weight of the total composition, and the wt / wt ratio of lopinavir to ritonavir present in the composition is approximately 12:1.

[0167] In one embodiment, a. Unsaturated free fatty acids; b. A first emulsifier having an HLB value greater than approximately 14; c. A second emulsifier having an HLB value of less than approximately 6; d. A third emulsifier; e. Antioxidants; f. Lopinavir; and g. Ritonavir; A self-emulsifying pharmaceutical composition is provided, comprising the above, wherein the total emulsifier content is less than 30% by weight of the total composition.

[0168] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value greater than approximately 14; c. A second emulsifier having an HLB value of less than approximately 6; d. A third emulsifier; e. Antioxidants; f. Lopinavir; and g. Ritonavir; A self-emulsifying pharmaceutical composition is provided, comprising the above, wherein the total emulsifier content is less than 30% by weight of the total composition.

[0169] In one embodiment, a. Unsaturated free fatty acids (e.g., oleic acid); b. A first emulsifier having an HLB value greater than approximately 14; c. A second emulsifier having an HLB value of less than approximately 6; d. A third emulsifier having an HLB value between approximately 8 and 15; e. Antioxidants; f. Lopinavir; and g. Ritonavir; A self-emulsifying pharmaceutical composition is provided, comprising the above, wherein the total emulsifier content is less than 30% by weight of the total composition.

[0170] In one embodiment, a. Unsaturated free fatty acid (e.g., oleic acid); b. A first emulsifier having an HLB value greater than about 14; c. A second emulsifier having an HLB value less than about 6; d. A third emulsifier having an HLB value between about 10 and about 15 (e.g., between about 12 and about 14); e. An antioxidant; f. Ritonavir; and g. Lopinavir; There is provided a self-emulsifying pharmaceutical composition comprising the above and having a total emulsifier content less than 30% by weight of the total composition.

[0171] In one embodiment, a. Unsaturated free fatty acid; b. A first emulsifier having an HLB value greater than about 14; c. A monoglyceride emulsifier having an HLB value less than about 6 (e.g., glyceryl monooleate); d. A third emulsifier having an HLB value between about 10 and about 15 (e.g., between about 12 and about 14); e. An antioxidant; f. Ritonavir; and g. Lopinavir; There is provided a self-emulsifying pharmaceutical composition comprising the above and having a total emulsifier content less than 30% by weight of the total composition.

[0172] In one embodiment, a. Unsaturated free fatty acid; b. A polysorbate emulsifier having an HLB value greater than about 14 (e.g., polysorbate 20); c. A monoglyceride emulsifier having an HLB value less than about 6 (e.g., glyceryl monooleate); d. A third emulsifier having an HLB value between about 10 and about 15 (e.g., between about 12 and about 14); e. An antioxidant; f. Ritonavir; and g. Lopinavir; A self-emulsifying pharmaceutical composition is provided, comprising the above, wherein the total emulsifier content is less than 30% by weight of the total composition.

[0173] In one embodiment, a. Unsaturated free fatty acids; b. Polysorbate emulsifiers having an HLB value greater than approximately 14 (e.g., Polysorbate 20); c. Monoglyceride emulsifiers having an HLB value of less than approximately 6 (e.g., glycerol monooleate); d. Polyoxyl castor oil derivative emulsifier (e.g., PEG-35 castor oil); e. Antioxidants; f. Lopinavir; and g. Ritonavir; A self-emulsifying pharmaceutical composition is provided, comprising the above, wherein the total emulsifier content is less than 30% by weight of the total composition.

[0174] In one embodiment, a. Oleic acid; b. A first emulsifier having an HLB value greater than 14; c. Monoglyceride emulsifiers having an HLB value of less than approximately 6 (e.g., glycerol monooleate); d. Polyoxyl castor oil derivative emulsifier (e.g., PEG-35 castor oil); e. Antioxidants; f. Lopinavir; and g. Ritonavir; A self-emulsifying pharmaceutical composition is provided, comprising the above, wherein the total emulsifier content is less than 20% by weight of the total composition.

[0175] In one embodiment, a. Unsaturated free fatty acids (e.g., oleic acid); b. A first emulsifier having an HLB value greater than approximately 14; c. A second emulsifier having an HLB value of less than approximately 6; d. A third emulsifier having an HLB value between approximately 8 and 15; e. Antioxidants; f. Lopinavir; and g. Ritonavir; It consists of, the total emulsifier content is less than 30% by weight of the total composition, the wt / wt ratio of lopinavir present in the composition to ritonavir is about 12:1, and a self-emulsifying pharmaceutical composition is provided.

[0176] In one embodiment, a. Unsaturated free fatty acid (e.g., oleic acid); b. A first emulsifier having an HLB value greater than about 14; c. A second emulsifier having an HLB value less than about 6; d. A third emulsifier having an HLB value between about 8 and about 15; e. Antioxidant; f. Lopinavir; and g. Ritonavir; It consists of, the total emulsifier content is less than 30% by weight of the total composition, the wt / wt ratio of lopinavir present in the composition to ritonavir is about 12:1, and the wt / wt ratio of the second emulsifier present in the composition to the first emulsifier is between about 1.1:1 and 1.6:1 (e.g., between about 1.4:1 and 1.6:1), and a self-emulsifying pharmaceutical composition is provided.

[0177] In one embodiment, a. Oleic acid; b. Polysorbate 20; c. Glycerol monooleate; d. PEG35 castor oil; e. Antioxidant (e.g., butylated hydroxytoluene); f. Lopinavir; and g. Ritonavir; It consists of, the total emulsifier content is less than 30% by weight of the total composition, and the wt / wt ratio of lopinavir present in the composition to ritonavir is about 12:1, and a self-emulsifying pharmaceutical composition is provided. <977>

[0178] In one embodiment, a. Oleic acid; b. Polysorbate 20; c. Glycerol monooleate; d. PEG-35 castor oil; e. Antioxidants (e.g., butylated hydroxytoluene); f. Lopinavir; and g. Ritonavir; A self-emulsifying pharmaceutical composition is provided, comprising the following: the total emulsifier content is less than 30% by weight of the total composition; the wt / wt ratio of lopinavir to ritonavir present in the composition is about 12:1; and the wt / wt ratio of glycerol monooleate to polysorbate 20 present in the composition is between about 1.1:1 and 1.6:1 (for example, between about 1.4:1 and 1.6:1).

[0179] <Administration> The pharmaceutical composition according to the present invention can be administered by any suitable means that can be determined by those skilled in the art based on the active pharmaceutical ingredient(s) and the disease or disorder being treated with the composition. Preferably, the pharmaceutical composition is for oral or topical administration.

[0180] The pharmaceutical composition according to the present invention is typically a liquid composition. Therefore, to simplify drug administration and administration, the composition can also be filled into capsules.

[0181] In one embodiment, a capsule containing a pharmaceutical composition according to the first embodiment of the present invention is provided. In one embodiment, the capsule is for intravaginal administration of the pharmaceutical composition. In another embodiment, the capsule is for oral administration of the pharmaceutical composition.

[0182] In one embodiment, the capsule is a gelatin capsule. In another embodiment, the capsule is a hard capsule. In yet another embodiment, the capsule is a soft capsule. In one embodiment, the capsule is a hard gelatin capsule. In yet another preferred embodiment, the capsule is a soft gelatin capsule.

[0183] <Performance of self-emulsifying drug delivery systems> The pharmaceutical composition of the present invention comprises at least one active pharmaceutical ingredient (lopinavir) dissolved or suspended in an unsaturated fatty acid. When introduced into an aqueous-based environment, the composition rapidly emulsifies into a stable emulsion due to the presence of at least two emulsifiers in the composition. The droplet size of the resulting emulsion is important for stabilizing the emulsion and may also affect the API solubility.

[0184] The droplet size of the emulsion can be determined by dispersing a sample of the composition in water and analyzing the resulting emulsion by dynamic light scattering using a Zetasizer apparatus. Details of a suitable method for determining the average emulsion droplet size via dynamic light scattering are provided in Example 8 below.

[0185] In one embodiment, the average emulsion droplet size of the pharmaceutical composition defined herein is less than 1500 nm, for example, less than 1200 nm, less than 1000 nm, less than 750 nm, less than 600 nm, less than 500 nm, less than 400 nm, or less than 300 nm. In a preferred embodiment, the average emulsion droplet size of the pharmaceutical composition defined herein is less than 750 nm. In one embodiment, the average emulsion droplet size of the pharmaceutical composition defined herein is between 100 and 1500 nm, for example, between 100 and 1000 nm, 150 and 750 nm, 200 and 750 nm, or 200 and 500 nm.

[0186] The pharmaceutical compositions according to the present invention surprisingly exhibited excellent in vitro API dissolution despite their low total emulsifier content (see Figure 1). When comparing in vitro API dissolution with equivalent formulations containing only a single emulsifier (either PEG100 stearate or glycerol monooleate), the single-emulsifier formulations were found to exhibit slower API dissolution, even when their total emulsifier content was the same as the dual-emulsifier formulations (see Figures 2-6). Alternative lopinavir and ritonavir formulations with low total emulsifier content (comparative formulations 1 & 2 - Examples 4 & 5) were found to have significantly slower in vitro API dissolution profiles than the pharmaceutical compositions according to the present invention containing lopinavir and ritonavir (see Figure 7). In vitro dissolution behavior provides a good indicator of how rapidly the active pharmaceutical component(s) become available for bioavailability, and therefore the pharmaceutical compositions of the present invention are expected to yield good API bioavailability.

[0187] In vitro dissolution tests can be performed using various dissolution test models that are apparent to those skilled in the art. In the following embodiments, dissolution profiles were obtained by filling the composition into hard gel capsules using a sinker and measuring API dissolution in 0.7% w / v SLS medium at approximately 37°C using a USP instrument II at 25 rpm for 0–60 minutes and at 200 rpm for 60–75 minutes. At each time point, the medium was sampled and analyzed for API content by HPLC to determine the percentage of dissolution.

[0188] In one embodiment, when the dissolution of a pharmaceutical composition is measured in a 0.7% w / v SLS medium at approximately 37°C using a USP instrument II at 25 rpm for 0 to 60 minutes and at 200 rpm for 60 to 75 minutes, the dissolution profile includes more than 20% lopinavir dissolution after 10 minutes, for example, more than 30% lopinavir dissolution, more than 40% lopinavir dissolution, or more than 50% lopinavir dissolution after 10 minutes.

[0189] In a preferred embodiment, when the dissolution of the pharmaceutical composition is measured in a 0.7% w / v SLS medium at approximately 37°C using a USP instrument II at 25 rpm for 0 to 60 minutes and at 200 rpm for 60 to 75 minutes, the dissolution profile includes more than 60% lopinavir dissolution after 45 minutes, for example, more than 65% lopinavir dissolution, more than 70% lopinavir dissolution, more than 75% lopinavir dissolution, or more than 80% lopinavir dissolution after 45 minutes.

[0190] In a preferred embodiment, when the dissolution of the pharmaceutical composition is measured in a 0.7% w / v SLS medium at approximately 37°C using a USP instrument II at 25 rpm for 0 to 60 minutes and at 200 rpm for 60 to 75 minutes, the dissolution profile includes more than 90% lopinavir dissolution after 75 minutes, for example, more than 92% lopinavir dissolution, more than 95% lopinavir dissolution, or more than 97% lopinavir dissolution after 75 minutes.

[0191] In one embodiment, when the dissolution of the pharmaceutical composition is measured in a 0.7% w / v SLS medium at approximately 37°C using a USP instrument II at 25 rpm for 0 to 60 minutes and at 200 rpm for 60 to 75 minutes, the dissolution profile includes more than 20% lopinavir dissolution after 10 minutes and more than 60% lopinavir dissolution after 45 minutes. In another embodiment, when the dissolution of the pharmaceutical composition is measured in a 0.7% w / v SLS medium at approximately 37°C using a USP instrument II at 25 rpm for 0 to 60 minutes and at 200 rpm for 60 to 75 minutes, the dissolution profile includes more than 40% lopinavir dissolution after 10 minutes and more than 70% lopinavir dissolution after 45 minutes.

[0192] In one embodiment, when the dissolution of the pharmaceutical composition is measured in a 0.7% w / v SLS medium at approximately 37°C using a USP instrument II at 25 rpm for 0 to 60 minutes and at 200 rpm for 60 to 75 minutes, the dissolution profile includes more than 20% lopinavir dissolution after 10 minutes, more than 60% lopinavir dissolution after 45 minutes, and more than 90% lopinavir dissolution after 75 minutes. In another embodiment, when the dissolution of the pharmaceutical composition is measured in a 0.7% w / v SLS medium at approximately 37°C using a USP instrument II at 25 rpm for 0 to 60 minutes and at 200 rpm for 60 to 75 minutes, the dissolution profile includes more than 40% lopinavir dissolution after 10 minutes, more than 70% lopinavir dissolution after 45 minutes, and more than 90% lopinavir dissolution after 75 minutes.

[0193] In the following embodiments, the dissolution profile was obtained by filling the composition into a hard gel capsule using a sinker and measuring the API dissolution in a 0.7% cetyltrimethylammonium bromide (CTAB) medium at 37±0.5℃ in a USPII instrument at 50 rpm for 0 to 60 minutes. At each time point, the medium was sampled and the API content was analyzed by HPLC to determine the percentage of dissolution.

[0194] In one embodiment, when the dissolution of the pharmaceutical composition is measured in 0.7% w / v cetyltrimethylammonium bromide (CTAB) medium at 37±0.5℃ in a USPII instrument at 50 rpm for 0 to 60 minutes, the dissolution profile includes more than 30% lopinavir dissolution after 10 minutes, more than 60% lopinavir dissolution after 30 minutes, and more than 70% lopinavir dissolution after 60 minutes. In another embodiment, when the dissolution of the pharmaceutical composition is measured in 0.7% w / v cetyltrimethylammonium bromide (CTAB) medium at 37±0.5℃ in a USPII instrument at 50 rpm for 0 to 60 minutes, the dissolution profile includes more than 50% lopinavir dissolution after 10 minutes, more than 70% lopinavir dissolution after 30 minutes, and more than 80% lopinavir dissolution after 60 minutes.

[0195] In the following embodiments, the dissolution profile was obtained by filling a hard gel capsule with a sinker with the composition and measuring the dissolution of API in 0.05 M PEG10 oleyl ether (Brij® 10) with a 10 mM sodium monobasic phosphate pH 6.8 medium at 37 ± 0.5 °C in a USPII instrument at 50 rpm for 0 to 60 minutes. At each time point, the medium was sampled and analyzed for API content by HPLC to determine the percentage of dissolution.

[0196] In one embodiment, when the dissolution of the pharmaceutical composition is measured in 0.05 M PEG10 oleyl ether (Brij® 10) having a 10 mM sodium monobasic phosphate medium at pH 6.8, using a USPII instrument at 50 rpm for 0 to 60 minutes at 37 ± 0.5 °C, the pharmaceutical composition has a dissolution profile that includes more than 30% lopinavir dissolution after 10 minutes, more than 60% lopinavir dissolution after 30 minutes, and more than 80% lopinavir dissolution after 60 minutes. In another embodiment, when the dissolution of the pharmaceutical composition is measured in 0.05 M PEG10 oleyl ether (Brij® 10) having a 10 mM sodium monobasic phosphate medium at pH 6.8, using a USPII instrument at 50 rpm for 0 to 60 minutes at 37 ± 0.5 °C, the pharmaceutical composition has a dissolution profile that includes more than 60% lopinavir dissolution after 10 minutes, more than 80% lopinavir dissolution after 30 minutes, and more than 90% lopinavir dissolution after 60 minutes.

[0197] Advantageously, the pharmaceutical compositions of the present invention can generally have good lopinavir dissolution across the entire range of dissolving media that exhibit these possibilities, providing good lopinavir bioavailability. In one embodiment, the pharmaceutical composition is (A) When dissolution was measured in 0.7% w / v SLS medium at approximately 37°C using a USP instrument II at 25 rpm for 0-60 minutes and at 200 rpm for 60-75 minutes, more than 20% of lopinavir was dissolved after 10 minutes, more than 60% after 45 minutes, and more than 90% after 75 minutes; (B) When dissolution was measured in a 0.7% w / v cetyltrimethylammonium bromide (CTAB) medium at 37±0.5℃ in a USPII instrument at 50 rpm for 0 to 60 minutes, more than 30% of lopinavir was dissolved after 10 minutes, more than 60% after 30 minutes, and more than 70% after 60 minutes; and (C) When dissolution was measured in 0.05 M PEG10 oleyl ether (Brij® 10) with a 10 mM sodium monobasic phosphate pH 6.8 medium at 37 ± 0.5 °C using a USPII instrument at 50 rpm for 0 to 60 minutes, more than 30% of lopinavir was dissolved after 10 minutes, more than 60% after 30 minutes, and more than 80% after 60 minutes. It has a dissolution profile that includes [something].

[0198] In one embodiment, the pharmaceutical composition is (A) When dissolution was measured in 0.7% w / v SLS medium at approximately 37°C using a USP instrument II at 25 rpm for 0-60 minutes and at 200 rpm for 60-75 minutes, more than 40% of lopinavir was dissolved after 10 minutes, more than 70% after 45 minutes, and more than 90% after 75 minutes; (B) When dissolution was measured in a 0.7% w / v cetyltrimethylammonium bromide (CTAB) medium at 37±0.5℃ in a USPII instrument at 50 rpm for 0 to 60 minutes, more than 50% of lopinavir was dissolved after 10 minutes, more than 70% after 30 minutes, and more than 80% after 60 minutes; and (C) When dissolution was measured in 0.05 M PEG10 oleyl ether (Brij® 10) with a 10 mM sodium monobasic phosphate pH 6.8 medium at 37 ± 0.5 °C using a USPII instrument at 50 rpm for 0 to 60 minutes, more than 60% of lopinavir was dissolved after 10 minutes, more than 80% after 30 minutes, and more than 90% after 60 minutes. It has a dissolution profile that includes [something].

[0199] Cmax is the maximum serum concentration achieved by a drug in a specified compartment or test area of ​​the body after administration of the drug. A higher Cmax value corresponds to a higher systemic drug concentration and therefore to greater bioavailability of the drug. A PK experimental protocol for determining the Cmax of a composition according to the present invention is described in Example 9. In one embodiment, when a pharmaceutical composition according to the present invention is administered daily as an 800 mg or 900 mg capsule containing 150 mg of lopinavir, it has an average Cmax greater than 500 pg / ml, for example, greater than 1 ng / ml, greater than 500 ng / ml, or greater than 1 μg / ml.

[0200] <Medical Use> In one embodiment, a self-emulsifying pharmaceutical composition as defined herein is provided for use as a pharmaceutical.

[0201] In one embodiment, the pharmaceutical composition is intended to be used as a pharmaceutical that is applied topically (for example, to a mucous membrane) or administered orally.

[0202] In preferred embodiments, the self-emulsifying pharmaceutical composition of the present invention is encapsulated in a capsule. Such a capsule provides a convenient delivery form for both oral and topical administration (e.g., vaginally) of the pharmaceutical composition. In one embodiment, a self-emulsifying pharmaceutical composition as defined herein is provided for use as a pharmaceutical, and this pharmaceutical composition is administered orally as a capsule. In another embodiment, a self-emulsifying pharmaceutical composition as defined herein is provided for use as a pharmaceutical, and this pharmaceutical composition is administered topically (e.g., vaginally) as a capsule.

[0203] In one embodiment, the pharmaceutical composition is useful for treating and / or preventing diseases and / or disorders. In one embodiment, the pharmaceutical composition is useful for treating benign proliferative disorders.

[0204] In one embodiment, the pharmaceutical composition is useful for treating cancer, and particularly useful for preventing the onset of cancer. Therefore, a normal subject (i.e., a subject without detectable cancer), a subject with pre-malignant cells, or a subject particularly susceptible to developing cancer can be treated by topical administration of the composition according to the present invention for the purpose of preventing the onset of cancer.

[0205] Pharmaceutical compositions comprising lopinavir and ritonavir for use as pharmaceuticals for the treatment of cancer or benign proliferative disorders (e.g., warts) or for the prevention of the development of cancer. In one embodiment, a method is provided for treating and / or inhibiting the development or progression of cancer and benign proliferative disorders in a subject requiring such treatment or inhibition, the method comprising administering a therapeutically effective amount of the pharmaceutical composition disclosed herein.

[0206] The present invention can be applied to a wide range of cancers, such as ovarian cancer, breast cancer, lung cancer, uterine cancer, cervical cancer, and thyroid cancer, to the extent that it is applicable to the prevention and treatment of cancer. The present invention is particularly applicable to precancerous conditions and cancers caused by oncogenic viruses, such as high-risk forms of human papillomavirus (HPV), or even by low-risk forms of HPV, but is not limited to these.

[0207] Preferably, the compositions can be administered to treat and, in particular, prevent the development of cervical cancer. Preferably, inhibitors are used to treat or prevent the development of cervical cancer caused by HPV (particularly high-risk types of HPV, e.g., HPV16 or HPV18). In one embodiment, a method is provided for treating and / or inhibiting the development or progression of cancer and benign proliferative disorders in subjects requiring such treatment or inhibition, comprising administering a therapeutically effective amount of a pharmaceutical composition disclosed herein, wherein the cancer or disorder is caused or induced by human papillomavirus (HPV).

[0208] The composition can be used as a monotherapy (i.e., including the use of a pharmaceutical composition containing two or more active pharmaceutical ingredients) or in combination with other compounds or treatments used in cancer therapy (e.g., chemotherapy agents, radiotherapy) to prevent or treat cancer.

[0209] Pharmaceutical compositions comprising lopinavir and ritonavir for use as pharmaceuticals in the treatment of cancer or benign proliferative disorders (e.g., warts) or in the prevention of the development of cancer are disclosed herein.

[0210] Preferably, the composition is used to treat humans. However, it should be recognized that the composition also has some veterinary uses.

[0211] <Medication> It should be recognized that the required amount of at least one active pharmaceutical ingredient (lopinavir) is determined by its biological activity and bioavailability, and therefore, in part, depends on the precise mode of administration, the physicochemical properties of the pharmaceutical composition used, and whether the pharmaceutical composition is used as a monotherapy or in combination with other drugs. In fact, at least one active pharmaceutical ingredient (lopinavir) may also be applied topically in addition to oral administration of the same at least one active pharmaceutical ingredient or other active pharmaceutical ingredients. The frequency of administration is also influenced by the above factors, particularly the half-life of the active pharmaceutical ingredient within the subject being treated.

[0212] The daily dose may be administered as a single dose (e.g., in the form of a soft gel capsule, hard gel capsule, pessary, or suppository). Alternatively, administration may occur two or more times a day. For example, the pharmaceutical composition may be administered topically at least once a day, for example, once a day, or twice a day, (e.g., as a soft gel capsule or hard gel capsule).

[0213] The optimal dose to administer can be determined by those skilled in the art and will vary with the intensity of preparation, mode of administration, and progression of the disease. For example, it may also be necessary to adjust the dose based on additional factors specific to the subject being treated, including age, weight, sex, diet, and time of administration.

[0214] An appropriate amount of at least one active pharmaceutical ingredient to be administered as a daily dose is approximately 0.01 mg to approximately 10 g, for example, approximately 0.1 mg to approximately 10 g, for example, approximately 1 mg to approximately 5 g, for example, approximately 1 mg to approximately 1 g, for example, approximately 5 mg to approximately 2 g, for example, approximately 10 mg to approximately 1 g, for example, approximately 5 mg to approximately 500 mg, for example, approximately 10 mg to approximately 500 mg, for example, approximately 10 mg to approximately 400 mg, for example, approximately 5 mg to approximately 200 mg g, for example, approximately 5mg to approximately 50mg, for example, approximately 10mg to approximately 40mg, for example, approximately 20mg to approximately 40mg, for example, approximately 25mg to approximately 35mg, for example, approximately 27mg to approximately 32mg, for example, approximately 29mg, for example, 29mg, for example, approximately 28.7mg, for example, 28.7mg, for example, approximately 15mg to approximately 35mg, for example, approximately 20mg to approximately 30mg, for example, approximately 23mg to approximately 27mg, for example, approximately 25mg, example For example, 25mg, for example, approximately 5mg to approximately 25mg, for example, approximately 10mg to approximately 20mg, for example, approximately 12mg to approximately 16mg, for example, approximately 14mg, for example, 14mg, for example, approximately 14.3mg, for example, approximately 14.3mg, for example, approximately 11mg to approximately 15mg, for example, approximately 13mg, for example, 13mg, for example, approximately 12.5mg, for example, 12.5mg, for example, approximately 100mg to approximately 400mg, for example, approximately 200 mg to approximately 400 mg, for example, approximately 250 mg to approximately 350 mg, for example, approximately 280 mg to approximately 320 mg, for example, approximately 290 mg to approximately 310 mg, for example, approximately 300 mg, for example, 300 mg, for example, approximately 25 mg to approximately 325 mg, for example, approximately 50 mg to approximately 250 mg, for example, approximately 125 mg to approximately 175 mg, for example, approximately 140 mg to approximately 160 mg, for example, approximately 150 mg, or for example, 150 mg.

[0215] The appropriate daily dose of lopinavir to be administered is approximately 0.01 mg to 10 g, for example, approximately 0.1 mg to 10 g, for example, approximately 1 mg to 5 g, for example, approximately 5 mg to 2 g, for example, approximately 10 mg to 1 g, for example, approximately 10 mg to 500 mg, for example, approximately 10 mg to 400 mg, for example, approximately 100 mg to 400 mg, for example, approximately 200 mg to 400 mg, for example The daily dose is approximately 250 mg to 350 mg, for example, approximately 280 mg to 320 mg, for example, approximately 290 mg to 310 mg, for example, approximately 300 mg, for example, 300 mg, for example, approximately 25 mg to 325 mg, for example, approximately 50 mg to 250 mg, for example, approximately 125 mg to 175 mg, for example, approximately 140 mg to 160 mg, for example, approximately 150 mg, or for example, 150 mg. In a convenient embodiment, the daily dose of lopinavir is approximately 150 mg or approximately 300 mg. Most preferably, the daily dose of lopinavir is 300 mg.

[0216] The appropriate daily dose of ritonavir should be approximately 0.01 mg to 10 g, for example, approximately 0.1 mg to 10 g, for example, approximately 1 mg to 5 g, for example, approximately 1 mg to 1 g, for example, approximately 5 mg to 500 mg, for example, approximately 5 mg to 200 mg, for example, approximately 5 mg to 50 mg, for example, approximately 10 mg to 40 mg, for example, approximately 20 mg to 40 mg, for example, approximately 25 mg to 35 mg, for example, approximately 27 mg to 32 mg, for example, approximately 29 mg, for example, approximately 29 mg, for example, approximately 28.7 mg, for example, The dosage is 28.7 mg, for example, about 15 mg to about 35 mg, for example, about 20 mg to about 30 mg, for example, about 23 mg to about 27 mg, for example, about 25 mg, for example, 25 mg, for example, about 5 mg to about 25 mg, for example, about 10 mg to about 20 mg, for example, about 12 mg to about 16 mg, for example, about 14 mg, for example, 14 mg, for example, about 14.3 mg, for example, 14.3 mg, for example, about 11 mg to about 15 mg, for example, about 13 mg, for example, 13 mg, for example, about 12.5 mg, or for example, 12.5 mg. In a convenient embodiment, the daily dose of ritonavir is about 12.5 mg or about 25 mg. Most preferably, the daily dose of ritonavir is 25 mg.

[0217] In one embodiment, about 150 mg of lopinavir and about 12.5 mg of ritonavir may be administered daily to patients who require it.

[0218] In one embodiment, about 300 mg of lopinavir and about 25 mg of ritonavir may be administered daily to patients who require it.

[0219] <Treatment Regimen> The pharmaceutical composition can be administered to a subject as long as treatment is needed. The period for which treatment is needed depends on the exact condition being treated or prevented and its severity. One skilled in the art will recognize that treatment should be maintained considering several factors including any requirements for eradicating the disease and / or disorder.

[0220] In one embodiment, the course of treatment can be 2 - 4 weeks, 7 - 21 days or about 14 days. After this course of treatment, the clinician can evaluate whether the course of treatment was successful. Then a decision can be made whether to continue treatment.

[0221] It is recognized that when determining a treatment regimen for a woman with a condition related to the cervix, a clinician may wish to take into account the menstrual cycle. Preferably, the treatment regimen can be about 14 - 21 days and may be administered during menstruation. The clinician may choose to stop local treatment of the cervix during menstruation and resume a new course of treatment in the next menstrual cycle. By way of example, the treatment regimen can be (1) administration for 14 - 21 days; (2) followed by 1 - 14 days without treatment (during which menstruation can occur if the cervix is being treated); and (3) a further cycle of treatment for 14 - 21 days if medically required.

[0222] <Treatment of HPV - related Dysplasia> Preferably, the pharmaceutical composition can be used to treat female subjects having HPV - related dysplasia of the cervix.

[0223] As used herein, “dysplasia” encompasses pre-invasive lesions and cancers. HPV-related pre-invasive lesions include high-grade squamous intraepithelial lesions (HSILs), atypical squamous cell lesions of undetermined severity (ASCUS), and low-grade squamous intraepithelial lesions (LSILs). HPV-related cancers include, for example, cervical intraepithelial neoplasia (CINs) and invasive cervical cancer (ICCs).

[0224] The disclosed methods and treatment regimens can be used to treat HPV-related dysplasia. In some embodiments, for example, the disclosed methods and treatment regimens can be used to treat HSIL. In some embodiments, the disclosed methods and treatment regimens can be used to treat ASCUS. In other embodiments, the disclosed methods and treatment regimens can be used to treat LSIL. In other embodiments, the disclosed methods and treatment regimens can be used to treat CIN. In yet another embodiment, the disclosed methods and treatment regimens can be used to treat ICC. Furthermore, the disclosed methods and treatment regimens can be used to inhibit the progression of HPV-related dysplasia. In some embodiments, for example, the disclosed methods and treatment regimens can be used to inhibit the progression of HSIL. In some embodiments, the disclosed methods and treatment regimens can be used to inhibit the progression of ASCUS. In other embodiments, the disclosed methods and treatment regimens can be used to inhibit the progression of LSIL. In other embodiments, the disclosed methods and treatment regimens can be used to inhibit the progression of CIN. In further embodiments, the disclosed methods and treatment regimens can be used to inhibit the progression of ICC.

[0225] In one embodiment, a method is provided for treating a patient having HPV-related cervical dysplasia, comprising intravaginally administering a therapeutically effective amount of the pharmaceutical composition according to the first embodiment to the patient. In an alternative embodiment, a method is provided for treating a patient having HPV-related cervical dysplasia, comprising orally administering a therapeutically effective amount of the pharmaceutical composition according to the first embodiment to the patient.

[0226] In one embodiment, the pharmaceutical composition reduces the severity of HPV-related dysplasia. In one embodiment, the HPV severity is reduced from CIN3 to CIN2, from CIN3 to CIN1, from CIN3 to HPV-negative, from CIN2 to CIN1, from CIN2 to HPV-negative, or from CIN1 to HPV-negative.

[0227] In one embodiment, the patient or subject has a cervical cytology finding of high-grade squamous intraepithelial lesion (HSIL), an atypical squamous cell cytology finding of undetermined severity (ASCUS), or a low-grade squamous intraepithelial lesion (LSIL).

[0228] In one embodiment, the pharmaceutical composition reduces cervical cytology from HSIL to normal cells, from HSIL to ACSUS, from HSIL to LSIL, from ACSUS to normal cells, or from LSIL to normal cells.

[0229] In some embodiments, the composition induces apoptosis in HPV-infected cells.

[0230] <Manufacturing Process> A second embodiment provides a process for producing the self-emulsifying pharmaceutical composition of the first embodiment, comprising the step of incorporating together (e.g., by mixing) at least one active pharmaceutical ingredient (lopinavir), an unsaturated free fatty acid, and at least two emulsifiers to obtain the self-emulsifying pharmaceutical composition, wherein the at least two emulsifiers comprise a first emulsifier having an HLB value greater than about 14 and a second emulsifier having an HLB value less than about 6, and the total emulsifier content is less than 30% by weight of the total composition.

[0231] In one embodiment, the process includes a first step of incorporating at least one active pharmaceutical ingredient (lopinavir) into an unsaturated free fatty acid to obtain a mixture, and a second step of subsequently incorporating at least two emulsifiers into the mixture obtained in the first step to obtain a self-emulsifying pharmaceutical composition. Therefore, in one embodiment, the process is a. The step of incorporating at least one active pharmaceutical ingredient (lopinavir) into an unsaturated free fatty acid (for example, by mixing it); b. To obtain a self-emulsifying composition, the step of incorporating at least two emulsifiers obtained in step a) into a mixture (for example, by mixing them) The composition includes at least two emulsifiers, a first emulsifier having an HLB value greater than approximately 14, and a second emulsifier having an HLB value less than approximately 6, with the total emulsifier content being less than 30% by weight of the total composition.

[0232] In one embodiment, the process is a. The step of incorporating lopinavir and a second active pharmaceutical ingredient (e.g., ritonavir) into an unsaturated free fatty acid (e.g., by mixing them); b. To obtain a self-emulsifying composition, the step of incorporating at least two emulsifiers into the mixture obtained in step a) (for example, by mixing them) The composition includes at least two emulsifiers, a first emulsifier having an HLB value greater than approximately 14 and a second emulsifier having an HLB value less than approximately 6, and the total emulsifier content is less than 30% by weight of the total composition.

[0233] In one embodiment, the process is a. The step of incorporating lopinavir and a second active pharmaceutical ingredient (e.g., ritonavir) into an unsaturated free fatty acid (e.g., by mixing them); b. To obtain a self-emulsifying composition, the three emulsifiers are incorporated into the mixture obtained in step a) (for example, by mixing). The three emulsifiers include a first emulsifier with an HLB value of approximately 14 or higher, a second emulsifier with an HLB value of less than approximately 6, and a third emulsifier with an HLB value in the range of approximately 8 to approximately 15, with the total emulsifier content being less than 30% by weight of the total composition.

[0234] In one embodiment, the first step and / or the second step includes stirring. In one embodiment, stirring is carried out at a speed of at least 10 rpm, for example, at least 30 rpm, at least 50 rpm, at least 100 rpm, at least 150 rpm, at least 200 rpm, at least 250 rpm, at least 300 rpm, at least 400 rpm, at least 500 rpm, or for example, about 600 rpm. In one embodiment, the stirring in the first step results in the dissolution of at least one active pharmaceutical ingredient in the unsaturated free fatty acid. In one embodiment, stirring is carried out for 5 minutes after the at least one active pharmaceutical ingredient has been incorporated with the unsaturated free fatty acid. This advantageously assists the initial fragmentation of the components of the pharmaceutical composition during this part of the process. In one embodiment, stirring is repeated every 30 minutes.

[0235] In one embodiment, the process is carried out at room temperature. In one embodiment, the process is carried out at room temperature, and the wt / wt ratio of the second emulsifier to the first emulsifier present in the composition is between about 1:10 and about 10:1, for example, between about 1:5 and about 5:1, between about 1:3 and about 3:1, between about 1:1 and about 5:1, between about 1:1 and about 3:1, between about 1:1 and about 2:1, between about 1:2 and about 2:1, between about 1:1.5 and about 2:1, between about 1:1.3 and about 1:1.1 (for example, about 1:1.2), between about 1.1:1 and 1.6:1, between about 1.1:1 and 1.2:1, or between about 1.4:1 and 1.6:1 (for example, about 1.5:1). Advantageously, this process is particularly well suited to active pharmaceutical ingredients that tend to degrade (e.g., lopinavir), and the rate and / or range of degradation increases when exposed to temperatures above room temperature, e.g., >30°C, >40°C, >50°C, and >60°C.

[0236] In one embodiment, this process is a. The step of incorporating lopinavir and a second active pharmaceutical ingredient (e.g., ritonavir) into an unsaturated free fatty acid (e.g., by mixing them); b. To obtain a self-emulsifying composition, the step of incorporating at least two emulsifiers into the mixture obtained in step a) (for example, by mixing them) The composition includes at least two emulsifiers, a first emulsifier having an HLB value greater than about 14 and a second emulsifier having an HLB value less than about 6, the total emulsifier content being less than 30% by weight of the total composition, and steps a and b are carried out at a temperature below 40°C (e.g., below 30°C).

[0237] In one embodiment, this process is a. The step of incorporating lopinavir and a second active pharmaceutical ingredient (e.g., ritonavir) into an unsaturated free fatty acid (e.g., by mixing them); b. To obtain a self-emulsifying composition, the three emulsifiers are incorporated into the mixture obtained in step a) (for example, by mixing). The three emulsifiers include a first emulsifier having an HLB value greater than approximately 14, a second emulsifier having an HLB value less than approximately 6, and a third emulsifier having an HLB value in the range of approximately 8 to approximately 15, the total emulsifier content being less than 30% by weight of the total composition, and steps a and b are carried out at a temperature below 40°C (e.g., below 30°C).

[0238] In one embodiment, the process involves incorporating at least two emulsifiers, at least one active pharmaceutical ingredient (lopinavir and ritonavir), and unsaturated free fatty acids by low-shear mixing. In another embodiment, the process involves incorporating at least two emulsifiers, at least one active pharmaceutical ingredient (lopinavir and ritonavir), and unsaturated free fatty acids by high-pressure homogenization.

[0239] In one embodiment, the process according to the second embodiment is carried out under an inert atmosphere. In one embodiment, the inert atmosphere is provided by a vacuum. In a further embodiment, the vacuum is approximately -0.5 bar. Carrying out the process under an inert atmosphere has the advantage that any component of the pharmaceutical composition, for example, at least one active pharmaceutical component (lopinavir and / or ritonavir) that is prone to decomposition (e.g., oxidative decomposition), is protected from such decomposition during the manufacturing process.

[0240] In one embodiment, the process according to the second embodiment uses an unsaturated free fatty acid having an assay of at least 95% by weight, for example, at least 98% by weight, for example, at least 99% by weight, or for example, at least 99.5% by weight. Advantageously, by using an unsaturated free fatty acid with a high assay level, control over the pharmaceutical composition, for example, the identity, quantity, and purity of the free fatty acid within the composition.

[0241] In one embodiment, the process according to the second aspect further includes the step of filtering the composition obtained in step b. Filtration can be carried out by any suitable conventional filtration means. In a preferred embodiment, filtration is carried out by passing the composition through a GAF bag filter.

[0242] In one embodiment, the process according to the second aspect further includes the step of filling the composition into capsules.

[0243] In one embodiment, a self-emulsifying pharmaceutical composition obtained or available by the process described herein is provided.

[0244] The following numbered descriptions 1-50 are not claims, but instead define various aspects and embodiments of the present invention: 1. a. Unsaturated free fatty acids; b. At least two emulsifiers; and c. At least one active pharmaceutical ingredient (lopinavir); A self-emulsifying pharmaceutical composition comprising at least two emulsifiers, the first emulsifier having an HLB value of at least about 14 and the second emulsifier having an HLB value of at least about 6, and the total emulsifier content being less than 30% by weight of the total composition. 2. A pharmaceutical composition according to description 1, wherein the unsaturated free fatty acid is oleic acid. 3. A pharmaceutical composition according to claim 1 or 2, wherein at least two emulsifiers are two emulsifiers. 4. Any pharmaceutical composition according to any prior description, wherein the first emulsifier has an HLB value greater than 14 and the second emulsifier has an HLB value less than 6. 5. Any pharmaceutical composition according to any prior description, wherein the first emulsifier has an HLB value greater than approximately 15, for example, greater than approximately 16, greater than approximately 17, or greater than approximately 18. 6. A pharmaceutical composition according to any prior description, wherein the first emulsifier is solid at room temperature. 7. Any pharmaceutical composition according to any prior description, wherein the first emulsifier is a polyol ester, for example, polyol stearate (e.g., PEG100 stearate). 8. A pharmaceutical composition according to descriptions 1 to 5, wherein the first emulsifier is liquid at room temperature. 9. A pharmaceutical composition according to claim 8, wherein the first emulsifier is a polyethoxylated sorbitan ester, for example, polysorbate 20, polysorbate 60, or polysorbate 80. 10. A pharmaceutical composition according to any prior description, wherein the second emulsifier has an HLB value of less than approximately 5.5, for example, less than approximately 5, less than approximately 4.5, or less than approximately 4. 11. A pharmaceutical composition according to any prior description, wherein the second emulsifier is semi-solid at room temperature. 12. Any pharmaceutical composition according to any prior description, wherein the second emulsifier is a monoglyceride, for example, glycerol monooleate. 13. Any pharmaceutical composition according to any preceding description, wherein the wt / wt ratio of a second emulsifier present in the composition to a first emulsifier is between approximately 1:10 and approximately 10:1, for example, between approximately 1:5 and approximately 5:1, between approximately 1:3 and approximately 3:1, between approximately 1:1 and approximately 5:1, between approximately 1:1 and approximately 3:1, between approximately 1:1 and approximately 2:1, between approximately 1:2 and approximately 2:1, between approximately 1:1.5 and approximately 2:1, between approximately 1:1.3 and approximately 1:1.1 (for example, approximately 1:1.2), or between approximately 1.4:1 and 1.6:1 (for example, approximately 1.5:1). 14. A pharmaceutical composition according to any prior description, wherein at least two emulsifiers are two emulsifiers. 15. A pharmaceutical composition according to claim 14, wherein the first emulsifier has an HLB value greater than 14, the second emulsifier has an HLB value less than 6, the third emulsifier has an HLB value in the range of 8 to 15, and the total emulsifier content is less than 30% by weight of the total composition. 16. A pharmaceutical composition according to claim 15, wherein the third emulsifier has an HLB value in the range of 10 to 15, for example, 11 to 15, 12 to 15, 13 to 15, 11 to 14, or 12 to 14. 17. A pharmaceutical composition according to claim 15 or 16, wherein the third emulsifier is a polyoxyl castor oil derivative (e.g., PEG35 castor oil). 18. Any pharmaceutical composition according to any of the preceding descriptions, wherein the total emulsifier content is less than 25% by weight, less than 20% by weight, less than 15% by weight, 2% to 20% by weight, 2.5% to 15% by weight, 5% to 15% by weight, 8% to 12% by weight, 10% to 20% by weight, 12% to 20% by weight, 10% to 18% by weight, 12% to 18% by weight, 12% to 16% by weight, 13% to 20% by weight, 14% to 20% by weight, 15% to 20% by weight, 13% to 25% by weight, 14% to 25% by weight, 15% to 25% by weight, 20% to 25% by weight, 20% to 26% by weight, 20% to 27% by weight, 20% to 28% by weight, or 20% to 29% by weight of the total composition. 19. A pharmaceutical composition according to any prior description, wherein unsaturated free fatty acids are present in the pharmaceutical composition at a level of at least 25% by weight of the total pharmaceutical composition, for example, at least 35% by weight, at least 45% by weight, about 50% to about 85% by weight, about 50% to about 75% by weight, about 50% to about 70% by weight, about 60% to about 80% by weight, about 65% to about 80% by weight, about 65% to about 75% by weight, or about 68% to about 72% by weight of the total composition. 20. Any pharmaceutical composition according to any preceding description, wherein the first emulsifier is present in the pharmaceutical composition in an amount of about 1% to about 20% by weight of the total pharmaceutical composition, for example, about 1% to about 10% by weight, about 10% to about 20% by weight, about 10% to about 15% by weight, about 1% to about 5% by weight, about 3% to about 7% by weight, about 3% to about 6% by weight, about 3% to about 5% by weight (for example, about 4% by weight), about 4% to about 5% by weight (for example, about 4.3% by weight), or about 5% to about 6% by weight (for example, about 5.5% by weight). 21. Any pharmaceutical composition according to any preceding description, wherein the second emulsifier is present in the pharmaceutical composition in an amount of about 1% to about 20% by weight of the total pharmaceutical composition, for example, about 1% to about 10% by weight, about 2% to about 8% by weight, about 4% to about 7% by weight, about 5% to about 7% by weight (for example, about 6% by weight), about 4% to about 6% by weight (for example, about 5% by weight), or about 4% to about 5% by weight (for example, about 4.5% by weight). 22. A pharmaceutical composition according to any one of claims 14 to 21, wherein the third emulsifier is present in the pharmaceutical composition in an amount of about 1% to about 10% by weight of the total pharmaceutical composition, for example, about 2% to about 8% by weight, about 3% to about 7% by weight, about 4% to about 6% by weight, or about 5% by weight of the total pharmaceutical composition. 23. Any pharmaceutical composition according to any preceding description, wherein at least one active pharmaceutical ingredient (lopinavir) is present in a dissolved state. 24. A pharmaceutical composition according to any prior description, wherein at least one active pharmaceutical ingredient (lopinavir) is stable within the pharmaceutical composition. 25. A pharmaceutical composition according to any prior description, wherein at least one active pharmaceutical ingredient has a solubility of at least 1% w / v in an unsaturated free fatty acid. 26. Any pharmaceutical composition according to any prior description, wherein at least one active pharmaceutical ingredient has an aqueous solubility of less than 0.1 mg / ml, for example, less than 0.01 mg / ml. 27. A pharmaceutical composition according to any prior description, wherein at least one active pharmaceutical ingredient has a LogP value greater than 4, for example, greater than 5. 28. A pharmaceutical composition according to any prior description, wherein at least one active pharmaceutical ingredient is an HIV protease enzyme inhibitor. 29. A pharmaceutical composition according to claim 28, wherein the HIV protease enzyme inhibitor is selected from lopinavir and ritonavir. 30. A pharmaceutical composition according to any prior description, wherein at least one active pharmaceutical ingredient is two active pharmaceutical ingredients. 31. Any pharmaceutical composition according to any prior description, comprising lopinavir and ritonavir. 32. The molar ratio of lopinavir to ritonavir present in the composition is between approximately 1:10 and approximately 18:1, for example between approximately 1:10 and approximately 15:1, for example between approximately 1:5 and approximately 15:1, for example between approximately 1:1 and approximately 15:1, for example between approximately 2:1 and approximately 15:1, for example between approximately 4:1 and approximately 15:1, for example between approximately 8:1 and approximately 14:1, for example between approximately 9:1 and approximately 14:1, for example between approximately 10:1 and approximately 14:1, for example between approximately 10.5:1 and approximately 18:1, for example between 10.5:1 and approximately 18:1, for example between approximately 10.5:1 and approximately 14:1, for example between approximately 11:1 and approximately 13:1, for example between approximately 11.5 and approximately 17:1, for example between approximately 11.5:1 and approximately 16.0:1 A pharmaceutical composition according to description 31, for example, between approximately 11.5:1 and approximately 15:1, for example, approximately 14.5:1, for example, 14.5:1, for example, approximately 14:1, for example, 14:1, for example, approximately 13.8:1, for example, 13.8:1, for example, approximately 13.75:1, for example, 13.75:1, for example, approximately 13.5:1, for example, 13.5:1, for example, approximately 13:1, for example, 13:1, for example, approximately 12.5:1, for example, 12.5:1, for example, approximately 12:1, for example, 12:1, for example, approximately 11.75:1, for example, 11.75:1, for example, approximately 9:1, for example, 9:1, for example, approximately 5:1, for example, 5:1, for example, approximately 4.6:1, or for example, 4.6:1. 33. The wt / wt ratio of lopinavir to ritonavir present in the composition is between approximately 1:10 and approximately 18:1, for example between approximately 1:10 and approximately 15:1, for example between approximately 1:5 and approximately 15:1, for example between approximately 1:1 and approximately 15:1, for example between approximately 2:1 and approximately 15:1, for example between approximately 4:1 and approximately 15:1, for example between approximately 8:1 and approximately 14:1. For example, between approximately 9:1 and 14:1, for example, between approximately 10:1 and 14:1, for example, between 10.5:1 and 18:1, for example, between 10.5:1 and 18:1, for example, between approximately 10.5:1 and 14:1, for example, between approximately 11:1 and 13:1, for example, between approximately 11.5 and 17:1, for example, between approximately 11.5:1 and 16.0:1, example For example, a pharmaceutical composition according to description 31, between approximately 11.5:1 and approximately 15:1, for example, approximately 14.5:1, for example, 14.5:1, for example, approximately 14:1, for example, 14:1, for example, approximately 13.8:1, for example, 13.8:1, for example, approximately 13.75:1, for example, 13.75:1, for example, approximately 13.5:1, for example, 13.5:1, for example, approximately 13:1, for example, 13:1, for example, approximately 12.5:1, for example, 12.5:1, for example, approximately 12:1, for example, 12:1, for example, approximately 11.75:1, for example, 11.75:1, for example, approximately 11.5:1, for example, 11.5:1, for example, approximately 11.25:1, for example, 11.25:1, or for example, approximately 11:1, for example, 11:1. 34. A pharmaceutical composition according to any prior description, further comprising an antioxidant, for example, butylated hydroxytoluene. 35. a. Unsaturated free fatty acids; b. A first emulsifier having an HLB value greater than approximately 14; c. A second emulsifier having an HLB value of less than approximately 6; d. Antioxidants; and e. At least one active pharmaceutical ingredient (lopinavir); A self-emulsifying pharmaceutical composition comprising the above, wherein the total emulsifier content is less than 30% by weight of the total composition. 36. a. Unsaturated free fatty acids; b. A first emulsifier having an HLB value greater than approximately 14; c. A second emulsifier having an HLB value of less than approximately 6; d. A third emulsifier; e. Antioxidants; f. Lopinavir; and g. Ritonavir; A self-emulsifying pharmaceutical composition comprising the above, wherein the total emulsifier content is less than 30% by weight of the total composition. 37. A pharmaceutical composition according to any prior description, wherein the pharmaceutical composition is enclosed within a capsule. 38. When the composition was filled into a hard gel capsule using a sinker and measured in 0.7% w / v SLS medium at approximately 37°C using a USP instrument II at 25 rpm for 0 to 60 minutes and at 200 rpm for 60 to 75 minutes, A pharmaceutical composition according to any prior description having a dissolution profile including more than 20% API dissolution after 10 minutes, for example, more than 40% API dissolution after 10 minutes. 39. When the composition was filled into a hard gel capsule using a sinker and measured in 0.7% w / v SLS medium at approximately 37°C using a USP instrument II at 25 rpm for 0 to 60 minutes and at 200 rpm for 60 to 75 minutes, A pharmaceutical composition according to any prior description having a dissolution profile including more than 60% API dissolution after 45 minutes, for example, more than 70% API dissolution after 45 minutes. 40. When the composition was filled into a hard gel capsule using a sinker and measured in 0.7% w / v SLS medium at approximately 37°C using a USP instrument II at 25 rpm for 0 to 60 minutes and at 200 rpm for 60 to 75 minutes, A pharmaceutical composition according to any prior description having a dissolution profile including more than 90% API dissolution after 75 minutes, for example, more than 95% API dissolution after 75 minutes. 41. A pharmaceutical composition as described in any prior description, for use as a pharmaceutical. 42. A method for treating and / or inhibiting the onset or progression of cancer and benign proliferative disorders in a subject requiring such treatment or inhibition, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to any of the descriptions 1 to 40. 43. Cancer or disorder caused or induced by human papillomavirus (HPV) by the method described in 42. 44. A method for treating a patient having HPV-related cervical dysplasia, comprising administering to the patient, either vaginally or orally, a therapeutically effective dose of a pharmaceutical composition according to any one of the descriptions 1 to 40. 45. A method according to description 44, wherein the pharmaceutical composition reduces the severity of HPV-related dysplasia. 46. ​​The method described in 45, which reduces the severity of HPV from CIN3 to CIN2, CIN3 to CIN1, CIN3 to HPV-negative, CIN2 to CIN1, CIN2 to HPV-negative, or CIN1 to HPV-negative. 47. A method according to any one of the descriptions in 43 to 46, wherein the composition induces apoptosis in HPV-infected cells. 48. A method according to any one of the descriptions in 43-47, in which the patient has cervical cytology of high-grade squamous intraepithelial lesion (HSIL), atypical squamous cell cytology of undetermined severity (ASCUS), or low-grade squamous intraepithelial lesion (LSIL). 49. The method according to claim 48, wherein the composition reduces cervical cytology from HSIL to normal cells, from HSIL to ACSUS, from HSIL to LSIL, from ACSUS to normal cells, or from LSIL to normal cells. 50. A process for producing a self-emulsifying pharmaceutical composition according to any one of items 1 to 40, a. The step of incorporating at least one active pharmaceutical ingredient (lopinavir) into an unsaturated free fatty acid (for example, by mixing it); b. To obtain a self-emulsifying composition, the step of incorporating at least two emulsifiers into the mixture obtained in step a) (for example, by mixing them) A process comprising, wherein at least two emulsifiers include a first emulsifier having an HLB value greater than about 14 and a second emulsifier having an HLB value less than about 6, and the total emulsifier content is less than 30% by weight of the total composition.

[0245] Specific embodiments of the present invention are further described below herein with reference to the accompanying figures: [Brief explanation of the drawing]

[0246] [Figure 1] The lopinavir dissolution profiles (25 rpm) of formulations 3a, 3b, and 3c in SLS media are shown. [Figure 2] The lopinavir dissolution profile of formulation 3a (25 rpm) is shown, compared to the lopinavir dissolution profiles of comparative formulations 3f and 3h in SLS medium. [Figure 3] The ritonavir dissolution profile of formulation 3a (25 rpm) is shown, compared to the ritonavir dissolution profiles of comparative formulations 3f and 3h in SLS medium. [Figure 4] The lopinavir dissolution profiles (25 rpm) of comparative formulations 3e, 3g, and 3h in SLS media are shown. [Figure 5] The ritonavir dissolution profiles (25 rpm) of comparative formulations 3e, 3g, and 3h in SLS media are shown. [Figure 6] The lopinavir dissolution profile of formulation 3a (25 rpm) is shown, compared to the lopinavir dissolution profiles of comparative formulations 3g and 3h in SLS medium. [Figure 7] The lopinavir dissolution profile (25 rpm) of formulation 3a is shown in comparison with the dissolution profiles of comparative formulation 1 (Example 4) and comparative formulation 2 (Example 5) in SLS medium. [Figure 8A] The lopinavir dissolution profile of formulation 3j in SLS medium (50 rpm) is shown, compared to the dissolution profiles of comparative formulations 3k, 3l, and comparative formulation 2 (Example 5). [Figure 8B]The lopinavir solubility profiles of formulations 3m, 3n, and 3o in SLS medium (50 rpm) are shown, compared to the solubility profile of comparative formulation 2 (Example 5). [Figure 9A] The lopinavir dissolution profiles of formulations 3a, 3i, and 3j in CTAB medium (50 rpm) are shown, compared to the dissolution profile of comparative formulation 2 (Example 5). [Figure 9B] The lopinavir dissolution profile of formulation 3j in CTAB medium s (50 rpm) is shown, compared to the dissolution profiles of comparative formulations 3k, 3l, and comparative formulation 2 (Example 5). [Figure 10] The lopinavir solubility profiles of formulations 3m, 3n, and 3o in CTAB medium (50 rpm) are shown, compared to the solubility profile of comparative formulation 2 (Example 5). [Figure 11] This shows the lopinavir dissolution profile of formulation 3a in Brij® 10 medium (50 rpm) compared with the dissolution profiles of comparative formulation 3h and comparative formulation 2 (Example 5). [Figure 12] The lopinavir solubility profiles of formulations 3a, 3i, and 3j in Brij® 10 medium (50 rpm) are shown, compared to the solubility profile of comparative formulation 2 (Example 5). [Figure 13] The lopinavir solubility profiles of formulations 3m, 3n, and 3o in Brij® 10 medium s (50 rpm) are shown, compared to the solubility profile of comparative formulation 2 (Example 5). [Examples]

[0247] The following abbreviations are used in the examples: API-Active Pharmaceutical Ingredients HPMC (Hydroxypropyl Methylcellulose) PEG-Polyethylene Glycol

[0248] [Example 1: Solubility of ritonavir and / or lopinavir] The solubility of ritonavir and lopinavir, as well as ritonavir alone, in various pharmaceutically acceptable solvents is shown below. As can be seen, ritonavir and lopinavir, as well as ritonavir alone, exhibit high solubility in oleic acid.

[0249] JPEG0007839091000002.jpg84169

[0250] [Example 2: Chemical and physical stability of ritonavir and lopinavir] The loss of potency of lopinavir and ritonavir is induced by thermal decomposition, and it is known from the literature that ritonavir, in particular, tends to undergo hydrolysis due to its carbamate functional group (Donato et al, "LC Method for Studies on the Stability of Lopinavir and Ritonavir in Soft Gelatin Capsules", Chromatographia, April 2006, 63, 437-443). It is also known that ritonavir is oxygen-unstable. Therefore, the preferred manufacturing route for compositions containing lopinavir / ritonavir is a manufacturing route that excludes heat, water, and / or oxygen.

[0251] [Example 3: Preparation of the Formulation] In all the formulations presented below, all materials used are pharmaceutical grade (either United States Pharmacopeia or European Pharmacopoeia), with the exception of white ceresin wax, which is graded according to the Japanese Pharmaceutical Excipient standards. The oleic acid used was ultra-refined grade (manufacturer: Croda).

[0252] <General Procedure> The manufacturing of formulations 3a to 3h is carried out according to the following general procedure, and the amounts of the constituent components are specified in Tables 1 to 8 below.

[0253] The bulk supplies of oleate and lopinavir were purged with nitrogen after use. Ritonavir was protected from ultraviolet light. i. Butylated hydroxytoluene, lopinavir, and ritonavir were added to oleic acid in the main vessel. The mixture was stirred and the API was dissolved at 600 rpm. ii. Polyoxyl stearate 100 and glycerol monooleate were added to the main container. The mixture was further stirred to dissolve the emulsifier at 600 rpm. iii. The product was released from the container and passed through a GAF bag filter. iv. The filtered product was concentrated and placed in a glass bottle, which was then stored in the dark at 0-5°C. v. Next, if necessary, the formulation (800 mg) was filled into hard gelatin capsules and sealed with ethanol.

[0254] JPEG0007839091000003.jpg142169

[0255] The viscosity of liquid formulation 3a was measured using a Brookfield DV-II+Pro viscometer with a 10g sample, using an SC4-34 spindle, 60 rpm, and 25°C. The sample was found to have a kinematic viscosity coefficient of 130 cP.s and a torque of 13.0%.

[0256] JPEG0007839091000004.jpg145169

[0257] The viscosity of liquid formulation 3b was measured using a Brookfield DV-II+Pro viscometer with a 10g sample, using an SC4-34 spindle at 60 rpm and 25°C. The sample was found to have a kinematic viscosity coefficient of 138 cP.s and a torque of 13.8%.

[0258] JPEG0007839091000005.jpg145169

[0259] The viscosity of liquid formulation 3c was measured using a Brookfield DV-II+Pro viscometer with a 10g sample, using an SC4-34 spindle, 60 rpm, and 25°C. The sample was found to have a kinematic viscosity coefficient of 125 cP.s and a torque of 12.5%.

[0260] JPEG0007839091000006.jpg147169

[0261] JPEG0007839091000007.jpg126169

[0262] JPEG0007839091000008.jpg128169

[0263] JPEG0007839091000009.jpg129169

[0264] JPEG0007839091000010.jpg130169

[0265] The manufacturing of formulations 3i to 3t is carried out according to the following general procedure, and the amounts of the constituent components are specified in Tables 9 to 20 below.

[0266] The bulk supplies of oleic acid and lopinavir were purged with nitrogen after use. Ritonavir was protected from ultraviolet light. i. In the main container, lopinavir and ritonavir were added to butylated hydroxytoluene dissolved in oleic acid. The mixture was stirred and the API was dissolved at 600 rpm. ii. PEG35 castor oil, glycerol monooleate, and polyoxyl stearate 100 / polysorbate 20 / polysorbate 60 / polysorbate 80 (if applicable) were added to the main container. The mixture was further stirred to dissolve the emulsifier at 600 rpm. iii. The product was released from the container and passed through a GAF bag filter. iv. The filtered product was concentrated and placed in a glass bottle, which was then stored in the dark at 0-5°C. v. Next, if necessary, the formulation (800 mg) was filled into hard gelatin capsules and sealed with ethanol.

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[0280] [Example 4: Comparative Formulation 1 (Ointment)] Oleic acid / stearic acid ointment formulations containing lopinavir and ritonavir were prepared as follows, according to the components specified in Table 21: i. Add the following ingredients to the blender: 3, 4, 5, 6, 7, 8, 9, 1, 10 & 11. ii. Air was removed from inside the container. iii. The mixture was heated to 70°C while low-shear mixing to obtain a clear, transparent molten product. iv. Add the following ingredients: 2 to the blender. v. Air was removed from inside the container. vi. The batch was mixed via low shear to finely disperse HPMC(2) within the molten material. vii. The batch temperature was reduced to 45°C while maintaining low shear mixing. viii. The product was released into a storage container, and the air was removed during storage. ix. If necessary, the formulation (800 mg) was then filled into hard gelatin capsules and sealed with ethanol.

[0281] JPEG0007839091000024.jpg155169

[0282] The ointment formed according to Example 4 has a complex viscosity of 1500-2000 cP.s. when measured at an angular frequency of 0.1 rad / s. The complex viscosity was measured using a Discovery Hybrid Rheometer (Model HR-3, TA instruments) [The sample was introduced in excess (1-2 g) into a Peltier plate (base; 37°C), and the spindle was lowered to contact the sample. The excess sample was removed. The spindle was then rotated in the predetermined manner to apply a series of shear forces to the sample. The vibration frequency method parameters were: speed range 0.1-1 rad / s; strain 0.5%; spindle 40 mm parallel plate; gap setting 1000 μm].

[0283] [Example 5: Comparative Formulation 2] WO2002 / 096395 discloses soft elastic capsules filled with formulations containing oleic acid, lopinavir, and ritonavir. The comparative formulation is formed according to Fill Batch PS-A (WO2002 / 096395; page 24) and contains the amounts of the components specified in Table 22: i. Oleic acid was added to the blender. ii. Add propylene glycol to the container and mix for 5 minutes. iii. Add ritonavir to the container and continue stirring until dissolution occurs. iv. Add lopinavir to the container and continue stirring until dissolution occurs. v.Cremophor(registered trademark)EL was added, and mixing was continued for 10 minutes. vi. The product was stored under a nitrogen atmosphere. vii. An 800 mg sample of comparative formulation 2 was then filled into hard gelatin capsules and sealed with ethanol.

[0284] JPEG0007839091000025.jpg91169

[0285] [Example 6: Stability Experiment] The compositions according to Example 3 have been shown to be stable during the process used to produce them (i.e., the process described in Example 3). Furthermore, the compositions according to Example 3 have been shown to be stable during storage.

[0286] Formulations 3a, 3b, and 3c were stored at 5°C for one month. Subsequently, dissolution tests according to Example 7 showed that these formulations completely released the API, indicating that the API content did not decompose during storage.

[0287] The formulations were analyzed using the following analytical methods.

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[0290] [Example 7: API dissolution performance] [Example 7A: 0.7% SLS dissolution medium] The encapsulated compositions of the present invention, prepared according to Example 3, were subjected to dissolution experiments in a 0.7% sodium laureth sulfate (SLS) medium at 37±0.5℃ in a USPII apparatus at 25 rpm for 0-60 minutes, followed by 200 rpm for 60-75 minutes (hard gel capsules using a sinker). All analyses were performed in two replicates.

[0291] Figure 1 shows the results of dissolution experiments with formulations 3a, 3b, and 3c. All three formulations showed 40-60% lopinavir dissolution after 10 minutes, 70-90% after 45 minutes, and 90-100% after 75 minutes.

[0292] An encapsulated composition prepared according to Example 3, containing 4% wt polyoxyl stearate 100 and 6% wt glycerol monooleate (formulation 3a), was compared with an encapsulated composition prepared according to Example 3, containing 3% wt glycerol monooleate and 10% wt glycerol monooleate (comparative formulations 3f and 3h, respectively). Dissolution tests were performed according to the method described above. All analyses were performed in two replicates.

[0293] Figures 2 and 3 show the comparative results of these dissolution experiments with respect to the release of lopinavir and ritonavir, respectively. When both emulsifiers are present at a total emulsifier level of 10% wt, the in vitro release of lopinavir can be seen to be faster than when polyoxyl stearate 100 is removed, regardless of whether the residual glycerol monooleate emulsifier content is at a lower level (3% wt - Example 3f) or increased to 10% wt (Example 3h).

[0294] An encapsulated composition containing 10% wt glycerol monooleate, prepared according to Example 3 (comparative formulation 3h), was compared with encapsulated compositions containing 2% wt polyoxyl stearate 100 and 10% wt polyoxyl stearate 100, prepared according to Example 3 (comparative formulations 3e and 3g, respectively). Dissolution tests were performed according to the method described above. All analyses were repeated twice.

[0295] Figures 4 and 5 show the results of comparing these dissolution experiments with respect to the release of lopinavir and ritonavir, respectively. Although there is some variability between replicate experiments in the comparative formulation containing only polyoxyl stearate 100 as an emulsifier, even the fastest lopinavir release in the formulation with only polyoxyl stearate 100 (comparative formulation 3e; 77% released in 45 minutes) is inferior to the release of the two emulsifier systems (see Figure 2: formulation 3a; 93% released in 45 minutes). Therefore, when both emulsifiers are present at a total emulsifier level of 10% wt, the in vitro release of lopinavir is faster than when glycerol monooleate is removed, regardless of whether the residual polyoxyl stearate 100 emulsifier content is at a lower level (2% wt - Example 3e) or increased to 10% wt (Example 3g).

[0296] Figure 6 also shows a comparison of the lopinavir solubility profiles of formulation 3a (4% wt polyoxyl stearate 100 and 6% wt glycerol monooleate), comparative formulation 3g (10% wt polyoxyl stearate 100) and comparative formulation 3h (10% wt glycerol monooleate). Formulation 3a showed 50-60% lopinavir solubility after 10 minutes and approximately 90% after 45 minutes; comparative formulation 3g showed approximately 10% lopinavir solubility after 10 minutes and 45-55% after 45 minutes; comparative formulation 3h showed 30-40% lopinavir solubility after 10 minutes and 60-70% after 45 minutes. A comparative formulation containing only 10% wt glycerol monooleate emulsifier showed better solubility than a comparative formulation containing only 10% wt polyoxyl stearate emulsifier; however, both systems were significantly inferior to formulations containing 10% wt emulsifiers made from a combination of two emulsifiers.

[0297] An encapsulated composition (formulation 3a) containing 4% wt polyoxyl stearate 100 and 6% wt glycerol monooleate, prepared according to Example 3, was compared with the encapsulated compositions (comparative formulations 1 and 2, respectively) prepared according to Examples 4 and 5, according to the dissolution test method described above. All analyses were performed in two replicates.

[0298] Figure 7 shows the results of the comparison of lopinavir dissolution experiments. Formulation 3a showed 50-60% lopinavir dissolution after 10 minutes, approximately 90% lopinavir dissolution after 45 minutes, and approximately 100% lopinavir dissolution after 75 minutes. Soft gel comparative formulation 2 (Example 5) showed 10-20% lopinavir dissolution after 10 minutes, 40-60% lopinavir dissolution after 45 minutes, and 90-100% lopinavir dissolution after 75 minutes. Ointment comparative formulation 1 (Example 4) showed 0% API dissolution up to 60 minutes and 0-10% lopinavir dissolution after 75 minutes.

[0299] Therefore, it can be seen that the formulation according to the present invention has a faster and more complete API dissolution profile in the SLS medium than the comparative formulation tested.

[0300] Furthermore, the encapsulated composition of the present invention, prepared according to Example 3, was subjected to a dissolution experiment in a USPII apparatus at 37±0.5℃ for 0 to 60 minutes in a 0.7% sodium laureth sulfate (SLS) medium (hard gel capsule using a sinker).

[0301] An encapsulated composition (formulation 3j) prepared according to Example 3, containing 4% wt polyoxyl 100 stearate, 6% wt glycerol monooleate, and 5% wt PEG35 castor oil, was compared with the following compositions according to Example 5 (comparative formulation 2): an encapsulated composition prepared according to Example 3 containing 6% wt glycerol monooleate and 5% wt PEG35 castor oil (comparative formulation 3k), an encapsulated composition prepared according to Example 3 containing 4% wt polyoxyl 100 stearate and 5% wt PEG35 castor oil (comparative formulation 3l), and a composition prepared according to Example 5 (comparative formulation 2), according to the dissolution test method described above. Figure 8A shows that formulation 3j resulted in a more rapid dissolution than Example 5, and that removal of glycerol monooleate from this formulation reduced API release (comparative formulation 3l). Removal of PEG100 stearate from the formulation actually resulted in an increase in the release rate (comparative formulation 3k). Figure 8B shows that when polysorbate 20 (formulation 3m), polysorbate 60 (formulation 3n), or polysorbate 80 (formulation 3o) is used as a high HLB emulsifier, all three formulations exhibit similar lopinavir release and are all superior to soft gel comparative formulation 2 (Example 5) in the SLS medium.

[0302] [Example 7B: 0.7% CTAB dissolving medium] The encapsulated compositions of the present invention, prepared according to Example 3, were subjected to a dissolution experiment in a 0.7% cetyltrimethylammonium bromide (CTAB) medium at 37±0.5℃ in a USPII apparatus at 50 rpm for 0 to 60 minutes (using a hard gel capsule sinker).

[0303] Figure 9A shows that formulation 3a yielded a lower release than comparative formulation 2 (Example 5) in CTAB medium. The addition of PEG35 castor oil to the formulations (formulations 3i and 3j) improved API release, and the addition of 5% wt PEG35 castor oil (formulation 3j) resulted in superior release compared to comparative formulation 2 (Example 5). Figure 9B shows that the removal of glycerol monooleate from formulation 3j resulted in a faster API release rate in CTAB medium (comparative formulation 3l). The removal of PEG100 stearate from the formulation did not affect the release rate (comparative formulation 3k).

[0304] Figure 10 shows that when polysorbate 20 (formulation 3m), polysorbate 60 (formulation 3n), or polysorbate 80 (formulation 3o) is used as a high HLB emulsifier, all three formulations exhibit similar lopinavir release and are all significantly superior to comparative formulation 2 (Example 5) of the soft gel in CTAB medium.

[0305] [Example 7C: 0.05M Brij® 10 dissolving medium] The encapsulated composition of the present invention, prepared according to Example 3, was subjected to a dissolution experiment in 0.05 M PEG10 oleyl ether (Brij® 10) with a 10 mM sodium monobasic phosphate pH 6.8 medium, at 37 ± 0.5 °C, using a USPII apparatus at 50 rpm for 0 to 60 minutes (hard gel capsules using a sinker).

[0306] Figure 11 shows that formulation 3a in Brij® 10 medium resulted in a lower release than comparative formulation 2 (Example 5). Removal of PEG100 stearate (comparative formulation 3h) was found to result in a slower API release rate. Figure 12 shows that the addition of PEG35 castor oil to the formulations (formulations 3i and 3j) improved API release, and the addition of 5% wt PEG35 castor oil (formulation 3j) resulted in a release equivalent to comparative formulation 2 (Example 5) in this medium.

[0307] Figure 13 shows that when polysorbate 20 (formulation 3m), polysorbate 60 (formulation 3n), or polysorbate 80 (formulation 3o) are used as high-HLB emulsifiers, all three formulations exhibit similar lopinavir release and are equivalent to the soft gel comparative formulation 2 (Example 5) in Brij® 10 medium.

[0308] Table 23 summarizes the lopinavir release data for all formulations tested in Brij® 10 dissolution medium (0.05 M PEG10 oleyl ether (Brij® 10) in a 10 mM sodium monobasic phosphate pH 6.8 medium, at 37 ± 0.5°C, using a USPII instrument at 50 rpm for 0 to 60 minutes).

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[0310] [Example 7D: Dissolving medium for simulated vaginal fluid (SVF)] The encapsulated compositions of the present invention, prepared according to Example 3, were subjected to a dissolution experiment in a USPII apparatus at 100 rpm for 0 to 480 minutes at 37 ± 0.5°C in an SVF medium at pH 4.2 (hard gel capsules using a sinker). The SVF medium was an aqueous solution of sodium chloride (3.51 g / L), potassium hydroxide (1.40 g / L), calcium hydroxide (0.222 g / L), bovine serum albumin (0.018 g / L), lactic acid (2.00 g / L), acetic acid (1.0 g / L), glycerol (0.16 g / L), urea (0.40 g / L), and glucose (5.00 g / L).

[0311] The data in Table 24 shows that formulations 3m and 3p and comparative formulation 2 (Example 5) yielded the lowest amount of lopinavir release in the SVF medium. Increasing the total emulsifier content to 30% (comparative formulation 3q) increased lopinavir release in the non-surfactant SVF medium.

[0312] JPEG0007839091000030.jpg45169

[0313] [Example 8: Emulsion Droplet Size Test] Formulations 3a, 3b, and 3c, and comparative formulations 2, 3f, and 3h were analyzed for emulsion droplet size as follows.

[0314] Each sample (1 g) was dispersed in 10 mL of milli-Q water. The dispersed sample was then vortexed rapidly at room temperature for 1 minute before being added to a cuvette. The cuvette was placed in a Zetasizer (Zetasizer Nano series, Malvern Instrument, UK; measurement range 1 nm to 6000 μm) and analyzed by dynamic light scattering (particle refractive index: 1.30; absorption: 0.01; dispersion refractive index: 1.33). Each sample was measured over three cycles, and the mean and standard deviation were obtained using Excel® software. The results are shown in Table 25.

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[0316] The ability of formulations 3a-3c to generate fine emulsions upon contact with water confirms that they are self-emulsifying compositions. The droplet size results in formulations 3a-3c are related to the total emulsifier level; the higher the emulsifier content, the smaller the droplet size. Formulations 3a and 3b showed superior emulsification compared to comparative formulation 2, as evidenced by their smaller emulsion droplet sizes.

[0317] From the dissolution experiments described in Example 7A, the comparative formulation having a single emulsifier (glycerol monooleate; Figure 6) that yielded the best results was compared with the formulation of the present invention. As can be seen from Table 11, the droplet size in the two-emulsifier formulation (e.g., formulations 3a and 3b) was an order of magnitude smaller than that of the single-emulsifier formulation (comparative formulations 3f and 3h), regardless of whether the "individual" or "total" glycerol monooleate levels were equivalent compared to the two-emulsifier formulation. This suggests that both emulsifiers (high HLB and low HLB) present in the formulation according to the present invention are necessary to produce smaller emulsion droplet sizes.

[0318] [Example 9: Phase 1, single-center, double-blind, randomized, parallel-group, escalating single-dose and multi-dose, safety and tolerance, pharmacokinetic (PK) and pharmacodynamic (PD) studies of Formulation 3p in healthy female volunteers] The composition (formulation 3p) according to Example 3 will be investigated in accordance with the clinical trial described below.

[0319] <Experimental Objective> 1. To evaluate safety, obtain the PK and PD of the composition in healthy female volunteers after multiple administrations of formulation 3p. 2. Observe the rate of side effects reported by women using the composition compared to placebo.

[0320] <Research Plan / Experimental Design> This experiment included six healthy volunteers without cervical conditions. Three of the participants received the active substance, and three received a placebo (the same formulation as formulation 3p, but without lopinavir or ritonavir). In all formulations tested, the amount of composition administered per dose was 1500 mg. This is equivalent to the 300 mg of lopinavir and 25 mg of ritonavir administered to a patient per dose in formulation 3p.

[0321] Period 1: Single-dose formulation 3p or placebo formulation, followed by isolation. PK blood sampling will be performed during isolation.

[0322] Period 2: 21 daily doses of either the formulation (3p) or placebo, followed by PK blood sampling.

[0323] <Participation criteria> Inclusion criteria: a. The patient is a woman between the ages of 20 and 45, with an intact uterus and vagina. b. Generally, the patient is in good health, free from clinically significant lung, heart, digestive, pancreatic, nervous, renal, musculoskeletal, rheumatic, metabolic, neoplasm, or endocrine disorders. c. BMI ≥ 19 and ≤ 30.0. d. ECG and vital signs are within the normal range. e. I agree not to consume alcohol from 48 hours before the medication is administered in Period 1 until 7 days after the last medication is administered in Period 2. f. Throughout the experiment, avoid foods or beverages containing grapefruit, star fruit, pomegranate, pineapple, or pomelo. g. During periods 1 and 2, sexual intercourse can and is willing to be refrained from for + / - 6 hours between doses. After the required suppression period up to day 29 (7 days after the last dose in period 2), participants may and willingly use strict contraception, including the use of non-latex condoms (for partner protection). A second acceptable method of contraception is permitted: vasectomy, birth control pills, birth control implants, or IUDs. (Note: IUDs should have been inserted at least one month prior to registration, not for participation in this experiment.) i. You agree to refrain from any actions such as vaginal douching or insertion of any vaginal product other than the experimental drug for at least 48 hours prior to registration and throughout the experiment. j. Negative Pap test result from screening or within 3 years of registration, and no history of cervical intraepithelial lesions within the past 3 years. k. I am able to return to the clinic for all experimental procedures and am willing to do so. l. We are able to provide informed consent and are willing to do so.

[0324] Exclusion criteria: a. Women who are pregnant, planning to become pregnant in the next three months, or breastfeeding. b. A history of genital herpes or active non-HPV vaginal infection occurring more than 3 times per year. c. A positive result for HepB, HepC, or HIV. d. The patient has an active pelvic infection. (Positive urine screening for gonorrhea or chlamydia infection, positive and symptomatic tests for bacterial vaginosis, candidiasis, or trichomoniasis) e. Diagnosed by the researcher within three months prior to random sampling with current or recent abnormal vaginal discharge and / or abnormal vaginal bleeding. f. Abortion or miscarriage within three months prior to the random selection. g. The following medications: currently taking any of the following: oral corticosteroids, inhaled salmeterol, or fluticasone; immunomodulatory treatments, over-the-counter (OTC) vaginal preparations, or any prescription medications that, in the opinion of the researchers, may interfere with the interpretation of the results. h. You are currently taking any of the following medications listed here: alfuzosin, amiodarone, dronedarone, lanolazine, fusidic acid, colchicine, astemizole, terfenadine, lurasidone, pimozide, quetiapine, dihydroergotamine, ergonovine, ergotamine, methylergonovine, cisapride, lovastatin, simvastatin, avanafil, sildenafil, vardenafil, oral midazolam, triazolam, or St. John's wort. i. Recent medical history (within the past 3 months) of Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema, deep vein thrombosis, tinnitus, vertigo, glycemic disorder, pancreatitis, or hemophilia. j. Hypersensitivity to any component of the vaginal preparation excipient of Example 3. k. Participation in any clinical study using the experimental drug or device within 30 days or 5 half-lives (whichever is longer) of registration. l. The researcher has diagnosed the patient as currently having alcohol dependence or drug abuse. m. Employees or first-degree relatives of employees, sponsors, CROs, or experimental sites. n. Does not have a GP.

[0325] <Screening Evaluation> The screening evaluation must be conducted within three months of random sampling for the experiment. The screening consists of the following components:

[0326] (Demographics / Medical History) Obtain a complete medical history from each participant.

[0327] (health check) The health checkup consists of a physical examination, including height and weight (while wearing loungewear).

[0328] (Blood test) The following blood tests will be performed at the testing facility: • Electrolytes (sodium and potassium), ALT, GGT, ALP, albumin, total protein, total bilirubin, urea, uric acid, serum creatinine, TFT, fasting lipids, amylase, glucose, and HbA1c Hemoglobin, red blood cell count, PCV, MCV, MCH, platelet count, white cell count, neutrophils, lymphocytes, monocytes, eosinophils, and basophils. CD4 / CD8 count. HIV, hepatitis B, and hepatitis C.

[0329] The measurements taken during screening serve as a baseline for monitoring any abnormalities that may arise as a result of medication.

[0330] (Other exams) As part of the screening procedure, all participants will undergo drug dependence testing. Urine samples will be required for testing for cannabinoids (marijuana), amphetamines, benzodiazepines, and opiates (i.e., morphine, heroin, and codeine). Dipstick urine tests will be performed to check for protein, white blood cells, nitrite, pH, specific gravity, glucose, ketones, and blood. Vaginal swabs will be collected for microbiology (gonorrhea, chlamydia, bacterial vaginosis, candidiasis) and HPV genotyping. An alcohol breath test will be performed in clinical practice on the first night of each isolation period. As part of the screening procedure and within three days prior to the first dose, all participants will undergo a serum hCG test.

[0331] (Vital signs) Record vital signs. Vital signs include blood pressure (measured in supine and sitting positions), heart rate, temperature, and respiratory rate. Participants' vital signs should be within the following limits: Heart rate ≥ 60 or ≤ 99 beats / minute Lying on your back: Cardiac systolic blood pressure ≥ 90 or ≤ 160 mmHg; cardiac diastolic blood pressure ≥ 50 or ≤ 90 mmHg Sitting position: Cardiac systolic blood pressure ≥ 90 or ≤ 160 mmHg; cardiac diastolic blood pressure ≥ 50 or ≤ 90 mmHg Temperature ≥ 36°C or ≤ 37.7°C Respiratory rate ≥ 12 or ≤ 20 breaths / minute

[0332] <Overview of the event's experimental activities / schedule> Informed consent is required from each participant. Participants will be screened to confirm their eligibility for the experiment.

[0333] (Random sampling) After reviewing the completed screening procedures, the principal investigator or their representative will document the acceptance of participants, and then participants will be randomly selected.

[0334] (Isolation for experimentation) Participants will gather at approximately 5 pm on days 1 and 22. The isolation period for the experiment will be approximately 27 hours. Participants will be released from the clinical setting once the diagnosis 24 hours after drug administration is complete.

[0335] (dosage) Medication is administered starting at approximately 8 pm each day it is scheduled. Participants are instructed to insert the medication themselves.

[0336] (Sample collection) Vaginal swabs are performed by the participants themselves. PK blood sample: A blood sample (8 mL) is collected via an intravenous catheter and transferred to a vacuum containing sodium heparin as an anticoagulant. The collection time is recorded as the time when all 8 mL of blood has been collected. After each sample, the intravenous catheter is flushed with 1.5 mL to 2.0 mL of heparinized saline and kept open (0 to 24 hours). Sampling intervals are: Day 1-2: 0, 1, 2, 4, 8, 12, 24 hours; Day 22-23: 0, 1, 2, 4, 8, 12, 24 hours. Samples are collected at these fixed times. Any time deviations should be noted.

[0337] (Sample processing and storage) Plasma: Separate the plasma by centrifugation at 3500 rpm for 5 minutes at approximately 4°C. Do not use any aids for separating plasma from red blood cells. Transfer the plasma sample to a clean pipette. Determine the assay using a validated analytical method. Place each plasma sample into a screw-cap polypropylene storage tube. Store the plasma frozen at -60°C or below and keep it in the clinical setting until sent to the laboratory for assay.

[0338] <End of experiment> Within one week of the final experiment date, each participant must provide a blood sample for analysis. Monitor for any abnormalities compared to the initial screening and continue this until they return to normal. Participants will be evaluated for adverse events in each cohort from the date of consent to the final experiment date. Vital signs (blood pressure, heart rate, respiratory rate, and temperature) will be obtained at the final clinical examination.

[0339] • Clinical trials in the final experimental clinical examination (blood (CBC, CD4+ / CD8+ peripheral lymphocyte count), biochemistry (RFT, LFT, electrolytes, TFT, fasting lipids, HbA1c, amylase), serum hCG pregnancy test, and urine test (dipstick)). • Within 7 days (+2 days) of the end of the experiment, follow-up calls will be made to each participant to record any possible adverse events (AEs) that occurred after the experiment. Any events will be recorded in the source documentation.

[0340] All adverse events (AEs) will be followed up until they are resolved, or until the researcher determines that follow-up is no longer necessary, or until 30 days after the last dose (only if the researcher is convinced that follow-up is no longer necessary), whichever comes first.

[0341] (Adverse events) During isolation, the designated administrator or commissioned representative for the experiment must be present at the experiment site throughout the entire experiment. The principal investigator or at least one commissioned clinical trial physician must be on standby throughout the entire experiment. Each participant must be asked for their feedback at every clinical inspection. This must be done at each sampling point throughout the entire experiment. AEs must be documented in the source documentation. Each AE must be classified by the principal investigator as a serious adverse event (SAE) or non-serious. Non-serious adverse events must be assessed as mild, moderate, or serious, and the maximum intensity of the AE must be recorded. The principal investigator must also provide a possible relationship between the AE and the experimental drug, categorized as highly likely, likely, possible, weakly related to the experimental drug, or unrelated ("unrelated"). The principal investigator must describe whether the cause of the AE is related to a concurrent non-research drug (if any) (if any were ingested), an underlying disease, a combination of these factors, or is unknown.

[0342] <Pharmacokinetic Analysis> (Pharmacokinetic parameters) For each subject receiving effective treatment, the area under the drug plasma concentration-time curve (AUC), peak drug plasma concentration (Cmax), and time to maximum drug concentration (Tmax) for lopinavir and ritonavir are determined.

[0343] Pharmacokinetic parameters are obtained by analyzing data comparing drug plasma concentration (C) with actual sampling time (t) using a "non-compartment" method. First, linear regression is used to obtain the post-distribution phase of the plasma concentration-time plot. InC=InCo-t.Kel Fit the formula to the region (AUC) from time zero to the final determined concentration-time point (t) in the post-distribution phase (wherein Co is the extrapolated zero-time intercept and Kel is the final emission ratio constant). 0-t ) is calculated using the trapezoidal rule.

[0344] (Cmax) In comparative ointment formulation 1 (Example 4) containing 12% w / w lopinavir, the mean Cmax after topical administration of 300 mg of lopinavir as a 2.5 g ointment daily for 21 days was 396.3 ± 297.3 pg / mL.

[0345] For comparison, the mean Cmax of lopinavir after oral administration of 400 mg of lopinavir (as Kaletra 400 mg / 100 mg tablets) twice daily for two weeks was 12.3 ± 5.4 μg / mL [SPMC Kaletra]. When adjusted to a 300 mg dose for dose matching, the mean Cmax was 9.23 ± 4.1 μg / mL. The oral / topical Cmax ratio was >23,000, indicating that a topical dose of less than 0.004% of ointment comparison formulation 1 is systemically available.

[0346] (AUC 0-t) In comparative ointment formulation 1 (Example 4) containing 12% w / w lopinavir, the AUC0-t after administering a topical dose of 300 mg of lopinavir daily for 21 days in the form of 2.5 g of ointment was 7368.1 ± 4973.1 pg / mL.

[0347] For comparison, the AUC0-t of lopinavir after oral administration of 400 mg lopinavir (as Kaletra 400 mg / 100 mg tablets) twice daily for two weeks was 113.2 ± 60.5 μg·h / mL [SPMC Kaletra]. When adjusted to a 300 mg dose to make it comparable, the AUC0-t was 84.9 ± 45.4 μg·h / mL. The oral / topical AUC ratio was >11,500, indicating that the topical dose of ointment comparison formulation 1 (less than 0.009%) is systemically available.

[0348] [Example 10: Phase 1b, multicenter, open-label study on the efficacy, safety, and tolerance of formulation 3p in women with cervical cytological abnormalities] The composition according to Example 3 (formulation 3p) will be investigated in accordance with the clinical trial described below.

[0349] <Experimental Objective> (Purpose regarding effectiveness) • To demonstrate histological clearance of cytological abnormalities after administration of formulation 3p in women with high-grade or low-grade CIN (intraepithelial neoplasia of the cervix). • Demonstrate changes in the appearance of the cervix as measured by colposcope after administration of formulation 3p; • Evaluate changes in HPV status after administration of formulation 3p.

[0350] (Purpose regarding safety) • Evaluate the incidence of adverse events (AEs) after administration of formulation 3p.

[0351] (Purpose regarding resistance) • Tolerance to Formulation 3p is assessed by compliance with the dosing schedule of Formulation 3p over 21 consecutive treatment days.

[0352] <Main efficacy endpoints> • Changes in tissue appearance from screening to PTAV.

[0353] <Endpoints for secondary efficacy> • Cytological changes from screening to PTAV, as seen in the results of cervical smears. • Colposcopy-based changes in disease from screening to PTAV. • Changes in HPV status (presence / absence of HPV genotype) between screening and PTAV.

[0354] <Safety endpoint> • Incidence rate of adverse events. • Baseline changes in the following: • Vital signs (blood pressure, heart rate, and temperature). • Safety: Evaluation by the clinical laboratory (hematology, biochemistry, urinalysis).

[0355] <Resistance endpoint> • Review participant diary cards to monitor the application of research products according to the protocol.

[0356] <Experimental Design> This study is designed as a Phase 1b, multicenter, open-label trial to investigate the efficacy, safety, and resistance of formulation 3p in women with cervical cytological abnormalities diagnosed with HPV.

[0357] In this single-group experiment, participants are stratified according to the severity of these cytological abnormalities: • A high-grade cytological abnormality of the cervix, defined as CIN2 or higher, as confirmed by biopsy; • A low-grade cytological abnormality of the cervix, defined as CIN1 / LSIL.

[0358] Participants will self-insert a capsule filled with 3 pups of 1500 mg of the formulation, or, alternatively, two capsules each filled with 3 pups of 750 mg of the formulation (thus containing 300 mg of lopinavir and 25 mg of ritonavir), once daily for 21 consecutive days. Participants will complete all items of the daily diary card and the Vaginal Irritation Questionnaire (VIQ) to report compliance with the study product administration, adverse events, and changes in concomitant medications. Record it.

[0359] Each registered participant will complete four follow-up visits between the experimental screening, treatment, treatment completion, and follow-up visits, as follows: • Clinical examination 1 - Screening clinical examination: Day 42 to Day 0. • Clinical examination 2 - Treatment: Day 1-21: Treatment cycle 1 - The research product is administered once daily for 21 days; Days 8, 15, and 22: Telephone follow-up; check for AEs, conmeds, compliance, and medication issues; • Inspection 3 - Treatment completed: Day 28: Visually assess the disease. • Clinical examination 4 - Follow-up survey (Post-treatment evaluation clinical examination - PTAV): Between 3 and 6 weeks after the end of treatment (final dose of formulation 3p) - 49 to 70 days. *Day 1 will begin at the end of the participant's menstrual cycle. If the disease is absent, as defined by the absence of evidence of CIN by colposcope, the participant is considered a responder. If the disease is detected, as defined by the presence of evidence of CIN by colposcope, the participant is considered a non-responder.

[0360] <Participation criteria> Inclusion criteria: To be eligible to participate in the experiment, you must meet all of the following criteria: 1. Submission of written informed consent prior to any specific experimental procedure; 2. Female participants aged 22-50 years (including both extremes) at the time of the screening examination; 3. A positive result for high-risk cervical HPV (type 16, type 18, or "other"); 4. A high-grade cytological abnormality of the cervix, defined as CIN2 or higher, as evidenced by a colposcopy biopsy taken at the time of screening or within 30 days prior to screening; or A low-grade cytological abnormality of the cervix, defined as CIN1 / LSIL, as demonstrated by a colposcopy biopsy performed within six months prior to screening, or by a biopsy taken during screening. Participants are stratified according to the severity of their cytological abnormalities; 5. The zone of change must be fully visible; 6. Generally, a state of good health, free from clinically significant diseases as determined by the researcher; 7. A regular menstrual cycle of approximately 28 days. or Women with amenorrhea despite effective contraception (e.g., Mirena, Jadelle, or continuous COC) 8. You agree to refrain from any actions, such as vaginal douching or insertion of any vaginal product other than the experimental drug, for at least 48 hours prior to registration and throughout the experiment. Tampons may only be used during the menstrual cycle. 9. Women of childbearing age (WOCBP) use highly effective forms of contraception (as confirmed by researchers). The rhythm method is not considered highly effective. As for highly effective forms of contraception, • True sexual restraint (defined as refraining from heterosexual sexual intercourse during the experimental period and for at least 30 days after the final dose of the experimental drug); • A partner who has undergone a vasectomy (provided the partner is the sole sexual partner of a woman of childbearing age, and the partner who underwent the vasectomy has received a medical evaluation confirming the success of the surgery); • Oral or transdermal hormonal contraceptives (containing estrogen and progestin) associated with ovulation suppression; • Oral, injectable, or implantable progestin-only hormonal contraceptives associated with ovulation suppression (Depo-Provera® Implanon, or Cerazette, Noriday “Mini Pills”); • Any valid intrauterine device / levonorgestrel intrauterine system; • Contraception for women due to tubal obstruction; ·Evra Patch(trademark) These are some examples.

[0361] WOCBP must agree to use a highly effective method of contraception as defined above from the time of registration and at least 14 days prior to day 1, throughout the entire experimental period, and within 30 days of the final dose of IMP.

[0362] WOCBP is defined as a woman who has not undergone permanent contraception (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) and has not gone through menopause. A woman is considered postmenopausal if she has not had amenorrhea for 12 months or more without using alternative biological or medical methods, such as birth control pills, such as Mirena. 10. The male partners of female participants must agree to use condoms during sexual intercourse from the first dose of the research product until 30 days after the participant's final dose, in order to avoid any possibility of the research product being transferred. 11. The patient is able to and willing to refrain from sexual intercourse from 6 hours before taking the medication until 6 hours after taking the medication; 12. Having the ability and willingness to attend necessary inspections at the experimental center; 13. Ability to understand all experiment-related documents, including written informed consent forms, and to complete all experiment-related tasks, including daily diaries; 14. I am willing and able to abide by the prohibitions and restrictions specified in the protocol.

[0363] Exclusion criteria: Participants will be removed from the experiment if one or more of the following criteria apply: 1. Any significant disease or disorder (e.g., cardiovascular, pulmonary, gastrointestinal, hepatic, renal, nervous system, musculoskeletal, endocrine, metabolic, malignant, psychiatric, or major physical impairment). These, in the opinion of the researchers, could put participants at risk by participating in the experiment or could affect the experimental outcome or the participant's ability to participate in the experiment; 2. Any clinically significant abnormal findings in health examinations, vital signs, hematology, clinical chemistry, or urinalysis during screening or at baseline. These, in the opinion of the researchers, could put participants at risk by participating in the experiment or could affect the outcome of the experiment or the participant's ability to complete the entire duration of the experiment; 3. Women who are pregnant, breastfeeding, or nursing (WOCBP must be negative on a pregnancy serum screening and negative on a pregnancy urine test at the start of treatment [i.e., day 1]); 4. Women who plan to become pregnant in the next six months; 5. A history of genital herpes or active non-HPV vaginal infection occurring >3 times per year; 6. Active pelvic infection (positive for gonorrhea or chlamydia infection, positive for bacterial vaginosis, candidiasis, or trichomoniasis). Participants with positive results may undergo one retest during screening; 7. A positive result on a bilateral test for pelvic peritonitis. The patient can be treated appropriately and rescreened. 8. A positive result for hepatitis B, hepatitis C, or human immunodeficiency virus; 9. The researcher has diagnosed that the patient has had abnormal vaginal discharge and / or abnormal vaginal bleeding, either currently or recently, within the past 1 to 3 months; 10. An abortion or miscarriage within three months prior to registration, or taking the morning-after pill; 11. In the researchers' opinion, you are currently taking any immunosuppressants, vaginal preparations, or prescription medications that may have safety concerns or may interfere with the interpretation of results; 12. Past exposure to lopinavir / ritonavir (within 3 months prior to screening), contraindications to the use of lopinavir / ritonavir, or known allergies, hypersensitivity, or intolerances to any component of lopinavir / ritonavir excipients; 13. Recent medical history (within 3 months prior to screening) of Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema, deep vein thrombosis, tinnitus, vertigo, hypoglycemia, pancreatitis, or hemophilia; 14. The patient received any research product within 30 days or 5 half-lives prior to the administration of the drug; 15. An employee of the clinical research team or an individual or relative (first-degree relative) involved in the planning and / or implementation of the experiment. The clinical research team refers to an employee directly involved in the experiment to whom experiment-related tasks are delegated as appropriate; 16. Participants who, in the opinion of the researchers, do not understand or are not suitable for the experimental information and procedures (including the limitations and risks of the experiment).

[0364] (Medication schedule) The research product will be self-administered by participants nightly at approximately 10 p.m. (±1 hour). Participants will be provided with medication instructions and important usage instructions.

[0365] Participants will monitor compliance by recording details of the application of research products on a daily diary card. Participants will also be asked to record any disposal / discharge incidents on their diary cards.

[0366] Participants must bring their research products and diary cards to the clinic visit on day 28. Tubes will be weighed before distribution to participants and again at the day 28 visit to assess compliance.

[0367] There are no fasting requirements related to the timing of application of the research product.

[0368] (Safety assessment) The following safety assessments will be conducted at the time points outlined in the event schedule. Please refer to Table 26.

[0369] Medical history ·health check • Vital signs • Weight and height • 12-lead electrocardiogram • Safety testing in clinical laboratories (hematology, biochemistry, urinalysis, vaginal microbiology, viral serology, drug addiction screening, alcohol screening, pregnancy screening)

[0370] (Efficacy diagnosis) The effectiveness of the research product will be evaluated by the improvement of cytological abnormalities in the cervix. Efficacy assessments will be performed at the time points outlined in the event schedule. See Table 26. • Visual evaluation using a colposcope • Biopsy using a colposcope • Cytological sampling • HPV genotype determination

[0371] JPEG0007839091000032.jpg254169JPEG0007839091000033.jpg63169

Claims

1. a. Unsaturated free fatty acids; b. At least two emulsifiers; c. Lopinavir; and d. Ritonavir A self-emulsifying pharmaceutical composition comprising, wherein the at least two emulsifiers include a first emulsifier having an HLB value of at least about 14 and a second emulsifier having an HLB value of at least less than about 6; the total emulsifier content is less than 30% by weight of the total composition; and the wt / wt ratio of lopinavir to ritonavir is between about 10:1 and about 14:

1.

2. The pharmaceutical composition according to claim 1, wherein the unsaturated free fatty acid is oleic acid.

3. The pharmaceutical composition according to any one of claims 1 or 2, wherein the first emulsifier has an HLB value greater than about 15, for example, greater than about 16, greater than about 17, or greater than about 18.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the first emulsifier is a polyol ester, for example, polyol stearate (e.g., PEG-100 stearate), or a polyethoxylated sorbitan ester, for example, polysorbate 20.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the second emulsifier has an HLB value of less than about 5.5, for example, less than about 5, less than about 4.5, or less than 4.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the second emulsifier is a monoglyceride, for example, glycerol monooleate.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the wt / wt ratio of the second emulsifier present in the composition to the first emulsifier is between about 1:10 and about 10:1, for example between about 1:5 and about 5:1, between about 1:3 and about 3:1, between about 1:1 and about 5:1, between about 1:1 and about 3:1, between about 1:1 and about 2:1, between about 1:2 and about 2:1, between about 1:1.5 and about 2:1, between about 1:1.3 and about 1:1.1 (for example, about 1:1.2), between about 1.1:1 and about 1.2:1 (for example, about 1.2:1), or between about 1.4:1 and about 1.6:1 (for example, about 1.5:1).

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the at least two emulsifiers are three emulsifiers.

9. The pharmaceutical composition according to claim 8, wherein the first emulsifier has an HLB value greater than 14, the second emulsifier has an HLB value less than 6, and the third emulsifier has an HLB value in the range of 8 to 15; and the total emulsifier content is less than 30% by weight of the total composition.

10. The pharmaceutical composition according to claim 8 or 9, wherein the third emulsifier is a polyoxyl castor oil derivative (for example, PEG35 castor oil).

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the total emulsifier content is less than 25% by weight, less than 20% by weight, less than 15% by weight, 2% to 20% by weight, 2.5% to 15% by weight, 5% to 15% by weight, 8% to 12% by weight, 10% to 20% by weight, 12% to 20% by weight, 10% to 18% by weight, 12% to 18% by weight, 12% to 16% by weight, 13% to 20% by weight, 14% to 20% by weight, 15% to 20% by weight, 13% to 25% by weight, 14% to 25% by weight, 15% to 25% by weight, 20% to 25% by weight, 20% to 26% by weight, 20% to 27% by weight, 20% to 28% by weight, or 20% to 29% by weight of the total composition.

12. The pharmaceutical composition according to any one of claims 1 to 11, wherein the first emulsifier is present in the pharmaceutical composition in an amount of about 1% to about 20% by weight of the total pharmaceutical composition, for example, about 1% to about 10% by weight, about 10% to about 20% by weight, about 10% to about 15% by weight, about 1% to about 5% by weight, about 3% to about 7% by weight, about 3% to about 6% by weight, about 3% to about 5% by weight (for example, about 4% by weight), about 4% to about 5% by weight (for example, about 4.3% by weight), or about 5% to about 6% by weight (for example, about 5.5% by weight).

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the second emulsifier is present in the pharmaceutical composition in an amount of about 1% to about 20% by weight of the total pharmaceutical composition, for example, about 1% to about 10% by weight, about 2% to about 8% by weight, about 4% to about 7% by weight, about 5% to about 7% by weight (for example, about 6% by weight), about 4% to about 6% by weight (for example, about 5% by weight), or about 4% to about 5% by weight (for example, about 4.5% by weight) of the total pharmaceutical composition.

14. The pharmaceutical composition according to any one of claims 8 to 13, wherein the third emulsifier is present in the pharmaceutical composition in an amount of about 1% to about 10% by weight of the total pharmaceutical composition, for example, about 2% to about 8% by weight, about 3% to about 7% by weight, about 4% to about 6% by weight, or about 5% by weight of the total composition.

15. The wt / wt ratio of lopinavir to ritonavir present in the composition is between approximately 10.5:1 and approximately 14:1, for example between approximately 11:1 and approximately 13:1, for example approximately 14:1, for example 14:1, for example approximately 13.8:1, for example 13.8:1, for example approximately 13.75:1, for example 13.75:1, for example approximately 13.5:1, for example 13.5:1, for example approximately 13:1, for example The pharmaceutical composition according to any one of claims 1 to 14, wherein the ratio is 13:1, for example, about 12.5:1, for example, 12.5:1, for example, about 12:1, for example, about 11.75:1, for example, 11.75:1, for example, about 11.5:1, for example, 11.5:1, for example, about 11.25:1, for example, 11.25:1, or for example, about 11:1, for example, 11:

1.

16. a. Unsaturated free fatty acids; b. A first emulsifier having an HLB value greater than approximately 14; c. A second emulsifier having an HLB value of less than approximately 6; d. A third emulsifier; e. Antioxidants; f. Lopinavir; and g. Ritonavir; A self-emulsifying pharmaceutical composition comprising the following, wherein the total emulsifier content is less than 30% by weight of the total composition, and the wt / wt ratio of lopinavir to ritonavir is between approximately 10:1 and approximately 14:

1.

17. A pharmaceutical composition according to any one of claims 1 to 16, enclosed within a capsule.

18. A pharmaceutical composition according to any one of claims 1 to 17, for use as a pharmaceutical.

19. A therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 17 for use in a method of treating and / or inhibiting the onset or progression of cancer and benign proliferative disorders in subjects requiring treatment or inhibition of the onset or progression of cancer and benign proliferative disorders.

20. A therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 17 for use in a method of treating a patient having HPV-related dysplasia of the cervix.

21. A therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 17 for use in a method of treating a patient having HPV-related dysplasia of the cervix, wherein the use reduces the severity of the HPV-related dysplasia.

22. A therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 17 for use in a method of treating a patient having HPV-associated dysplasia of the cervix, wherein the use induces apoptosis of HPV-infected cells.

23. A therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 17 for use in a method of treating a patient having HPV-associated cervical dysplasia, wherein the patient has cervical cytology of high-grade squamous intraepithelial lesion (HSIL), atypical squamous cells of undetermined severity (ASCU), or low-grade squamous intraepithelial lesion (LSIL).

24. A method for producing a self-emulsifying pharmaceutical composition according to any one of claims 1 to 17, a. The step of incorporating lopinavir and ritonavir by mixing them with unsaturated free fatty acids; b. To obtain a self-emulsifying composition, the step involves incorporating at least two emulsifiers by mixing them into the mixture obtained in step a). A method comprising, wherein the at least two emulsifiers include a first emulsifier having an HLB value greater than about 14 and a second emulsifier having an HLB value less than about 6; the total emulsifier content is less than 30% by weight of the total composition; and the wt / wt ratio of lopinavir to ritonavir is between about 10:1 and about 14:1.

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