Propionate ester van 25r spirostan-6-one-3-oneContinuation-in-part of application No. Provisional Spirostan-6-ome-3-one Application No. Provisional Patent Application Ser. The challenge of preparing emulsion carriers and compositions that are capable of forming stable breakable foams suitable for topical or mucosal application is beset with a multitude of challenges. The active agents are often sensitive and also may interact with propionate ester van 25r spirostan-6-one-3-one components in a composition.
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Continuation-in-part of application No. Provisional Patent Application No. Provisional Patent Application Ser. The challenge of preparing emulsion carriers and compositions that are capable of forming stable breakable foams suitable for topical or mucosal application is beset with a multitude of challenges. The active agents are often sensitive and also may interact with other components in a composition.
Agents may have limited biocompatibility or poor solubility. The agents may be difficult to deliver to a target site. Some emulsions may be stable but do no meet the criteria of shakability or flowability as is required for a foamable formulation to be expelled under pressure through a canister valve using a propellant. Other emulsions albeit shakable may not produce stable breakable foams. Moreover, there is a need that these formulations be resistant or resilient to aging and do not separate into two phases as can be determined by exposing the formulations to temperature changes, or by centrifugation.
To the extent such formulations display creaming there is a need for them to be easily and effectively redispersible upon exposure to light shaking. Some steroids, such as betamethasone valerate, are known to be particularly unstable and tend to isomerize. Upon actuation of the foam onto the skin, the propellant immediately vaporizes and the emulsion deposits on the skin surface.
The foam should ideally spread easily on skin with minimal greasy or sticky feeling and should be absorbed quickly. These foam qualities are desirable for usability and compliance. Further desirable positive attributes are acceptable odor and color. Usage of foam provides a better skin moisturizing and protective capacity and is less irritable than the other dosage forms. Foams easily spread on large skin areas can be efficiently rubbed into the skin.
Usage of foam provides a better cavity moisturizing and protective capacity and may be less irritable than the other dosage forms. Stability is a primary feature that has to be ensured when a pharmaceutical formulation, and in particular a foam pharmaceutical product, is being developed. Surfactants reduce the free energy between oil and aqueous phase and build a separation film between the two immiscible phases.
Stronger and compact separation film contributes to enhanced stability and longer shelf life. The creaming phenomenon which may cause emulsion breaking and phase separation should be avoided since it may finally contribute to separation and a non-usable product. Producing such steroid foamable compositions which are chemically stable and retain the desired physical properties is a double challenge.
Compositions containing steroids for topical treatment of dermatologic disorders are available primarily in cream, lotion, gel and ointment forms. While semi-solid compositions, such as creams, lotions, gels and ointments are commonly used by consumers, new forms are desirable, in order to achieve better control of the application, while maintaining or bestowing beneficial properties of such products on the skin.
Thus, the development of new compositions having breakable foam consistency when released from a container and liquid properties when applied onto the skin are advantageous. Pharmaceutical foam compositions including a an active ingredient; b an occlusive agent; c an aqueous solvent; and d an organic cosolvent; wherein the active ingredient is insoluble in water and insoluble in both water and the occlusive agent; and wherein there is enough occlusive agent to form an occlusive layer on the skin are known.
Moreover, formulations that are able to remain physically stable and chemically stable or substantially so, over a sufficient period of time to allow for normal pharmaceutical use.
Particularly, there remains an unmet need for improved, easy to use, stable and non-irritating steroid foam formulations, with unique therapeutic properties.
The problems of protecting active steroid pharmaceutical agents in emulsion compositions are multifold and can vary according to the type of emulsion environment and the nature of the agent and excipients being used. It has been surprisingly found that factors like small levels of acid residues in the raw materials can be significant in influencing agent stability.
Similarly, the presence of low levels of metal ions can act to catalyze reactions or breakdown. There is therefore a need for simple and elegant solutions to stabilize active steroid ingredients in an emulsion environment. On one level it is far from simple or obvious to produce emulsion foamable compositions that when released produce foams of quality suitable for pharmaceutical or cosmetic application that are capable of satisfying the need for both physical stability of the foam and for chemical stability of the active steroid ingredient.
On a further level having realized a composition that will produce an emulsion foam of quality there is an additional difficulty to be overcome, namely how to adapt the formula and achieve a formulation, which can accept a range of various other active pharmaceutical and cosmetic agents such that the composition, steroid and other active agents are compatible and capable of remaining stable for a prolonged period and the foam produced remains of quality.
Specifically, one of the challenges in preparing such foamable compositions is ensuring that the active pharmaceutical or therapeutic agent does not react, isomerize or otherwise break down to any significant extent during is storage and use. Particularly, there remains an unmet need for improved, easy to use, stable and non-irritating foamable formulations, with unique therapeutic or beneficial properties containing a stable or stabilized active pharmaceutical or cosmetic agent which when stored in and subsequently expelled from a canister can be delivered as a breakable foam.
The vaginal wall consists of an inner glandular mucous type stratified squamous cell epithelium supported by a thick lamina propia.
This epithelium undergoes hormone-related cyclical changes including slight keratinization of the superficial cells during the menstrual cycle. Deep in the epithelium lies the smooth muscles of the muscularis. There is a deeper surrounding fibrous layer above the muscularis which provides structural support to the vagina and is rich is collagen and elastin to allow for expansion of the cavity.
Three sets of skeletal muscles surround the vagina including the ischiocavernosum, bulbocavernosus, transverse perinei and levator ani and pubococcygeus muscles.
Intercourse, lack of lubrication during intercourse, changes in the cervix during the menstrual cycle, and asymptomatic infections facilitate the transmission of infection to women. Prepubertal girls and adolescents are particularly vulnerable because their vaginal and cervical tissues may be less mature and are more readily penetrated by organisms e.
Postmenopausal women are more likely than younger women to get small abrasions in the vagina during sexual activity as a result of thinning of the tissue and dryness. Women who already have an infection particularly one that causes genital lesions are more likely to acquire or transmit another sexually transmitted disease STD , including HIV. Other biological risks include the use of vaginal douches, which increase the risk of pelvic inflammatory disease PID , and the influence of hormonal contraceptives on acquiring or transmitting an STD e.
These factors include the vaginal anatomy, the mucosal surface, the presence and composition of vaginal fluids and secretions, cervical fluids mucus , cyclic changes and endogenous microflora. Drug stability to enzyme activity, which is quite high in vaginal environment, and is again a function of menstrual cycle and lifecycle, should also be taken into account.
Topical drug delivery through the cervix, as needed to treat disorders of the cervix and uterus also presents a challenge.
Several types of formulations are known for delivery to the vaginal cavity. While semi-solid formulations, such as creams, lotions, gels and ointments are commonly used, they are often reported to be messy, require frequent application and can be difficult to remove after use.
Furthermore, application of topical gels and creams require several steps of operation. Solid formulations such as tablets, suppositories and pessaries also require frequent application, show a poor retention in vagina, and exhibit insufficient spreadability. It has been effectively used to treat local diseases of the anorectal area as well as an alternative to oral administration in the systemic administration of drugs.
Solid suppositories are the most common dosage form used for rectal drug administration and represent the majority of rectal dosage forms; however, creams ointments and foams are also being used. They are difficult to insert through the anal orifice; they are difficult to spread throughout the target cavity; and if spreadable, they tend to leak, causing major discomfort to the patient.
Such negative attributes lead to their very limited use. A product for intravaginal and anorectal application would ideally exhibit the following properties: The duration of the drug inside the vagina or rectum is also important for ensuring extended activity.
A quiescence agent may have more than one of these characteristics. In certain compositions a combination of two or more agents is used to achieve a quiescence foamable composition having more than one of there characteristics. It has been further found that it is possible to improve the chemical stability of the steroid or other active agent in the composition.
The emulsion foam platform is made of oily phase and water phase emulsified and stabilized with surfactants and polymers and co-stabilizers that impart better foam properties. One of the advantages, is that they can be formulated to exhibit bioadhesive properties and can be used for body cavity applications with minimal or no leakage. They are also of pleasant appearance and skin feeling and do not sting, making them suitable for delivery to sensitive areas. Also by storing them in sealed canisters with propellant, they can provide a safer medium for active agents that tend to break down upon exposure to light or air.
In other aspects, the present invention provides a steroid and a lubricating vaginal drug vehicle for moisture replenishing or moisturizing vaginal vehicles. In other aspects, the invention provides an improved delivery system for steroids alone or in combination with other active agents to other body cavities, such as the rectum, penile urethra, nasal cavity and ear cavity and to mucosal surfaces.
The compositions contain at least one active steroid agent in a biocompatible alcohol-free foamable carrier, including, oil-in-water foamable emulsions and water-in-oil foamable emulsions, liposome-based foams and nanoparticle-based foams. These compositions provide long lasting, drip-free, expandable formulations for drug delivery into body cavities. The kit includes an aerosol packaging assembly having a container accommodating a pressurized product and an outlet capable of releasing the pressurized product as a foam.
For example, an applicator ideal for intravaginal use for example to deliver a steroid hormone such as esradiol or prgestron will be of an appropriate length to facilitate delivery to the area of the uterine entrance.
In one or more embodiments, the foam adjuvant includes fatty alcohols having 15 or more carbons in their carbon chain, fatty acids having 16 or more carbons in their carbon chain, and combinations or mixtures thereof. A further class of foam adjuvant agent includes a branched fatty alcohol or fatty acid. The carbon chain of the fatty acid or fatty alcohol also can be substituted with a hydroxyl group, such as hydroxy stearic acid.
Mary's thistle, ginkgo biloba , saw palmetto, panax , siberian ginseng, foeniculum vulgare, cimicifuga racemosa , licorice root, red clover, sage, sarsaparilla, sassafras, angelica sinensis achillea millefolium, anemone pratensis, angelica sinensis, glycyrrhiza glabra, hypericum perforatum, larrea, panax, piscidia erythrina, plantago psyllium , serenoa repens, symphytum, taraxacum officinale, trifolium pratense , turnera spp.
In one or more embodiments the composition is physically and chemically stable within acceptable pharmaceutical limits for a foamable composition for about six months, for about a year or for about 2 years. Thus, there is also provided according to specific embodiments a foamable carrier composition containing an active agent without steroid.
In one embodiment the active agent is coal tar or a coal tar extract. In some embodiments, the API is stable or is stabilized in the presence of at least one quiescence agent. In some embodiments, the API and at least one quiescence agent function synergistically to achieve improved chemical or physical characteristics for the composition. In some embodiments, the API demonstrates improved characteristics when combined with at least one quiescence agent.
In some embodiments, the improved chemical or physical characteristics is improved stability over time, whether chemical or physical stability. In some embodiments, the improved chemical or physical characteristics include, without limitation, one or more of the following properties: Moreover, in some embodiments, the improved chemical or physical characteristics are demonstrated under various storage conditions e. In some embodiments, the compositions demonstrate improvement in at least one property.
In some embodiments, the compositions demonstrate improvement at least in two properties. In some embodiments, the compositions demonstrate improvement in at least three properties. In some embodiments, the compositions demonstrate improvement in at least four properties.
In some embodiments, the compositions demonstrate improvement in at least five properties. In some embodiments, the compositions demonstrate improvement in at least six properties. In some embodiments, the compositions demonstrate improvement in at least seven properties. In some embodiments, the compositions demonstrate improvement in at least eight properties.
In some embodiments, the compositions demonstrate improvement in at least nine properties. In some embodiments, the compositions demonstrate improvement in at least ten properties. In some embodiments, the compositions demonstrate improvement in at least eleven properties. In some embodiments, the compositions demonstrate improvement in at least twelve properties.