WO2019224777A1 - Compositions pharmaceutiques - Google Patents

Compositions pharmaceutiques Download PDF

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Publication number
WO2019224777A1
WO2019224777A1 PCT/IB2019/054290 IB2019054290W WO2019224777A1 WO 2019224777 A1 WO2019224777 A1 WO 2019224777A1 IB 2019054290 W IB2019054290 W IB 2019054290W WO 2019224777 A1 WO2019224777 A1 WO 2019224777A1
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WIPO (PCT)
Prior art keywords
weight
pharmaceutical composition
fatty acid
free fatty
unsaturated free
Prior art date
Application number
PCT/IB2019/054290
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English (en)
Inventor
Fergus Cameron Binnie
Marten Geert Vos
Original Assignee
Douglas Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Douglas Pharmaceuticals Ltd filed Critical Douglas Pharmaceuticals Ltd
Publication of WO2019224777A1 publication Critical patent/WO2019224777A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • compositions comprising an unsaturated free fatty acid, a stiffening agent and at least one active pharmaceutical ingredient; methods for their manufacture; and the use of said pharmaceutical compositions as a medicament.
  • pharmaceutical compositions comprising lopinavir and ritonavir for use in treating and/or inhibiting the progression of diseases and/or disorders such as HPV related dysplasia of the cervix.
  • Semi-solid materials have unique rheological behaviour.
  • Semi-solid systems have a permanent three-dimensional structure which imparts solid-like properties to the system.
  • semi-solids have applications as pharmaceutical compositions, such as compositions for topical application.
  • the semi-solid can be mechanically spread uniformly over a surface, such as skin or a mucus membrane, to yield a film covering said surface.
  • Semi-solid pharmaceutical compositions include ointments, pastes, oil-in water (o/w) creams (semi-solid emulsions with solid internal phases), semi-solid emulsions with fluid internal phases, gels, and rigid foams.
  • Ointments typically contain a dissolved or suspended active pharmaceutical ingredient.
  • ointments are smooth oil compositions and contain a significant proportion of a pharmaceutically acceptable oil or fat.
  • Ointments are often hydrocarbon based.
  • fluid hydrocarbons such as C 16 -C 30 straight chain and branched, are entrapped in a fine crystalline matrix of C 30 -C 50 hydrocarbons and as such serve to act as the ointment base.
  • the extent and nature of the crystalline matrix determines the stiffness of the ointment, for example the manufacturing process used to produce the ointment can affect the size and number of crystallites of the C 30 -C 50 hydrocarbons.
  • White and yellow petrolatum are examples of hydrocarbon-based ointments.
  • compositions for topical application frequently contain fixed oils of vegetable origin consisting essentially of mono-, di-, and tri-glycerides of mixtures of saturated and unsaturated fatty acids.
  • the most common oils include peanut, sesame, olive, cotton seed, almond, arachis, maize, and persic oil.
  • Glycerides are esters formed from glycerol and fatty acids. Glycerol has three hydroxyl functional groups, which can be esterified with one, two, or three fatty acids to form mono-, di-, or tri-glycerides respectively.
  • Fatty acids are carboxylic acids with an aliphatic carbon chain which can be saturated or unsaturated, the length of the chain can vary from five or fewer carbon atoms (short-chain fatty acids, such as butyric acid), to twenty-two or more carbons (very long chain fatty acids).
  • Fatty acids are usually derived from triglycerides or phospholipids.
  • Phospholipid molecules consist of two hydrophobic fatty acid“tails” and a hydrophilic“head” consisting of a phosphate group. These two components are joined together by a glycerol molecule. Both triglyceride and phospholipids comprise fatty acids in a bound state. Conversely, free fatty acids are fatty acids which are not bound, that is they are not esterified.
  • excipients can be used, primarily in topical compositions, to increase the composition’s viscosity.
  • excipients include cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax, and yellow wax.
  • Semi-solid compositions employing the above-mentioned ointment base materials and/or additional excipients are associated with certain drawbacks.
  • vegetable oils may contain low levels of free fatty acids and the free fatty acid component of the vegetable oil can vary from batch to batch and/or over time.
  • identity of the free fatty acid and the relative amounts can vary from batch to batch and/or over time. This can be particularly problematic for active ingredient containing pharmaceutical products, which are required to be produced to a consistent and reproducible quality. Indeed, it is imperative that excipients used to manufacture pharmaceutical product are also of a consistent quality, i.e., minimal batch to batch variation.
  • semi-solid compositions upon topical administration to a site of application, can often leave significant residue, which is disadvantageous to the patient during treatment and/or may affect patient compliance.
  • the present invention is based on work carried out by the inventors to formulate a semi-solid composition comprising at least one active pharmaceutical ingredient. They have unexpectedly established that when a stiffening agent is combined with an unsaturated free fatty acid, a semi-solid composition is formed at room temperature. Accordingly, the present invention provides a pharmaceutical composition which is semi-solid at room temperature and comprises an unsaturated free fatty acid, a stiffening agent, and at least one active pharmaceutical ingredient.
  • the combination of an unsaturated free fatty acid and stiffening agent has broad applicably in semi-solid dosage forms such as, for example, ointments and creams for topical application, liquid filled hard gel capsules, soft gel capsules, pessaries and suppositories.
  • a free fatty acid (unsaturated free fatty acid and/or a saturated free fatty acid) in the composition is particularly advantageous as the quality of the free fatty acid in the composition can be controlled, such as identity, amount and purity of the free fatty acid.
  • other excipients such as vegetable oils and polysorbates, may contain low and variable levels of free fatty acids.
  • the free fatty acid composition of vegetable oil and polysorbate such as the identity of the free fatty acid and the amount, can vary from batch to batch, and over time.
  • the active pharmaceutical ingredient is soluble in the unsaturated free fatty acid and no heat above room temperature is required to achieve solubilisation. This is particularly advantageous when using an active pharmaceutical ingredient that is prone to degradation especially when the extent and/or rate of degradation, such as degradation by oxidation and/or hydrolysis, is increased when the active pharmaceutical ingredient is exposed to heat.
  • the weight ratio of the unsaturated free fatty acid: stiffening agent can be varied depending on the exact nature of the composition, for example further excipients may be present in the composition, so that the composition is particularly well suited for a certain type of dosing, for example syringe applicator vaginal dosing.
  • This is particularly useful in providing a topically applied treatment for the prevention or treatment of diseases as the composition can be specifically tailored for the site of application and/or the route of application.
  • Topical treatments also potentially allow a patient to self-administer the treatment and/or the topical treatment can be used as an alternative to other medical treatments, such as surgery. Both of these are particularly beneficial to patients who live in a country with poor access to medical alternatives.
  • the inventors have found that upon topical application of the pharmaceutical composition to a site of application, the pharmaceutical composition leaves minimal or no visible residue.
  • the pharmaceutical composition upon topical application of the pharmaceutical composition to the skin, the pharmaceutical composition can be absorbed by the skin leaving no residue.
  • the pharmaceutical composition when the pharmaceutical composition only comprises fats in the form of free fatty acids (unsaturated free fatty acids and/or saturated free fatty acids) the composition during and after application to the skin is more silky, less greasy, less oily, less tacky and/or less glossy compared to pharmaceutical compositions comprising fats in which the fatty acid is predominantly present in a bound state (i.e., not a free fatty acid). Fats not in the form of free fatty acids are not easily absorbed by the skin.
  • the inventors have found that when the composition further comprises a muco-adhesive, the pharmaceutical composition transforms in-situ into a muco-adhesive composition upon mucosal application of the pharmaceutical composition.
  • compositions of the invention are useful in the treatment of cancer.
  • the incidence of cancer varies, but it represents the second highest cause of mortality, after heart disease, in most developed countries.
  • Human tumour viruses are recognised to be a major cause of human cancer, and there is a great deal of evidence which supports the contention that these viruses cause cancer by inducing genetic instability in infected cells. Indeed, both the human T-cell leukemia virus type 1 (HTLV1) Tax and the human papilloma virus type 16 (HPV16) E6 oncoproteins are known to induce genetic instability producing abnormal numbers of centrosomes,
  • ICC Invasive cervical cancer
  • CIN1 low-grade cervical intraepithelial neoplasia
  • CIN2/3 high-grade cervical intraepithelial neoplasia
  • Lesions can be screened for by cervical cytology testing where they are diagnosed (or graded) as either borderline atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL).
  • ASCUS borderline atypical squamous cells of undetermined significance
  • LSIL low-grade squamous intraepithelial lesions
  • HSIL high-grade squamous intraepithelial lesions
  • cryotherapy has a higher failure rate compared to other treatment modalities.
  • HPV related cervical dysplasia An effective, inexpensive, non-surgical, self-applied treatment for HPV related cervical dysplasia would have great potential particularly in low resource settings. Furthermore, improved compliance with topical treatment would be enhanced, if the side effects are minimised.
  • WO2015/059485 which describes the protease inhibitors, lopinavir and ritonavir (which had previously been used as orally ingested medicaments for the clinical management of retroviral infections such as HIV) as being clinically useful for topical administration to tissues to prevent or treat malignancies caused by human papilloma virus.
  • the authors were particularly surprised to find that soft capsules of KALETRA ® (which is marketed by Abbott/ Abbvie for the treatment of HIV infections by oral administration) can be
  • administered topically e.g. inserted into the vagina for treatment of the cervix
  • 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 orders.
  • KALETRA ® (or its equivalent LOPIMUNE) is available for oral consumption as a solution comprising 80 mg lopinavir and 20 mg ritonavir per millilitre or as a soft capsule for oral administration that comprises 133.3 mg lopinavir and 33.3 mg ritonavir.
  • the solution additionally contains alcohol (42% w/w), high fructose corn syrup, propylene glycol, purified water, glycerol, povidone, flavourings, polyoxyl 40 hydrogenated castor oil, acesulfame potassium, saccharin sodium, sodium chloride, peppermint oil, sodium citrate, citric acid, and menthol.
  • the soft capsule contents contain, along with lopinavir and ritonavir, oleic acid, propylene glycol, polyoxy 35 castor oil, and purified water.
  • KALETRA ® Summary of Product Characteristics, EMA Summary of Product Characteristics, EMA.
  • compositions of the invention offer significant benefits when compared to oral soft capsule compositions when a topical formulation is required. Accordingly, in one particular embodiment, when the composition comprises lopinavir and ritonavir is topically applied, for example to the skin or vaginal wall, the composition can be used to treat and prevent cancerous conditions, for the prevention or treatment of oncogenic viral infections, and for the prevention or treatment of benign proliferative orders.
  • compositions comprising an unsaturated free fatty acid, a stiffening agent, and at least one active pharmaceutical ingredient, wherein the pharmaceutical composition is a semi-solid at room temperature.
  • a pharmaceutical composition comprising: an unsaturated free fatty acid; a stiffening agent; and at least one active pharmaceutical ingredient; wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature.
  • a process to manufacture a pharmaceutical composition of the first aspect comprising the step of incorporating a stiffening agent, at least one active pharmaceutical ingredient, and an unsaturated free fatty acid together to provide the pharmaceutical composition which is a semi-solid at room temperature, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total composition.
  • composition of the first aspect comprising:
  • step b incorporating a stiffening agent into the mixture obtained from step a. to provide a semi-solid composition
  • the unsaturated free fatty acid is present at a level of at least 20% by weight of the total composition.
  • a pharmaceutical composition according to the first aspect of the invention for use as a medicament.
  • the pharmaceutical composition is used as a medicament for treating and/or inhibiting the development or progression of diseases and/or disorders.
  • the pharmaceutical composition is used as a medicament for treating and/or inhibiting the development or progression of cancers and/or benign proliferative disorders.
  • the pharmaceutical composition comprises an effective amount of the at least one active pharmaceutical ingredient.
  • the pharmaceutical composition comprises an effective amount of the at least one active pharmaceutical ingredient for treating and/or inhibiting the development or progression of a disease or disorder.
  • the pharmaceutical composition comprises an effective amount of the at least one active pharmaceutical ingredient for treating and/or inhibiting the development or progression of cancers and/or benign proliferative disorders. In a further embodiment, the pharmaceutical composition comprises an effective amount of the at least one active pharmaceutical ingredient for treating a Human Papilloma Virus (HPV) infection with or without attendant abnormal pathology. In one embodiment, the pharmaceutical composition is used as a medicament for treating and/or inhibiting the development of early stage neoplasias. In one embodiment, the pharmaceutical composition is used as a medicament for treating or preventing the development of HPV related cervical, vulval, vaginal, penile, anal, oral or laryngeal neoplasias and/or warts. In one embodiment, the pharmaceutical composition is for use as a medicament for treating or preventing the development of cervical neoplasias.
  • HPV Human Papilloma Virus
  • a method of treating and/or inhibiting the development or progression of diseases and/or disorders in a subject in need of such treatment or inhibition comprising administering a therapeutically effective amount of a composition according to the first aspect of the invention.
  • a method of treating and/or inhibiting the development or progression of cancers and/or benign proliferative disorders in a subject in need of such treatment or inhibition comprising administering a therapeutically effective amount of a composition according to the first aspect of the invention.
  • the cancer or disorder is caused or induced by a human papilloma virus (HPV).
  • a method of treating a Human Papilloma Virus (HPV) infection with or without attendant abnormal pathology in a subject in need of such treatment or inhibition comprising administering a therapeutically effective amount of the pharmaceutical composition according to the first aspect of the invention.
  • HPV Human Papilloma Virus
  • a method of treating and/or inhibiting the development of early stage neoplasias in a subject in need of such treatment or inhibition comprising administering a therapeutically effective amount of the pharmaceutical composition according to the first aspect of the invention.
  • a method of treating or preventing the development of HPV related cervical, vulval, vaginal, penile, anal, oral or laryngeal neoplasias and/or warts in a subject in need of such treatment or inhibition comprising administering a therapeutically effective amount of the pharmaceutical composition according to the first aspect of the invention.
  • a method of treating or preventing the development of cervical neoplasias in a subject in need of such treatment or inhibition comprising administering a therapeutically effective amount of the pharmaceutical composition according to the first aspect of the invention.
  • the cancer or benign proliferative disorder is caused by a viral infection, more preferably by an oncogenic virus and in particular human tumour viruses such as HPV.
  • the invention concerns treating a subject having an HPV related dysplasia of the cervix comprising administering to said subject a therapeutically effective dose of the disclosed pharmaceutical compositions.
  • compositions, processes of manufacture and methods may be understood more readily by reference to the following detailed description which form a part of this disclosure. It is to be understood that the disclosed compositions, processes of manufacture and methods are not limited to the specific compositions, processes of manufacture and methods described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed compositions, processes of manufacture and methods.
  • compositions, processes of manufacture and methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment.
  • various features of the disclosed compositions, processes of manufacture and methods that are, for brevity, described in the context of a single embodiment may also be provided separately or in any sub-combination.
  • human papilloma virus HPV
  • ASC-US Atypical squamous cells of undetermined significance
  • LSIL Low grade squamous intraepithelial lesion
  • HSIL High grade squamous intraepithelial lesion
  • Cervical intraepithelial neoplasia 1 CIN1
  • Cervical Intraepithelial neoplasia 2 CIN2
  • Cervical intraepithelial neoplasia 3 CIN3
  • Carcinoma in situ CIS
  • ICC Invasive Cervical Carcinoma
  • treating and like terms refer to reducing the severity and/or frequency of symptoms, eliminating symptoms and/or the underlying cause of said symptoms, reducing the frequency or likelihood of symptoms and/or their underlying cause, delaying, preventing and/or slowing the progression of diseases and/or disorders, such as cancers or benign proliferative disorders, and improving or remediating damage caused, directly or indirectly, by the diseases and/or disorders such as cancers or benign proliferative disorders.
  • the phrase“therapeutically effective dose” refers to an amount of a composition comprising at least one active pharmaceutical ingredient, as described herein, effective to achieve a particular biological or therapeutic result such as, but not limited to, biological or therapeutic results disclosed, described, or exemplified herein.
  • therapeutically effective dose may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the composition to cause a desired response in a subject. Such results include, but are not limited to, the reduction, remission, and/or regression of the benign or malignant disease or prevention of the development of the benign or malignant disease, as determined by any means suitable in the art.
  • subject includes a vertebrate, mammal, domestic animal or preferably a human being.
  • a pharmaceutical composition comprising: an unsaturated free fatty acid; a stiffening agent; and at least one active pharmaceutical ingredient; wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the composition is semi-solid at room temperature.
  • an unsaturated free fatty acid and a stiffening agent can be used to prepare a pharmaceutical composition which is a semi solid at room temperature.
  • a liquid unsaturated free fatty acid has been stiffened by a stiffening agent to yield a semi-solid composition.
  • a semi-solid is any material that can be present in a stationary material state until an external stress is applied resulting in flow of the material.
  • the physical properties of a semi solid are a mixture of a solid and liquid. It will be apparent to the skilled person that the pharmaceutical composition is in a form of a semi-solid, for example by testing the pharmaceutical composition using a rheometer. From rheometric testing of the
  • the yield stress is a direct measure for the initiation of material flow (solid state to fluid state) in response to an applied stress.
  • the storage modulus is a direct measure of a fluid’s solid-like behaviour.
  • the loss modulus is a direct measure of a fluid’s fluid-like behaviour.
  • Tan d is the ratio of the loss modulus to the storage modulus and is a unitless measure.
  • a tan d value of ⁇ 1 defines a material as largely solid like, while a tan d value >1 defines a material as predominantly fluid-like.
  • the rheological behaviour of the semi-solid can be tested according to the methodology described in Example 6
  • the pharmaceutical composition has a tan d value of between about 0.5 and about 1.5 at 37°C, such as about 0.8 and about 1.2.
  • a pharmaceutical composition comprising: a) an unsaturated free fatty acid;
  • the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the composition has a tan d value of between about 0.5 and about 1.5 at 37°C, such as about 0.8 and about 1.2.
  • the pharmaceutical composition is an ointment, a cream, an oral dose liquid filled hard gel capsule, a soft gel capsule, a pessary or a suppository. In one embodiment, the pharmaceutical composition is an ointment. In one embodiment, the pharmaceutical composition is an opaque ointment.
  • a pharmaceutical composition comprising: a) an unsaturated free fatty acid;
  • the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight; and wherein the pharmaceutical composition is an ointment at room temperature.
  • the pharmaceutical composition has a complex viscosity of between about 500 and about 20000 cps when measured at 37°C, such as between about 1000 to about 10000 cps, such as between about 3000 and about 9000 cps, such as between about 4000 and about 8000 cps, such as between about 5000 and about 7000 cps, or such as about 6000 cps.
  • the pharmaceutical composition has a complex viscosity of between about 500 and about 3000 cps when measured at 37°C, such as between about 800 and about 2500 cps, such as between about 1000 and about 2000 cps, or such as between about 1200 and about 2000 cps.
  • the pharmaceutical composition has a complex viscosity of about 1400 cps when measured at 37°C or about 1900 cps when measured at 37°C.
  • the pharmaceutical composition is for topical application. In one embodiment, the pharmaceutical composition is for topical application to skin or mucosa. In one embodiment, the pharmaceutical composition is for intravaginal delivery. In one embodiment, the pharmaceutical composition is for intravaginal delivery using a syringe. In one embodiment, the pharmaceutical composition is for dispensing from a tube.
  • the pharmaceutical composition is for topical delivery of the at least one active pharmaceutical ingredient to a site of application.
  • the site of application comprises mucosa.
  • the mucosa is vaginal mucosa.
  • the pharmaceutical composition is for topical delivery of the at least one active pharmaceutical ingredient to the cervix (e.g. as an ointment, a cream, an oral dose liquid filled hard gel capsule, a soft gel capsule, a pessary or a suppository) for preventing the development of, or treating, cervical cancer (e.g. caused by high-risk types of HPV such as HPV16).
  • the cervix e.g. as an ointment, a cream, an oral dose liquid filled hard gel capsule, a soft gel capsule, a pessary or a suppository
  • cervical cancer e.g. caused by high-risk types of HPV such as HPV16.
  • compositions can be formulated as creams or ointments that may be applied directly to the cervix by techniques known to the art.
  • the pharmaceutical composition is a topical pharmaceutical composition.
  • the topical pharmaceutical composition is a topical pharmaceutical composition.
  • the composition advantageously provides prolonged retention of the at least one active pharmaceutical ingredient at the site of application. This ensures that the composition remains at the site of application for long enough to allow a significant proportion of the active pharmaceutical ingredient to be released from the composition and have the desired efficacious effect on the disease and/or disorder being treated.
  • various in-vitro techniques can be employed to measure release of the active pharmaceutical ingredient from the composition. For example, the amount of active pharmaceutical ingredient delivered through a membrane can be determined using, for example, Vertical Diffusion Studies (“Topical and Transdermal Drug Products, Pharmacopeia Forum, Vol. 35(3) [May- June 2009]). The in-vitro release rate can be correlated to how the composition will perform in an in-vivo setting.
  • At least 50% by weight of the active pharmaceutical ingredient is released from the composition, such as at least 60% by weight, such as at least 70% by weight, such as at least 80% by weight, such as at least 90% by weight, or such as at least 95% by weight within 2 hours, within 3 hours, within 6 hours, or within 8 hours.
  • the composition remains at the site of application for at least 30 minutes, such as at least 1 hour, such as at least 2 hours, such as at least 4 hours, such as at least 6 hours, such as at least 8 hours, such as at least 12 hours, or such as at least 24 hours.
  • the pharmaceutical composition remains at the site of application for up to 4 hours, for up to 6 hours, for up to 8 hours, or for up to 10 hours.
  • the pharmaceutical composition upon topical application to a site of application, leaves minimal or no visible residue of the pharmaceutical composition at the site of application. In one embodiment, minimal or no visible residue is observed after at least 5 minutes from topical application, such as about 10 minutes. In one embodiment, the pharmaceutical composition upon topical application to skin is absorbed by the skin. In one embodiment, the pharmaceutical composition upon topical application to skin is absorbed by the skin leaving no visible residue.
  • a pharmaceutical composition comprising: a) an unsaturated free fatty acid;
  • the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight
  • the tackiness and/or greasiness of the pharmaceutical composition is reduced, for example no tackiness and/or greasiness is observed after at least 5 minutes from topical application, such as about 10 minutes.
  • the tackiness and/or greasiness of the pharmaceutical composition is reduced, for example no tackiness and/or greasiness is observed after at least 5 minutes from topical application, such as about 10 minutes.
  • the pharmaceutical composition readily thins upon topical application to skin.
  • the thinning of the pharmaceutical composition upon application to the skin enables easy spreading of the pharmaceutical composition on the skin resulting in complete coverage of the dosed site.
  • the pharmaceutical composition is opaque, and upon topical application to the opacity of the pharmaceutical composition decreases, for example, the administered pharmaceutical composition is transparent.
  • the pharmaceutical composition does not discolour the skin upon topical application of the pharmaceutical composition to the skin.
  • a pharmaceutical composition comprising: a) an unsaturated free fatty acid;
  • the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight
  • the pharmaceutical composition is opaque, and upon topical application to the skin the opacity of the pharmaceutical composition decreases, for example, the administered pharmaceutical composition is transparent.
  • the pharmaceutical composition is an anhydrous pharmaceutical composition.
  • the pharmaceutical composition comprises less than 5% by weight of water of the total pharmaceutical composition weight, such as less than 1% by weight, such as less than 0.5% by weight, such as less than 0.1% by weight, such as less than 0.05% by weight.
  • the pharmaceutical composition is substantially free of water. In one embodiment, the pharmaceutical composition is entirely free of water.
  • a pharmaceutical composition comprising: a) an unsaturated free fatty acid;
  • a pharmaceutical composition comprising: a) an unsaturated free fatty acid;
  • the unsaturated free fatty acid is present at a level of at least 45% by weight of the total pharmaceutical composition weight.
  • the pharmaceutical composition comprises:
  • the sum of the unsaturated free fatty acid and the stiffening agent present in the pharmaceutical composition is at least 50% by weight of the total pharmaceutical composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • the sum of the unsaturated free fatty acid and the stiffening agent present in the pharmaceutical composition is at least 60% by weight of the total pharmaceutical composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • composition weight wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • the sum of the unsaturated free fatty acid and the stiffening agent present in the pharmaceutical composition is at least 80% by weight of the total pharmaceutical
  • composition weight wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • the sum of the unsaturated free fatty acid and the stiffening agent present in the pharmaceutical composition is at least 85% by weight of the total pharmaceutical
  • composition weight wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • the stiffening agent is a saturated free fatty acid, wherein the sum of the unsaturated free fatty acid and the saturated free fatty acid present in the pharmaceutical composition is at least 50% by weight of the total pharmaceutical composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • the stiffening agent is a saturated free fatty acid, wherein the sum of the unsaturated free fatty acid and the saturated free fatty acid present in the pharmaceutical composition is at least 60% by weight of the total pharmaceutical composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • the stiffening agent is a saturated free fatty acid, wherein the sum of the unsaturated free fatty acid and the saturated free fatty acid present in the pharmaceutical composition is at least 75% by weight of the total pharmaceutical composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • the stiffening agent is a saturated free fatty acid, wherein the sum of the unsaturated free fatty acid and the saturated free fatty acid present in the pharmaceutical composition is at least 80% by weight of the total pharmaceutical composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • the stiffening agent is a saturated free fatty acid, wherein the sum of the unsaturated free fatty acid and the saturated free fatty acid present in the pharmaceutical composition is at least 85% by weight of the total pharmaceutical composition weight, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, and wherein the composition is semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, wherein the pharmaceutical composition is semi solid at room temperature, and wherein the pharmaceutical composition comprises at least one part stiffening agent by weight to 0.1 to 20 parts unsaturated free fatty acid by weight.
  • the pharmaceutical composition comprises:
  • the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight, wherein the pharmaceutical composition is semi- solid at room temperature, and wherein the pharmaceutical composition comprises at least one part stiffening agent by weight to 1 to 20 parts unsaturated free fatty acid by weight.
  • the pharmaceutical composition only comprises or predominantly comprises fats in the form of free fatty acids (unsaturated free fatty acid and/or saturated free fatty acid), for example all fatty acids present in the composition are in the form of a free fatty acid.
  • This allows the pharmaceutical composition to be manufactured at room temperature which is advantageous when the at least one active pharmaceutical is prone to degradation, such as oxidation and/or hydrolysis, and wherein the rate and/or extent of degradation is increased when the active pharmaceutical ingredient is exposed to heat.
  • at least 60% by weight of the fatty acids in the pharmaceutical composition are in the free form, such as at least 65% by weight, such as at least 70% by weight, such as at least 80% by weight, or such as at least 85% by weight.
  • the pharmaceutical composition comprises: a. an unsaturated free fatty acid
  • the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature.
  • the pharmaceutical composition consists of:
  • the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature.
  • the one active pharmaceutical ingredient is selected from the same list as for the at least one active pharmaceutical ingredient.
  • the pharmaceutical composition consists of:
  • the one active pharmaceutical ingredient is selected from the same list as for the at least one active pharmaceutical ingredient.
  • the pharmaceutical composition consists of:
  • a muco-adhesive agent d. a muco-adhesive agent; and e. an antioxidant;
  • the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature.
  • the two active pharmaceutical ingredients are selected from the same list as for the at least one active pharmaceutical ingredient.
  • the pharmaceutical composition consists of:
  • the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature.
  • the two active pharmaceutical ingredients are selected from the same list as for the at least one active pharmaceutical ingredient.
  • the combination of the stiffening agent and the unsaturated free fatty acid causes the pharmaceutical composition to be a semi-solid at room temperature.
  • the stiffening agent is a saturated free fatty acid
  • the combination of the saturated free fatty acid and the unsaturated free fatty acid causes the pharmaceutical composition to be a semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • a muco-adhesive agent e. a thickener
  • an antioxidant wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total pharmaceutical composition weight and wherein the pharmaceutical composition is semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • oleic acid is present at a level of at least 20% by weight of the total
  • composition weight and wherein the pharmaceutical composition is semi solid at room temperature.
  • the pharmaceutical composition comprises:
  • oleic acid is present at a level of at least 20% by weight of the total
  • composition weight wherein the pharmaceutical composition is semi-solid at room temperature, and wherein the pharmaceutical composition comprises at least 1 part stearic acid by weight to 0.1 to 20 parts oleic acid by weight.
  • the pharmaceutical composition comprises:
  • oleic acid is present at a level of at least 20% by weight of the total
  • composition weight wherein the pharmaceutical composition is semi-solid at room temperature, and wherein the pharmaceutical composition comprises at least 1 part stearic acid by weight to 0.5 to 20 parts oleic acid by weight.
  • the pharmaceutical composition comprises:
  • oleic acid is present at a level of at least 20% by weight of the total
  • composition weight wherein the pharmaceutical composition is semi-solid at room temperature, and wherein the pharmaceutical composition comprises at least one part stearic acid by weight to 1 to 20 parts oleic acid by weight.
  • the pharmaceutical composition comprises:
  • composition weight and wherein the pharmaceutical composition is semi solid at room temperature.
  • the pharmaceutical composition comprises:
  • composition weight wherein the pharmaceutical composition is semi-solid at room temperature, and wherein the pharmaceutical composition comprises at least one part stearic acid by weight to 1 to 20 parts oleic acid by weight.
  • the pharmaceutical composition comprises:
  • oleic acid is present at a level of at least 45% by weight of the total
  • the pharmaceutical composition comprises:
  • oleic acid is present at a level of at least 45% by weight of the total
  • composition weight wherein the pharmaceutical composition is semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • oleic acid is present at a level of at least 45% by weight of the total
  • composition weight wherein the pharmaceutical composition is semi-solid at room temperature.
  • the pharmaceutical composition comprises:
  • hydroxypropylmethylcellulose e. about 0.5 to about 1.5% by weight of hydroxypropylmethylcellulose; f. about 0.1 to about 0.3% by weight of butylated hydroxytoluene;
  • the pharmaceutical composition comprises:
  • hydroxypropylmethylcellulose e. about 0.5 to about 1.5% by weight of hydroxypropylmethylcellulose; f. about 0.1 to about 0.3% by weight of butylated hydroxytoluene; g. about 4 to about 6% by weight of mono diglyceride;
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • Free fatty acids are fatty acids which are not attached to a glycerol backbone, i.e., the fatty acid is not part of a glyceride.
  • One advantage of the pharmaceutical composition comprising a free fatty acid is that the identity, amount and purity of the free fatty acid used to manufacture the pharmaceutical composition can be controlled.
  • An unsaturated free fatty acid is a free fatty acid wherein there is at least one double bond between carbon atoms in the fatty acid.
  • oleic acid typically contains 7- 12% saturated free fatty acids, such as stearic and palmitic acid, together with other unsaturated free fatty acids, such as linoleic acid (Handbook of Pharmaceutical Excipients, 2 nd Edition, see entry for Oleic acid).
  • saturated free fatty acid or unsaturated free fatty acid are to be understood as meaning the saturated free fatty acid or the unsaturated free fatty acid are of Pharmacopeia grade, such as the ETS Pharmacopeia and/or the British Pharmacopeia, and that the saturated free fatty acid or unsaturated free fatty acid may contain small amounts of other free fatty acids.
  • At least 90% by weight such as at least 95% by weight such as at least 98% by weight, such as at least 99% by weight, or such as at least 99.5% by weight, is in the free form, i.e., not esterified or bound to other components such as glycerol.
  • the unsaturated free fatty acid is not in the form of a triglyceride or polysorbate.
  • the unsaturated free fatty acid has a melting point below about 25°C. In one embodiment, the unsaturated free fatty acid is selected from oleic acid, linoleic acid, alpha-linoleic acid, palmitoleic acid, gondoic acid, and ricinoleic acid.
  • the unsaturated free fatty acid is oleic acid.
  • the stiffening agent is an excipient used to stiffen the pharmaceutical composition such that the composition is a semi-solid at room temperature.
  • the stiffening agent is a solid at room temperature.
  • the stiffening agent is a saturated fatty acid, such as a C10-C38 saturated free fatty acid, such as a C16-C22 saturated free fatty acid.
  • a saturated free fatty acid is a free fatty acid (i.e., the fatty acid is not bound to another molecule, such as glycerol) wherein there are no double bonds between the carbon atoms in the fatty acid.
  • the saturated free fatty acid is selected from capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid, arachidic acid, heneicosylic acid, behenic acid, tricosylic acid, lignoceric acid, pentacosylic acid, cerotic acid, heptacosylic acid, montanic acid, nonacosylic acid, melissic acid, henatriacontylic acid, lacceroic acid, psyllic acid, geddic acid, ceroplastic acid, hexatriacontylic acid, heptatriacontanoic acid and
  • the saturated free fatty acid is stearic acid.
  • Stearic acid is a straight chained saturated fatty acid with an 18-carbon chain.
  • the stiffening agent is a solid at room temperature, for example, the stiffening agent has a melting point greater than 35°C, such as greater than 40°C, such as greater than 45°C, such as greater than 50°C, or such as greater than 55°C.
  • At least 90% by weight such as at least 95% by weight such as at least 98% by weight, such as at least 99% by weight, or such as at least 99.5% by weight, is in the free form, i.e., not esterified or bound to other components such as glycerol.
  • the saturated free fatty acid is not in the form of a triglyceride or polysorbate.
  • At least 90% by weight such as at least 95% by weight such as at least 98% by weight, such as at least 99% by weight, or such as at least 99.5% by weight, is in the free form, i.e., not esterified or bound to other components such as glycerol.
  • the saturated free fatty acid and the unsaturated free fatty acid are not in the form of a triglyceride or polysorbate.
  • the free fatty acid content can be measured by reacting the free fatty acid with a chromogeneous compound, thus changing the frequency that the chromogeneous compound absorbs electromagnetic radiation.
  • the concentration of the chromogeneous compound reacted can be determined by monitoring the chromogeneous compound using a suitable wavelength which in turn can be used to determine the free fatty acid content in the sample.
  • the sum of the unsaturated free fatty acid and the saturated free fatty acid present in the pharmaceutical composition is at least 50% by weight of the total pharmaceutical composition weight, such as at least 60% by weight, such as at least 75% by weight, such as at least 80% by weight, or such as at least 85% by weight.
  • excipients typically used in pharmaceutical compositions may contain very low levels of free fatty acids (unsaturated and/or saturated free fatty acids), such as ⁇ 4% w/w, such as ⁇ 2% w/w, such as ⁇ 1% w/w, or such as ⁇ 0.5% w/w.
  • free fatty acids unsaturated and/or saturated free fatty acids
  • polysorbates have an acid value of circa 2-3
  • soybean oil has an acid value of ⁇ 0.6.
  • free fatty acids have much higher acid values, for example oleic acid and stearic acid have acid values of circa 200, which is equivalent to 100% w/w (Handbook of Pharmaceutical Excipients, 2 nd Edition, see entries for Oleic acid, Stearic acid, Soybean Oil and Polyoxyethylene Sorbitan Fatty Acid Esters).
  • the acid value is defined as the weight of KOH in mg required to neutralise the organic acids present in 1 g of fat/oil. It is a measure of the free fatty acids present in the fat/oil.
  • identity and amount of the free fatty acid in said polysorbate or vegetable oil excipients can vary from batch to batch, and/or over time.
  • Vegetable oils and animal fats can be used to thicken pharmaceutical compositions and while the vegetable oil and animal fat may contain low levels of free fatty acids, the vast majority of the free fatty acid is esterified and as such bound to a glycerol molecule within the oil or fat.
  • the pharmaceutical composition comprises at least 1 part stiffening agent by weight to 0.1 to 20 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 0.5 to 20 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 1 to 20 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 3.5 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 1 to 5 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 1 to 3 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 2 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 5 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 10 to 18 parts unsaturated free fatty acid by weight, such as at least 1 part
  • the unsaturated free fatty acid and the stiffening agent are present in the pharmaceutical composition in a weight ratio of unsaturated free fatty acid: stiffening agent in the range of 1 : 1 to 5 : 1 , such as in the range of 1 : 1 to 3 : 1 , such as about 2 : 1 , or such as 2: 1.
  • the unsaturated free fatty acid and the stiffening agent are present in the composition in a weight ratio of unsaturated free fatty acid: stiffening agent in the range of 13 : 1 to 15: 1, such as about 14: 1, or such as 14: 1.
  • the unsaturated free fatty acid and the stiffening agent are present in the composition in a weight ratio of unsaturated free fatty acid: stiffening agent in the range of 12: 1 to 14: 1, such as about 13 : 1, or such as 13 : 1.
  • the unsaturated free fatty acid is present in the pharmaceutical compositions at a level of at least 25% by weight of the total pharmaceutical composition weight, such as at least 35% by weight, such as at least 45% by weight, such as about 25 to about 75% by weight, such as about 55 to about 75% by weight, such as about 45 to about 75% by weight, such as about 50 to about 70% by weight, such as about 55 to about 70% by weight, such as about 55 to about 65% by weight, such as about 50 to about 60% by weight, such as about 25 to about 60% by weight, or such as about 50 to about 65% by weight.
  • the unsaturated free fatty acid is present in the pharmaceutical composition at a level of about 20% by weight of the total pharmaceutical composition weight, such as about 55% by weight, such as about 57% by weight, such as about 58% by weight, such as about 60% by weight, such as about 62% by weight, such as about 63% by weight, such as about 65% by weight, such as about 67% by weight, or such as about 68% by weight.
  • the stiffening agent is present in the pharmaceutical composition at about 0.1 to about 65% by weight of the total pharmaceutical composition weight, such as about 3 to about 60% by weight, such as about 3 to about 50% by weight, such as about 3 to about 40% by weight, such as about 3 to about 35% by weight, such as about 3 to about 6% by weight, such as about 4 to about 5% by weight, such as about 4.5% by weight, such as 4.5% by weight, such as about 15 to about 25% by weight, such as about 18 to about 22% by weight, such as about 20% by weight, such as about 20 to about 30% by weight, such as about 24 to about 30% by weight, such as about 26% by weight, such as about 25 to about 35% by weight, such as about 28 to about 32% by weight, such as about 30% by weight, such as 30% by weight, such as about 32% by weight, or such as about 34% by weight.
  • the total pharmaceutical composition weight such as about 3 to about 60% by weight, such as about 3 to about 50% by weight, such as about 3 to about 40% by weight, such as about
  • the at least one active pharmaceutical ingredient is a solid at room temperature. In one embodiment, the at least one active pharmaceutical ingredient is synthetically prepared. In one embodiment, the at least one active pharmaceutical ingredient is not a fatty acid (free or bound state).
  • the at least one active pharmaceutical ingredient is present in a dissolved state in the pharmaceutical composition. In another embodiment, the at least one active pharmaceutical ingredient is present in a dispersed state in the pharmaceutical composition. In another embodiment, an amount of the least one active pharmaceutical ingredient is present in a dispersed state and an amount is present in a dissolved state in the pharmaceutical composition. It will be apparent to the skilled person that the active pharmaceutical ingredient is dissolved or dispersed within the pharmaceutical composition by the use of techniques such as optical microscopy using polarised light filters, differential scanning calorimetry or micro FTIR. For example, a placebo pharmaceutical composition (i.e., a composition containing no active pharmaceutical ingredients) can be spiked with a crystalline active pharmaceutical ingredient. When viewed under an optical microscope using polarised light filters, the crystalline active pharmaceutical ingredient will exhibit
  • the spiked placebo composition can be used as a comparison standard in order to confirm there is no crystalline active pharmaceutical ingredient in the pharmaceutical composition, and thereby demonstrating the active pharmaceutical ingredient is dissolved within the pharmaceutical composition.
  • micro FTIR can be used to confirm the active pharmaceutical ingredient is dissolved in the pharmaceutical composition.
  • spectra obtained for a pharmaceutical composition spiked with the active pharmaceutical ingredient and for the pharmaceutical composition can be compared and used to demonstrate the active pharmaceutical ingredient is dissolved in the
  • the at least one active pharmaceutical ingredient is stable within the pharmaceutical composition.
  • the compositions of the invention are particularly suitable for active pharmaceutical ingredients used in the composition that are prone to chemical or physical degradation.
  • the active pharmaceutical ingredient used in the composition is prone to degradation due to hydrolysis.
  • the active pharmaceutical ingredient used in the composition is prone to degradation due to oxidation.
  • the active pharmaceutical ingredient used in the composition is prone to degradation which is accelerated by heat. In one embodiment, the active pharmaceutical ingredient used in the composition is prone to physical form changes, e.g. solid-sate polymorphic transitions.
  • the at least one active pharmaceutical ingredient is stable within the pharmaceutical composition for at least 3 months, such as at least 6 months, such as at least 9 months, such as at least 12 months, such as at least 18 months, such as at least 24 months, or such as at least 36 months, at a temperature of 5°C, 25°C, 30°C or at 45°C, and/or at a relative humidity of 60%, 65%, or 75% RH.
  • the at least one active pharmaceutical ingredient is stable within the pharmaceutical composition during a process to manufacture the pharmaceutical composition. In one embodiment, the at least one active pharmaceutical ingredient is stable within the pharmaceutical composition during a process to manufacture the pharmaceutical composition wherein the process is performed at room temperature. In one embodiment, the at least one active pharmaceutical ingredient is stable within the pharmaceutical composition during a process to manufacture the pharmaceutical composition wherein the process is performed at elevated temperatures, such as >30°C, such as >40°C, such as >50°C, such as >60°C, such as >65°C, or such as 70°C. In one embodiment, the at least one active pharmaceutical ingredient is stable within the pharmaceutical composition during a process to manufacture the pharmaceutical composition wherein the process is performed under an inert atmosphere, such as a vacuum, such as a vacuum at about -0.5 bar.
  • an inert atmosphere such as a vacuum, such as a vacuum at about -0.5 bar.
  • the at least one active pharmaceutical ingredient has a solubility measured at ambient temperature of at least 1% w/v in the unsaturated free fatty acid, such as at least 5% w/v in the unsaturated free fatty acid, such as at least 10% w/v in the unsaturated free fatty acid, such as at least 12% w/v in the unsaturated free fatty acid, such as at least 15% w/v in the unsaturated free fatty acid, or such as at least 18% w/v in the unsaturated free fatty acid.
  • the at least one active pharmaceutical ingredient is present in the pharmaceutical composition between about 0.001 and about 50% by weight of the total composition weight, such as between about 0.01 and about 50% by weight, such as between about 0.001 and about 5% by weight, such as between about 0.1 and about 25% by weight, such as between about 0.5 and about 15% by weight, such as between about 0.5 and about 10% by weight, such as between about 0.01 and about 2.5% by weight, such as between about 0.1 and about 2.5% by weight, such as between about 0.2 and about 2% by weight, such as between about 0.2 and about 1.5% by weight, such as between about 0.4 and about 1.5% by weight, such as between about 0.4 and about 0.6% by weight, such as about 0.5% by weight, such as 0.5% by weight, such as between about 0.5 and about 0.7% by weight, such as about 0.6% by weight, such as 0.6% by weight, such as between about 0.9 and about 1.1% by weight, such as about 1% by weight, such as 1% by weight, such as between about 1.2 and about 1.4% by
  • the at least one active pharmaceutical ingredient is classified as a Biopharmaceutics Classification System (BCS) Class II or a BCS Class IV active
  • a BCS class II active pharmaceutical ingredient is classed as an active ingredient having a high permeability and a low solubility.
  • a BCS class IV active pharmaceutical ingredient is classed as an active ingredient having a low permeability and a low solubility.
  • the at least one active pharmaceutical ingredient is selected from a protease inhibitor, a retinoid, a vitamin D analog, an antileprosy active pharmaceutical ingredient, a calcineurin inhibitor, a cannabinoid, a 5 alpha-reductase inhibitor, an androgen receptor inhibitor, a peroxisome proliferator activated receptor activator, an antihistamine, a chloride channel activator, a tyrosine kinase inhibitor, a hormone, a protease inhibitor, and a mTOR kinase inhibitor.
  • the at least one active pharmaceutical ingredient is selected from abacavir, efavirenz, enfuvirtide, nevirapine, ritonavir, lopinavir, tenofovir, adefovir, entecavir, ribavirin, acyclovir, famciclovir, penciclovir, valacyclovir, cidofovir, ganciclovir, valganciclovir, oseltamivir, zanamivir, amprenavir, bexarotene, calcifediol, calcitriol, clofazimine, cyclosporin A, doxercalciferol, dronabinol, dutasteride, enzalutamide, fenofibrate, isotretinoin, loratadine, lubiprostone, nintedanib, paricalcitol, progesterone, sa
  • the at least one active pharmaceutical ingredient is selected from abacavir, efavirenz, enfuvirtide, nevirapine, ritonavir, lopinavir, tenofovir, adefovir, entecavir, ribavirin, acyclovir, famciclovir, penciclovir, valacyclovir, cidofovir, ganciclovir, valganciclovir, oseltamivir and zanamivir.
  • the pharmaceutical composition further comprises an active pharmaceutical ingredient synergist.
  • the active pharmaceutical ingredient synergist is a HIV protease enzyme inhibitor.
  • the at least one active pharmaceutical ingredient is a HIV protease enzyme inhibitor.
  • the HIV protease enzyme inhibitor is selected from lopinavir and ritonavir.
  • Lopinavir (CAS# 192725-17-0) is a protease inhibitor chemically designated as [1S- [lR*(R*), 3R*, 4R*]]-N-[4-[(2,6-dimethylphenoxyacetyl]amino]-3-hydroxy-5-phenyl-l- (phenylmethyl)pentyl]tetrahydro-alpha-(l-methylethyl)-2-oxo-l(2H)-pyrimidineacetamide. It has the molecular formula C37H48N405 and a molecular weight of 628.80.
  • Ritonavir (CAS# 155214-67-5) is a protease inhibitor chemically designated as 10- Hydroxy-2-methyl-5-(l-methylethl)-l-[2-(l-methylethyl)-4-thiazolyl]-3,6-dioxo-8,
  • the pharmaceutical composition comprises lopinavir and ritonavir.
  • the molar ratio of lopinavir to ritonavir present in the composition is between about 1 : 10 and about 18: 1, such as between about 1 : 10 and about 15: 1, such as between about 1 :5 and about 15: 1, such as between about 1 : 1 and about 15: 1, such as between about 2: 1 and about 15: 1, such as between about 4: 1 and about 15: 1, such as between about 8: 1 and about 14: 1, such as between about 9: 1 and about 14: 1, such as between about 10: 1 and about 14: 1, such as between 10.5: 1 and about 18: 1, such as between 10.5: 1 and 18: 1, such as between about 10.5: 1 and about 14: 1, such as between about 11 : 1 to about 13: 1, such as between about 11.5 and about 17: 1, such as between about 11.5: 1 and about 16.0: 1, such as between about 11.5: 1 and about 15: 1, such as about 14.5: 1, such as 1
  • lopinavir has a molecular weight of 628.8 daltons and ritonavir has a molecular weight of 720.95 daltons. Accordingly, molar ratios and w/w ratios will not be the same and a factor of 0.872 should be applied when converting molar ratios to w/w.
  • lopinavir is present in the pharmaceutical composition at about 0.01 to about 50% of the total pharmaceutical composition weight, such as about 0.1 to about 25% by weight, such as about 2 to about 20% by weight, such as about 2 to about 15% by weight, such as about 4 to about 12% by weight, such as about 4 to about 10% by weight, such as about 4 to about 6% by weight, such as at about 5% by weight, such as 5% by weight, such as about 5 to about 7% by weight, such as about 6% by weight, such as 6% by weight, such as about 9 to about 11% by weight, such as at about 10% by weight, such as 10% by weight, such as about 11 to about 13% by weight, such as about 12% by weight, or such as 12% by weight.
  • the total pharmaceutical composition weight such as about 0.1 to about 25% by weight, such as about 2 to about 20% by weight, such as about 2 to about 15% by weight, such as about 4 to about 12% by weight, such as about 4 to about 10% by weight, such as about 4 to about 6% by weight, such as
  • ritonavir is present in the pharmaceutical composition at about 0.001 to about 5% by weight of the total pharmaceutical composition weight, such as about 0.01 to about 2.5% by weight, such as about 0.1 to about 2.5% by weight, such as about 0.2 to about 2% by weight, such as about 0.2 to about 1.5% by weight, such as about 0.4 to about 1.5% by weight, such as about 0.4 to about 0.6% by weight, such as at about 0.5% by weight, such as at 0.5% by weight, such as about 0.9 to about 1.1% by weight, such as about 1% by weight, such as 1% by weight, such as about 1.2 to 1.4% by weight, such as about 1.3% by weight, such as 1.3% by weight, such as about 0.5 to about 0.7% by weight, such as about 0.6% by weight, or such as 0.6% by weight.
  • excipients may be included in the composition according to the present invention providing that inclusion of such excipients does not unacceptably impact the ability of the composition to be a semi-solid at room temperature.
  • the pharmaceutical composition further comprises a muco- adhesive.
  • a muco-adhesive is an excipient which adhere to a mucous membrane.
  • the muco-adhesive is selected from a non-ionic polymer and an ionic polymer.
  • the non-ionic polymer is a cellulose ether.
  • the muco-adhesive is selected from a cellulose ether and an ionic polymer.
  • the ionic polymer is sodium polyacrylate.
  • the cellulose ether is selected from methyl cellulose, ethylcellulose and hydroxypropylmethylcellulose.
  • the cellulose ether is hydroxypropylmethylcellulose.
  • the hydroxypropylmethylcellulose has a degree of methoxy substitution of between 19 and 24% by weight and a degree of hydroxypropyl substitution of between 4 and 12% by weight.
  • the muco-adhesive agent is present in the pharmaceutical composition at about 0.1 to 20% by weight of the total pharmaceutical composition weight, such as about 0.1 to about 10% by weight, such as about 0.5 to 10% by weight, such as about 0.5 to 3% by weight, such as about 0.5 to 1.5% by weight, such as about 1% by weight, or such as 1% by weight.
  • the muco-adhesive agent has a viscosity of about 2000 to about 6000 cps, such as about 3000 to about 5000 cps, such as about 3500 to about 4500 cps, such as about 3800 to about 4200 cps, such as about 4000 cps, or such as 4000 cps.
  • the pharmaceutical composition upon application to a site of application transform to a muco-adhesive composition wherein the site of application comprises a mucosal membrane and wherein the pharmaceutical composition comprises a muco-adhesive agent.
  • This in-situ transformation of the pharmaceutical composition to a muco-adhesive composition results in the muco-adhesive composition having a different rheological behaviour and/or an increase in adhesiveness compared to the pharmaceutical composition.
  • the muco-adhesive composition is a gel.
  • the resulting gel enables the composition to be retained at the site of application for a prolonged period.
  • the pharmaceutical composition further comprises a thickener and/or a blending agent.
  • a thickener is an excipient which when added to a mixture increases the viscosity of the mixture and for conferring the pharmaceutical composition with greater physical stability and/or control during delivery of the active pharmaceutical ingredient to the site of application.
  • a blending agent is an agent which promotes uniformity within the
  • the thickener is selected from mono di glyceride, ceresin wax, and hydrogenated vegetable oil.
  • the pharmaceutical composition comprises mono di glyceride, ceresin wax and hydrogenated vegetable oil.
  • the thickener is present within the pharmaceutical composition at a level of at least 0.1% by weight of the total pharmaceutical composition weight, such as at least 1% by weight, such as at least 3% by weight, such as at least 5% by weight, such as about 0.1 to about 40% by weight, such as about 3 to about 40% by weight, such as about 3 to about 35% by weight, such as about 3 to about 30% by weight, such as about 4 to about 25% by weight, such as about 5 to about 21% by weight, such as about 4 to about 12% by weight, such as about 4 to about 7% by weight, such as about 0.1 to about 10% by weight, such as about 0.1 to about 20% by weight, such as about 3% by weight, such as about 5% by weight, such as 5% by weight, such as about 6% by weight, such as 6% by weight, such as about 8 to about 12% by weight, such as about 10% by weight, such as 10% by weight, such as about 10 to about 35% by weight, such as about 15 to about 35% by weight, such as about 20 to
  • the mono di glyceride is present in the pharmaceutical composition at about 0.1 to about 30% by weight of the total pharmaceutical composition weight, such as about 0.1 to about 10% by weight, such as about 1 to about 10% by weight, such as about 3 to about 7% by weight, such as about 4 to about 6% by weight, such as about 5% by weight, or such as 5% by weight.
  • the ceresin wax is present in the pharmaceutical composition at about 0.1 to about 30% by weight of the total pharmaceutical composition weight, such as about 0.1 to about 10% by weight, such as about 1 to about 10% by weight, such as about 4 to about 8% by weight, such as about 5 to about 7% by weight, such as about 5% by weight, such as about 6% by weight, or such as 6% by weight.
  • the hydrogenated vegetable oil is present in the pharmaceutical composition at about 0.1 to about 30% by weight of the total pharmaceutical composition weight, such as about 0.1 to about 20% by weight, such as about 5 to about 15% by weight, such as about 8 to about 12% by weight, such as about 9 to about 11% by weight, such as about 10% by weight, or such as 10% by weight.
  • the blending agent is selected from polyoxy 100 stearate and glycerol monooeleate. In one embodiment, the composition comprises polyoxy 100 stearate and glycerol monooeleate. In one embodiment, the blending agent is present in the pharmaceutical composition at at least 0.1% by weight of the total pharmaceutical composition weight, such as at least 1% by weight, such as at least 1.5% by weight, such as about 0.1 to about 48% by weight, such as about 1 to about 10% by weight, such as about 2 to about 5% by weight, such as about 0.1 to about 38% by weight, such as about 0.1 to about 10% by weight, such as about 2% by weight, such as 2% by weight, such as 3% by weight, such as 3% by weight, such as about 5% by weight, or such as 5% by weight.
  • the polyoxy 100 stearate is present in the pharmaceutical composition at about 0.1 to about 38% by weight of the total pharmaceutical composition weight, such as about 0.1 to about 10% by weight, such as about 0.5 to about 5% by weight, such as about 1 to about 3% by weight, such as about 2% by weight, or such as 2% by weight.
  • the glycerol monooleate is present in the pharmaceutical composition at about 0.1 to about 10% by weight of the total pharmaceutical composition weight, such as about 0.5 to about 5% by weight, such as about 2 to about 4% by weight, such as about 3% by weight, or such as 3% by weight.
  • the pharmaceutical composition comprises an antioxidant.
  • the antioxidant is butylated hydroxytoluene.
  • the antioxidant is present in the pharmaceutical composition at about 0.05 to about 0.5% by weight of the total pharmaceutical composition by weight, such as about 0.05 to about 0.15% by weight, such as about 0.1 to about 0.3% by weight, such as about 0.2% by weight, such as 0.2% by weight, such as about 0.1% by weight, or such as 0.1% by weight.
  • the pharmaceutical composition is for use as a medicament.
  • the pharmaceutical composition is for use as a medicament wherein the pharmaceutical composition is applied topically. In one embodiment, the pharmaceutical composition is topically applied to skin. In one embodiment, the
  • the pharmaceutical composition is topically applied to mucosa.
  • the pharmaceutical composition is for use a medicament wherein the pharmaceutical composition is topically applied to the cervix. This is particularly advantageous as the patient can self- administer the pharmaceutical composition and/or treatment with the pharmaceutical composition negates the need of treatment by surgery.
  • the pharmaceutical compositions are useful in the treatment and/or prevention of diseases and/or disorders.
  • the pharmaceutical compositions are useful in the treatment of benign proliferative disorders.
  • the pharmaceutical compositions are useful in the treatment of cancer and particularly useful for preventing the development of cancers. Accordingly, normal subjects (i.e. subjects with no detectable cancer), subjects with pre-malignant cells or particularly cancer prone subjects may be treated by topical administration of compositions according to the invention with a view to preventing the development of cancer.
  • compositions comprising lopinavir and ritonavir for use as a medicament in the treatment of cancer or benign proliferative disorders (e.g. warts) or in the prevention of the development of cancer.
  • benign proliferative disorders e.g. warts
  • the invention may be applied to a wide range of cancers such as ovarian carcinoma, breast carcinoma, lung carcinoma, uterine carcinoma, cervical carcinoma and thyroid carcinoma.
  • the invention is applicable particularly, but by no means exclusively, to pre-cancerous conditions and cancers caused by oncogenic viruses, e.g. high-risk or even low-risk forms of human papilloma viruses (HPVs).
  • HPVs human papilloma viruses
  • compositions may be administered to treat, and particularly prevent, the development of cervical cancer.
  • the inhibitors are used to treat, or prevent the development of cervical cancers caused by HPV (particularly high-risk types of HPV such as HPVl6 or HPV 18).
  • compositions may be used to prevent or treat cancer as a monotherapy (i.e. including the use of the pharmaceutical composition comprising two or more active pharmaceutical ingredients) or in combination with other compounds or treatments used in cancer therapy (e.g. chemotherapeutic agents, radiotherapy).
  • monotherapy i.e. including the use of the pharmaceutical composition comprising two or more active pharmaceutical ingredients
  • other compounds or treatments used in cancer therapy e.g. chemotherapeutic agents, radiotherapy.
  • compositions comprising lopinavir and ritonavir for use as a medicament in the treatment of cancer or benign proliferative disorders (e.g. warts) or in the prevention of the development of cancer.
  • benign proliferative disorders e.g. warts
  • compositions are used to treat humans. However, it will be appreciated that the compositions may also have some veterinary use.
  • the amount of the at least one active pharmaceutical ingredient required is determined by biological activity and bioavailability, which in turn depends, in part, on the precise mode of administration, the physicochemical properties of the pharmaceutical composition employed, and whether the pharmaceutical compositions are being used as a monotherapy or in a combined therapy with other medicines.
  • the at least one active pharmaceutical ingredient could be topically applied in addition to oral dosing of the same at least one active pharmaceutical ingredient or other active pharmaceutical ingredient(s).
  • the frequency of administration will also be influenced by the abovementioned factors and particularly the half-life of the active pharmaceutical ingredients within the subject being treated.
  • Daily doses may be given as a single administration (e.g. as a soft gel capsule, a hard gel capsule, a pessary or a suppository). Alternatively, administration may be twice or more times during a day.
  • the pharmaceutical compositions e.g. as an ointment or as a cream
  • Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the strength of the preparation, the mode of administration, and the
  • Suitable amounts of the at least one active pharmaceutical ingredient to be given as a daily dose are of about 0.01 mg to about 10 g, such as about 0.1 mg to about 10 g, such as about 1 mg to about 5g, such as about 1 mg to about 1 g, such as about 5 mg to about 2 g, such as about 10 mg to about 1 g, such as about 5 mg to about 500 mg, such as about 10 mg to about 500 mg, such as about 10 mg to about 400 mg, such as about 5 mg to about 200 mg, such as about 5 mg to about 50 mg, such as about 10 mg to about 40 mg, such as about 20 mg to about 40 mg, such as about 25 mg to about 35 mg, such as about 27 mg to about 32 mg, such as about 29 mg, such as 29 mg, such as about 28.7 mg, such as 28.7 mg, such as about 15 mg to about 35 mg, such as about 20 mg to about 30 mg, such as about 23 mg to about 27 mg, such as about 25 mg, such as 25 mg, such as about 5 mg to about 25 mg, such
  • about 10 mg to about 400 mg such as about 100 mg to about 400 mg, such as about 200 mg to about 400 mg, such as about 250 mg to about 350 mg, such as about
  • about 300 mg of lopinavir and about 29 mg ritonavir per day may be administered to the cervix of a woman.
  • about 300 mg of lopinavir and about 25 mg ritonavir per day may be administered to the cervix of a woman.
  • about 150 mg of lopinavir and about 14 mg ritonavir per day may be administered to treat the cervix of a woman.
  • about 150 mg of lopinavir and about 13 mg ritonavir per day may be administered to treat the cervix of a woman.
  • Such dosage forms may comprise about 300 mg of lopinavir and about 29 mg of ritonavir; or about 150 mg of lopinavir and about 14 mg of ritonavir. In another embodiment, about 2.5 g of the pharmaceutical composition may be administered to a subject per day. Such dosage forms may comprise about 300 mg of lopinavir and about 25 mg of ritonavir; or about 150 mg of lopinavir and about 12.5 mg of ritonavir.
  • the pharmaceutical composition may be administered to a subject for as long as treatment is required.
  • the length of time for which treatment will be required will depend upon the exact condition being treated or prevented and its severity. A skilled person will appreciate that treatment should be maintained in view of a number of factors which will include any requirement to eradicate the disease and/or disorder.
  • a course of treatment may be for 2 - 4 weeks, 7-21 days or for about 14 days. After this time a clinician may assess whether the course of treatment has been successful. A decision may then be made whether or not to continue treatment.
  • a treatment regimen may be for about 14 - 21 days and can be administered between menses.
  • a clinician may elect to stop topical treatment of the cervix during menses and recommence a new course of treatment in the next menstrual cycle.
  • a treatment regimen can be: (1) 14 - 21 days of administration; (2) followed by 1 - 14 days without treatment (during which menses may occur if treating the cervix); and (3) a further cycle of 14 -21 days of treatment if this is considered medically necessary.
  • the pharmaceutical compositions may be used to treat female subjects having an HPV related dysplasia of the cervix.
  • HPV related pre-invasive lesions include high grade squamous intraepithelial lesion (HSIL), atypical squamous cells of undetermined significance (ASCUS), and low grade squamous intraepithelial lesion (LSIL).
  • HPV related cancers include, for example, cervical
  • CIN intraepithelial neoplasia
  • ICC invasive cervical cancer
  • the disclosed methods and treatment regimens can be used to treat HPV related dysplasia.
  • the disclosed methods and treatment regimens can be used to treat HSIL.
  • the disclosed methods and treatment regimens can be used to treat ASCUS.
  • the disclosed methods and treatment regimens can be used to treat LSIL.
  • the disclosed methods and treatment regimens can be used to treat CIN.
  • the disclosed methods and treatment regimens can be used to treat ICC.
  • the disclosed methods and treatment regimens can be used to inhibit the progression of HPV related dysplasia.
  • the disclosed methods and treatment regimens can be used to inhibit the progression of HSIL.
  • the disclosed methods and treatment regimens can be used to inhibit the progression of ASCUS. In other aspects, the disclosed methods and treatment regimens can be used to inhibit the progression of LSIL. In other aspects, the disclosed methods and treatment regimens can be used to inhibit the progression of CIN. In yet other embodiments, the disclosed methods and treatment regimens can be used to inhibit the progression of ICC.
  • a method of treating a patient having an HPV related dysplasia of the cervix comprising administering intravaginally to said patient a therapeutically effective dose of a pharmaceutical composition according to the first aspect.
  • the pharmaceutical composition reduces the severity of the HPV related dysplasia.
  • the severity of the HPV 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.
  • the patient has a cervical cytology of high grade squamous intraepithelial lesion (HSIL), atypical squamous cells of undetermined significance
  • HSIL high grade squamous intraepithelial lesion
  • the pharmaceutical composition reduces the cervical cytology from HSIL to a normal cytology, from HSIL to ACSUS, from HSIL to LSIL, from ACSUS to a normal cytology, or from LSIL to a normal cytology.
  • the composition induces apoptosis of HPV infected cells.
  • a process to manufacture a pharmaceutical composition of the first aspect comprising the step of incorporating (e.g. by mixing) a stiffening agent, at least one active pharmaceutical ingredient, and an unsaturated free fatty acid together to provide the pharmaceutical composition which is a semi-solid at room temperature, wherein the unsaturated free fatty acid is present at a level of at least 20% by weight of the total composition.
  • the process comprises a first step comprising incorporating the at least one active pharmaceutical ingredient into the unsaturated free fatty acid to provide a mixture, followed by a second step comprising incorporating a stiffening agent into the mixture from the first step to provide the pharmaceutical composition.
  • the first step and/or second step comprises stirring.
  • the stirring is at performed at a rate of at least 10 rpm, such as at least 30 rpm, such as at least 50 rpm, or such as about 60 rpm.
  • the first step and/or second step additionally comprise periodic stirring.
  • the periodic stirring is performed at a rate of at least 300 rpm, such as at least 400 rpm, such as at least 500 rpm, or such as about 600 rpm. In one embodiment, the stirring is performed at a rate of about 60 rpm and the periodic stirring is performed at a rate of about 600 rpm. In one embodiment, the stirring and the periodic stirring in the first step results in the at least one active pharmaceutical ingredient dissolving in to the unsaturated free fatty acid. In one embodiment, the periodic stirring is performed for 5 minutes after incorporating the at least one active pharmaceutical ingredient with the stiffening agent and the unsaturated free fatty acid together. This advantageously aids with the initial de-clumping of the components of the pharmaceutical composition during this part of the process. In one embodiment, the periodic stirring is repeated every 30 minutes. Advantageously, the periodic stirring results in a homogeneous pharmaceutical composition, for example, aids the solubilisation of the active pharmaceutical ingredient.
  • the process is performed at room temperature. In one embodiment, the process is performed at room temperature. In one
  • the process is performed at room temperature, and the unsaturated free fatty acid and the stiffening agent are present in the composition at a weight ratio of at least one part stiffening agent by weight to 1 to 5 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 1 to 3 parts unsaturated free fatty acid by weight, such as one part stiffening agent by weight to about 2 parts unsaturated free fatty acid by weight.
  • the process is particularly well suited to active pharmaceutical ingredients which are prone to degradation, and wherein the rate and/or extent of degradation is increased when exposed to temperatures above room temperature, for example >30°C, >40°C, >50°C, and >60°C.
  • the process is performed at a temperature greater than the melting point of the stiffening agent, such as greater than 40°C, such as greater than 50°C, such as greater than 60°C, such as greater than 65°C, or such as about 70°C.
  • the process is performed at a temperature greater than the melting point of the stiffening agent, such as greater than 40°C, such as greater than 50°C, such as greater than 60°C, such as greater than 65°C, or such as about 70°C, and the unsaturated free fatty acid and the stiffening agent are present in the composition at a weight ratio of at least 1 part stiffening agent by weight to 0.1 to 20 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 0.5 to 20 parts unsaturated free fatty acid by weight , or such as at least one part stiffening agent by weight to 1 to 20 parts unsaturated free fatty acid by weight.
  • such as at least one part stiffening agent by weight to 1 to 5 parts unsaturated free fatty acid by weight such as at least one part stiffening agent by weight to 1 to 3 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 2 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 10 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 12 to 16 parts unsaturated free fatty acid by weight, such as one part stiffening agent by weight to about 2 parts unsaturated free fatty acid by weight, such as one part stiffening agent by weight to about 13 parts unsaturated free fatty acid by weight, or such as one part stiffening agent by weight to about 14 parts unsaturated free fatty acid by weight.
  • the process comprises incorporating the stiffening agent, the at least one active pharmaceutical ingredient, and the unsaturated free fatty acid by low shear mixing. In another embodiment, the process comprises incorporating the stiffening agent, the at least one active pharmaceutical ingredient, and the unsaturated free fatty acid by high pressure homogenising.
  • a process to manufacture a pharmaceutical composition of the first aspect comprising:
  • step b incorporating (e.g. by mixing) a stiffening agent into the mixture obtained from step a. to provide a semi-solid composition;
  • the unsaturated free fatty acid is present at a level of at least 20% by weight of the total composition.
  • the process is performed at room temperature.
  • the process is performed at room temperature, and the unsaturated free fatty acid and the stiffening agent are present in the composition at a weight ratio of at least one part stiffening agent by weight to 1 to 5 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 1 to 3 parts unsaturated free fatty acid by weight, or such as one part stiffening agent by weight to about 2 parts unsaturated free fatty acid by weight.
  • This has the advantage of the process being particularly well suited to active pharmaceutical ingredients which are unstable when exposed to temperatures above room temperature, for example >30°C, >40°C, >50°C, and >60°C.
  • step a. and/or step b. comprises stirring.
  • the stirring is at performed at a rate of at least 10 rpm, such as at least 30 rpm, such as at least 50 rpm, or such as about 60 rpm.
  • step a. and/or step b. additionally comprise periodic stirring.
  • the periodic stirring is performed at a rate of at least 300 rpm, such as at least 400 rpm, such as at least 500 rpm, or such as about 600 rpm.
  • the stirring is performed at a rate of about 60 rpm and the periodic stirring is performed at a rate of about 600 rpm.
  • the stirring and the periodic stirring in the first step results in the at least one active pharmaceutical ingredient dissolving in the unsaturated free fatty acid.
  • the process is performed at a temperature greater than the melting point of the stiffening agent, such as greater than 40°C, such as greater than 50°C, such as greater than 60°C, such as greater than 65°C, or such as about 70°C.
  • the process is performed at a temperature greater than the melting point of the stiffening agent, such as greater than 40°C, such as greater than 50°C, such as greater than 60°C, such as greater than 65°C, or such as about 70°C, and the unsaturated free fatty acid and the stiffening agent are present in the composition at a weight ratio of at least 1 part stiffening agent by weight to 0.1 to 20 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 0.5 to 20 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 1 to 20 parts unsaturated free fatty acid by weight.
  • such as at least one part stiffening agent by weight to 1 to 5 parts unsaturated free fatty acid by weight such as at least one part stiffening agent by weight to 1 to 3 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 2 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 10 to 18 parts unsaturated free fatty acid by weight, such as at least one part stiffening agent by weight to 12 to 16 parts unsaturated free fatty acid by weight, such as one part stiffening agent by weight to about 2 parts unsaturated free fatty acid by weight, such as one part stiffening agent by weight to about 13 parts unsaturated free fatty acid by weight, or such as one part stiffening agent by weight to about 14 parts unsaturated free fatty acid by weight.
  • the process according to the second or third aspects is performed under an inert atmosphere.
  • the inert atmosphere is provided by a vacuum.
  • the vacuum is about -0.5 bar. Performing the process under an inert atmosphere has the advantage that any components of the pharmaceutical composition, such as the at least one active pharmaceutical ingredient, that are prone to degradation, such as oxidative degradation, are protected from said degradation during the manufacturing process.
  • the process according to the second or third aspect uses an unsaturated free fatty acid which has an assay of at least 95% by weight, such as at least 98% by weight, such as at least 99% by weight, or such as at least 99.5% by weight.
  • the process according to the second or third aspect uses a stiffening agent which has an assay of at least 95% by weight, such as at least 98% by weight, such as at least 99% by weight, or such as at least 99.5% by weight.
  • using an unsaturated free fatty acid of a high assay level ensures that the pharmaceutical composition is controlled in respect to, for example, the identity, amount and purity of the free fatty acid within the composition.
  • using a stiffening agent having a high assay level ensures that the pharmaceutical composition is controlled in respect to, for example, the identity, amount and purity of the stiffening agent within the composition.
  • a syringe comprising the pharmaceutical composition of the first aspect.
  • the syringe for vaginal dosing of the pharmaceutical composition.
  • kits of parts comprising instructions for use and a syringe comprising the pharmaceutical composition of the first aspect.
  • kit of parts comprising instructions for use and a syringe comprising the pharmaceutical composition, the syringe for vaginal dosing of the pharmaceutical composition.
  • a tube comprising the pharmaceutical composition of the first aspect.
  • the tube is an aluminium tube.
  • a kit of parts comprising instructions for use and a tube comprising the pharmaceutical composition of the first aspect.
  • the tube is an aluminium tube.
  • API active pharmaceutical ingredient
  • Lopinavir/Ritonavir is thus one that excludes heat, water, and/or oxygen.
  • Example 3 Preparation of formulations
  • Formulation 3a i mixture (oleic acid and stearic ; full and half strength- molar ratio of lo to ritonavir 9:1
  • Formulation 3b Binary mixture (oleic acid and stearic acid); placebo
  • Formulation 3c Mixture (oleic acid, stearic acid and thickeners); full strength - molar ratio of lopinavir to ritonavir 12:1
  • vaginal dosage form full strength active batch exhibiting rheology suitable for syringe applicator vaginal dosing is described below in accordance with Table 3:-
  • Formulation 3d Mixture (oleic acid, stearic acid and thickeners): half strength - molar ratio of lopinavir to ritonavir 12:1
  • vaginal dosage form half strength active batch exhibiting rheology suitable for syringe applicator vaginal dosing is described below in accordance with Table 4:- i.
  • Formulation 3e Mixture (oleic acid, stearic acid and thickeners); placebo
  • vaginal dosage form placebo batch exhibiting rheology suitable for syringe applicator vaginal dosing is described below in accordance with Table 5:- i. Add into the mixer the following materials - 3, 4, 5, 6, 7, 8, 9,1
  • Formulation 3f Mixture (oleic acid, stearic acid, HPMC and thickeners); full strength molar ratio of lopinavir to ritonavir 13.8:1
  • vaginal dosage form placebo batch exhibiting rheology suitable for syringe applicator vaginal dosing is described below in accordance with Table 6:- i.
  • Add into the mixer the following materials - 3, 4, 5, 6, 7, 8, 9, 1, 10, 11 ii. Exclude air from the interior of the vessel
  • Formulation 3g Mixture (oleic acid, stearic acid, HPMC and thickeners); half strength - molar ratio of lopinavir to ritonavir 13.8:1
  • vaginal dosage form placebo batch exhibiting rheology suitable for syringe applicator vaginal dosing is described below in accordance with Table 7:- i.
  • Formulation 3h Mixture (oleic acid, stearic acid, HPMC and thickeners); full strength - molar ratio of lopinavir to ritonavir 13.8:1; cold process
  • vaginal dosage form exhibiting rheology suitable for syringe applicator vaginal dosing is described below in accordance with Table 8:- i.
  • medicine mixer add 1, 9, 10, 11
  • Formulation 3i Binary mixture (oleic acid and stearic acid); full strength- molar ratio of lopinavir to ritonavir 13.8:1
  • Formulation 3i Binary mixture (oleic acid and stearic acid); full strength- molar ratio of lopinavir to ritonavir 9.2:1
  • Formulation 3k Mixture (oleic acid, stearic acid, HPMC and thickeners); full strength - molar ratio of lopinavir to ritonavir 13.8:1: cold process
  • vaginal dosage form exhibiting rheology suitable for syringe applicator vaginal dosing is described below in accordance with Table 11 :- i.
  • medicine mixer add 1, 9, 10, 11
  • Formulation 31 Cream comprising Lopinavir
  • Example 3 The formulations described in Example 3 are suitable for topical dosing and syringe dosing. Organoleptic assessments of formulations 3a, 3b, 3c, 3d, 3e, 3f, 3g, 3i, 3j, 3h and 3k were conducted.
  • the opaque ointment presents as easy to dispense from the tube and is controllable on the skin during rubbing. After a short period of rubbing, the ointment clarifies to leave the skin non-tacky and with minimal greasiness. Approximately 10 minutes after dosing, the skin presents as silky, with negligible greasiness. These attributes denote an ointment as particularly suitable for topical application.
  • the opaque ointment presents as easy to dispense from the tube into the syringe applicator, after a short period of rubbing the ointment becomes increasingly more opaque, increasing whiteness, embodied, gelatinous, and cream-like.
  • These attributes denote an ointment that is compatible with a water environment, and as such, particularly suitable for topical application to an area of the body where water is present, for example vaginal application.
  • compositions according to Example 3 have been proven to be stable during the process employed to manufacture them (i.e. processes described in Example 3). Additionally, the compositions according to Example 3 have been shown to be stable upon storage.
  • Formulations 3c, 3d, 3f, 3g, 3i, 3j, and 3h were stored under different time and stability conditions, and subsequently analysed.
  • the stability data is presented in Tables 14 and 15.
  • a stable product is defined as one demonstrating 90-110% w/w assay for both Lopinavir and Ritonavir. Based on the data generated, the hot processed product
  • Formulation 3f and 3g when stored at 5°C (range 2-8°C) affords at least 10 months stability.
  • Formulation 3h (prepared using a cold process) demonstrates greater stability than that for formulations 3c and 3d when stored for 3 months stored at 25°C. This is thought to be due to the absence of thermal exposure of Ritonavir and Lopinavir during the
  • **Formulation 3j was an early formulation. A stability assessment was not taken at the time of manufacture. For stability trending, formulation 3i (a close variant of formulation 3j) was manufactured.
  • **Formulation 3j was an early formulation. A stability assessment was not taken at the time of manufacture. For stability trending, formulation 3i (a close variant of formulation 3j) was manufactured. The following analytical methodology was used to analyse the formulations. UHPLC:
  • Example 6 Methodology for rheological characterisation of the pharmaceutical composition.
  • the following methodology can be used to determine the rheological behaviour of the pharmaceutical compositions, for example using a Discovery Hybrid Rheometer (Model HR- 3, TA instruments).
  • the sample is introduced onto the peltier plate (base) in excess (l-2g), and the spindle lowered to make contact with the sample. The excess sample is cleaned up.
  • the spindle is then rotated in a predetermined fashion to exert a series of shear forces on the sample.
  • the various sample shear force response parameters (complex viscosity, storage and loss moduli, tan 5) are captured and then plotted in order to make conclusions regarding inherent sample attributes.
  • Instalment parameters for the purpose of capturing complex viscosity, storage modus and loss modulus are as follows :- Peltier temperature: 37 °C
  • Example 7 Preparation of a 2 parts stearic acid by weight
  • Pelletized dissolved state API for solid state dosing Potential applications: Pelletized dissolved state API for solid state dosing.
  • the centre-point full-strength (Formulation 8a) /half- strength (Formulation 8b) formulations yield viscosities of approximately 2000-l500cps.
  • the half strength contains a higher solvent level than the full-strength, which translates to a somewhat lower viscosity (note: It is the full-strength formulation, with 13 % total drug substance, that dictates the minimum amount of solvent i.e. 55.3 %.
  • Formulation 8c (r) l8085cps) is so stiff as to be barely dose-able via the intended 6 mm tube orifice. A larger tube orifice (8-10 mm), or even use of pre-charged dosing applicators would facilitate easier dosing of product at this upper viscosity.
  • Formulation 8a Full strength ointment
  • step ii three times vii. Mix for e.g. 10 minutes, 60 rpm, homogenizer 600 rpm to disperse viii. Cool content to 45°C, mixing as required e.g. 60 rpm, homogenizer 600 rpm ix. Discharge the product into HDPE bag lined polypail, well labelled
  • Example 9 A Phase 1, single centre, double blind, randomised, parallel group, ascending single and multiple dose, safety and tolerability, pharmacokinetic (PK) and
  • compositions according to Example 3 were investigated according to the clinical trial described below.
  • This study comprised two cohorts, both in healthy volunteers with no cervical pathology. There were 9 participants per Cohort, of whom 6 received active and 3 received placebo. For all formulations tested, the amount of the composition administered per dose was 3 g.
  • Formulation 3c this equates to 300 mg of lopinavir and 28.7 mg of ritonavir being administered to the patients per dose.
  • Formulation 3d this equates to 150 mg of lopinavir and 14.3 mg of ritonavir administered per dose.
  • Period 1 Single dose of Formulation 3d or placebo Formulation 3e followed by confinement. PK blood sampling during confinement.
  • Period 2 21 daily doses of Formulation 3d or placebo Formulation 3e followed by PK blood sampling.
  • Period 1 Single dose of Formulation 3c or placebo Formulation 3e followed by confinement. PK blood sampling during confinement.
  • Period 2 21 daily doses of Formulation 3c or placebo Formulation 3e followed by PK blood sampling.
  • the physical examination consisted of a review of body systems with height and weight (in indoor clothing).
  • Electrolytes sodium and potassium
  • ALT sodium and potassium
  • GGT ALP
  • albumin total protein
  • total bilirubin urea
  • uric acid serum creatinine
  • TFT fasting lipids
  • amylase glucose
  • the measurement at screening serve as a baseline to monitor any abnormalities that may manifest as a result of dosing
  • Drugs of abuse testing were carried out on all participants as part of the screening procedures.
  • a urine sample was required to test for cannabinoids (marijuana), amphetamines, benzodiazepines and opiates (i.e. morphine, heroin and codeine).
  • Vaginal swabs for microbiology gonorrhoea, Chlamydia, bacterial vaginosis, Candida
  • Alcohol breath testing was carried out at the Clinical Site on the first night of each confinement period.
  • Serum HCG testing was carried out on all participants as part of the screening procedures and within 3 days before the lst dose.
  • Systolic Blood Pressure > 90 or ⁇ 160 mm Hg; Diastolic Blood Pressure > 50 or ⁇ 90 mm Hg
  • Systolic Blood Pressure > 90 or ⁇ 160 mm Hg; Diastolic Blood Pressure > 50 or ⁇ 90 mm Hg
  • Dosing began at approximately 8pm on each day dosing was scheduled. Participants were instructed to insert the medication in private. Dosing applicators were returned to study staff and examined to ensure the full dose has been applied and for reconciliation of study drug.
  • PK Blood samples blood samples (8 mL) were drawn through venous catheters and transferred into vacutainers containing sodium heparin as the anti-coagulant. The time of collection is recorded as the time the full 8 mL of blood was collected.
  • the venous catheters were kept patent by flushing with 1.5 mL-2.0 mL of heparinized saline following each sample (0-24 hours). The sampling intervals were at: Day 1-2: 0, 1, 2, 4, 8, 12, 24 hours; Day 22-23: 0, 1, 2, 4, 8, 12, 24 hours. Samples were collected at their due time. Any deviation was noted.
  • Plasma was separated by centrifugation at 3500 rpm for 5 minutes at about 4°C. No aids for separation of plasma from red cells was used. The plasma sample was transferred with clean pipettes. The assay was determined using a validated Analytical method.
  • Each plasma sample was placed into a polypropylene storage tube with a screw cap.
  • the plasma was stored frozen at -60°C or colder at the clinical site pending transfer to a Laboratory for assay.
  • each participant was required to provide a blood sample for analysis. Any abnormalities as compared to initial screening were monitored and followed up until they return to normal.
  • AE was classified by the Principal Investigator as serious adverse event (SAE) or non- serious.
  • SAE serious adverse event
  • Non- serious adverse events were assessed as being mild, moderate, or severe to describe the maximum intensity of the AE.
  • the Principal Investigator also provided the possible relationship between the AE and the study medication as highly probable, probable, possible, remotely or not ("no") related to the study medication.
  • the Principal Investigator should have stated if the cause of the AE is related to the concurrent non-investigational medication(s) if any are being taken, an underlying disease, a combination of these factors or is unknown.
  • Formulations 3c and 3d are deemed to be well-tolerated since all AEs were either minor or not related to administration of study medication
  • AUC area under the plasma drug concentration time curve
  • Cmax peak plasma drug concentration
  • Tmax time to maximum drug concentration
  • the plasma drug concentration (C) versus the real sampling time (t) data were analysed by a "noncompartmental" method to obtain the pharmacokinetic parameters. Initially the plasma data in the post distribution phase of the plasma concentration - time plot were fitted using linear regression to: ⁇
  • the mean lopinavir and ritonavir plasma concentration-time data for each sampling time is listed in Tables 21 and 22.
  • the pharmacokinetic parameters for lopinavir and ritonavir are listed in Tables 21 and 22.
  • Table 21 Mean ( ⁇ SD) Plasma Lopinavir and Ritonavir Concentration Data vs Sampling Times (Formulation 3d) Vaginal Ointment)
  • Table 22 Mean ( ⁇ SD) Plasma Lopinavir and Ritonavir Concentration Data vs Sampling Times (Formulation 3c) Vaginal Ointment)
  • the mean Cmax for lopinavir was 12.3 ⁇ 5.4 pg/mL (SPMC Kaletra). Adjusting for dose comparison with a 300 mg dose administered topically in ointment form, the mean Cmax would be 9.23 ⁇ 4.1 pg/mL.
  • the ratio of Cmax oral/Cmax topical is >23,000 indicating that less than 0.004% of the topical dose is available systemically.
  • the AUCO-t for lopinavir was 113.2 ⁇ 60.5 pg h/mL (SPMC Kaletra). Adjusting for dose comparison with a 300 mg dose administered topically in ointment form, the AUCO-t would be 84.9 ⁇ 45.4 pg h/mL.
  • the AUCO-t was 7368.1 ⁇ 4973.1 pg/mL.
  • the ratio of AUC oral/AUC topical is >11,500 indicating that less than 0.009% of the topical dose is available systemically.
  • Example 10 A Phase lb. Multicentre, Open Label, Study of the Efficacy, Safety and Tolerability of Formulation 3h in Women with Cvtological Abnormalities of the Uterine Cervix.
  • This study is designed as a Phase lb multicentre, open label study investigating the efficacy, safety and tolerability of Formulation 3h ointment in women with cytological abnormalities of the uterine cervix.
  • Formulation 3h ointment is self-applied to the vagina once a day for 21 consecutive days in up to
  • Participation in this study includes a screening visit, up to 3 treatment cycles and an end of study visit as follows:
  • Treatment Cycle 3 non-responders identified at Day 56, can continue investigational application once daily for 21 days OR be referred to their primary physician;
  • Post-treatment assessment visit PTAV
  • ETV Early termination visit
  • CIN l/LSIL low-grade cytological abnormality of the uterine cervix defined as CIN l/LSIL, as demonstrated by colposcopic biopsy within 6 months prior to screening.
  • Transformation zone needs to be fully visible
  • Vasectomised partner (provided that the partner is the sole sexual partner of the female participant with childbearing potential and that the vasectomised partner has received medical assessment of the surgical success);
  • WOCBP must agree to use a highly effective method of birth control, as defined above, from enrolment, and at least 14 days prior to Day 1, throughout the study duration and within 30 days after the last dose of IMP.
  • WOCBP are defined as women who are neither permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), nor who are postmenopausal. Women will be considered post-menopausal if they have been amenorrhoeic for 12 months or more without an alternative biological or medical cause e.g. contraceptive method such as Mirena.
  • Any significant disease or disorder e.g. cardiovascular, pulmonary, gastrointestinal, hepatic, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment
  • WOCBP Pregnant, breastfeeding, or lactating women (WOCBP must have a negative serum pregnancy test at screening and a negative urine pregnancy test at the start of each treatment period [i.e. Day 1, Day 28, Day 56]);
  • Active pelvic infection positive for gonorrhoea or chlamydial infection, positive test for bacterial vaginosis, Candida vaginitis or trichomonal vaginitis. Participants with positive results can be re tested once during screening;
  • Clinical study team refers to employees directly involved in the study who have been delegated study-related tasks accordingly;
  • Investigational product is administered every day for 21 days for up to 3 cycles as follows:
  • Cycle 1 (daily at 8pm from Day 1 to Day 21);

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Abstract

La présente invention concerne des compositions pharmaceutiques semi-solides comprenant un acide gras libre insaturé, un agent de raidissement et au moins un ingrédient pharmaceutique actif; l'utilisation desdites compositions pharmaceutiques en tant que médicament; et des procédés pour la préparation desdites compositions.
PCT/IB2019/054290 2018-05-24 2019-05-23 Compositions pharmaceutiques WO2019224777A1 (fr)

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WO2021105922A1 (fr) * 2019-11-27 2021-06-03 Douglas Pharmaceuticals Limited Compositions pharmaceutiques
US11738024B2 (en) 2018-05-24 2023-08-29 Douglas Pharmaceuticals Limited Lopinavir and ritonavir for the treatment of cervix disorders

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EP1570860A1 (fr) * 2002-12-13 2005-09-07 Ono Pharmaceutical Co., Ltd. Antagoniste et agoniste se liant a un site de liaison forte du recepteur de la chimiokine
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EP1570860A1 (fr) * 2002-12-13 2005-09-07 Ono Pharmaceutical Co., Ltd. Antagoniste et agoniste se liant a un site de liaison forte du recepteur de la chimiokine
US20040126424A1 (en) * 2002-12-17 2004-07-01 Jandacek Ronald James Compositions, methods, and kits useful for the alleviation of gastrointestinal effects
WO2010142457A1 (fr) * 2009-06-11 2010-12-16 Photocure Asa Compositions semi-solides et produits pharmaceutiques
EP2962732A1 (fr) * 2013-02-28 2016-01-06 Jimeno Martínez, Leonardo Produit à usage topique pour le cuir chevelu et son procédé d'élaboration
WO2014168193A1 (fr) * 2013-04-11 2014-10-16 大正製薬株式会社 Composition pour utilisation externe
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DONATO ET AL.: "LC Method for Studies on the Stability of Lopinavir and Ritonavir in Soft Gelatin Capsules", CHROMATOGRAPHIA, vol. 63, April 2006 (2006-04-01), pages 437 - 443, XP019388558, DOI: doi:10.1365/s10337-006-0785-y

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11738024B2 (en) 2018-05-24 2023-08-29 Douglas Pharmaceuticals Limited Lopinavir and ritonavir for the treatment of cervix disorders
WO2021105922A1 (fr) * 2019-11-27 2021-06-03 Douglas Pharmaceuticals Limited Compositions pharmaceutiques

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