Minocycline for treating inflammatory skin conditions

Abstract

To provide minocycline for treating inflammatory skin conditions.SOLUTION: The present application relates to a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein said administration results in an effective plasma or interstitial fluid concentration of minocycline to treat the inflammatory skin condition. The present application provides a method of treating an inflammatory skin condition, such as rosacea, by administering a pharmaceutical composition comprising a reduced dose of minocycline to provide an effective treatment for said inflammatory skin condition.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application claims priority to Indian Patent Application No. 201741023993, filed on January 7, 2018, the entire disclosure of which is incorporated herein by this reference.

[0002] Technical Field The present application relates to a method of treating an inflammatory skin condition by administering a pharmaceutical composition comprising a reduced dose of minocycline to a subject in need thereof, wherein said administration results in an effective plasma or interstitial fluid concentration of minocycline for treating said inflammatory skin condition. [Background technology]

[0003] Inflammatory skin conditions are those in which inflammatory cells (e.g., polymorphonuclear neutrophils and lymphocytes) infiltrate the skin without an apparent or known infectious etiology. Symptoms of inflammatory skin conditions generally include erythema (redness), edema (swelling), pain, itching, elevated surface temperature, and loss of function.

[0004] Rosacea is a type of inflammatory skin disorder characterized by inflammatory lesions that may resemble the papules and pustules ("acne-like" lesions) of acne vulgaris. It is a disorder of the skin's surface vasculature that results in erythema, prominent flushing, and telangiectasia. It occurs primarily in middle-aged and middle-aged individuals and is virtually absent in adolescents or young adults. Overall, rosacea is a type of inflammation that manifests as a rash, similar to other eruptions / pimples, causing areas of red, irritated, and inflamed skin. Such rashes are caused by irritation, allergies, infections, underlying diseases, and structural defects of the skin, including blocked pores or malfunctioning sebaceous glands. Over time, individuals with rosacea often develop persistent redness in the center of their face. Symptoms associated with rosacea include papules, pustules, blackheads, whiteheads, or milia, nodules, and cysts.

[0005] Although some people will have symptoms from more than one type at a time, there are actually four different types of rosacea. The four types of rosacea are: 1. Erythematotelangiectatic rosacea: redness, flushing, visible blood vessels, 2. Papulopustular rosacea: redness, swelling and acne-like pimples 3. Proliferative rosacea: thickened skin with uneven structure, redness and various symptoms from other subtypes; 4. Ocular rosacea: The eyes may be red and sensitive, the eyelids may be swollen, and the person may have an eye that looks like a stye.

[0006] Examples include, but are not limited to, facial pyoderma (also known as rosacea fulminans), rosacea conglobate, or phymatous rosacea. There are several subtypes of rosacea that are not well defined.

[0007] Thus, a rosacea-related disorder is any disorder that may occur in parallel with or be a contributing factor to the development of rosacea, or that may resemble rosacea. Perioral dermatitis is an erythematous, papulopustular facial rash that resembles rosacea and / or acne, but typically begins around the nose.

[0008] Rosacea is a chronic inflammatory disorder characterized by facial flushing, telangiectasia, erythema, papules, pustules, and in severe cases, rhinophyma. Rosacea is associated with elevated levels of cathelicidin or elevated levels of stratum corneum tryptic enzyme (SCTE). Rosacea includes any of the known types or subtypes classified in the art.

[0009] Acne is another such inflammatory skin disorder characterized by various types of lesions.The lesions associated with acne are usually classified as either non-inflammatory or inflammatory.The spectrum of acne lesions ranges from non-inflammatory open or closed comedones; the mild inflammatory acne lesions with comedones and a few papules and pustules; the moderate inflammatory acne lesions with comedones, a few papules and pustules and a few nodules; or the severe inflammatory acne lesions with comedones, a few papules and pustules, multiple nodules and scarring.

[0010] There are a variety of treatment options available for inflammatory skin conditions such as rosacea, which is treated with a variety of topical and / or oral therapies, including topical and oral antibiotics, sodium sulfacetamide, and metronidazole.

[0011] Topical azelaic acid is an alternative to topical antibiotics for treating mild to moderate plaque. However, some people have found that it can cause side effects such as burning, stinging, itching, scaling, and dry skin.

[0012] If antibiotics are ineffective or not well tolerated, oral isotretinoin may be effective; however, it has various side effects and may not be suitable for everyone. Ivermectin cream is sometimes used for people with rosacea. It works by killing the mite Demodex folliculorum and also reduces some of the skin inflammation. Brimonidine gel is used to treat facial redness. It causes short-term vasoconstriction but has no effect on telangiectasia. Certain medications, such as clonidine (an alpha-2 receptor agonist), can reduce vasodilation (widening of blood vessels) that leads to flushing. Oral nonsteroidal anti-inflammatory drugs, such as diclofenac, can reduce discomfort and redness in affected skin. Calcineurin inhibitors, such as tacrolimus ointment and pimecrolimus cream, have been reported to help some patients with rosacea. Aside from drug treatments, persistent telangiectasia has been shown to improve with surgical procedures, such as laser or intense pulsed light treatment of blood vessels. Papulopustular rosacea may also improve with laser treatment or radiofrequency. Other treatments such as cauterization, diathermy (electrosurgery), or sclerotherapy (strong saline injections) may also be useful. Nutritional supplements that target flushing, facial redness, and inflammation may be beneficial.

[0013] Among the various available treatment options, oral antibiotics such as doxycycline are preferred, as they significantly reduce inflammation. They reduce redness, papules, pustules, and the ocular symptoms of rosacea. Antibiotics are usually prescribed for 6 to 16 weeks, the duration depending on the severity of the rosacea. If antibiotics do not cure the lesion, further treatment is often required. In resistant cases, other oral antibiotics such as cotrimoxazole or metronidazole may be prescribed. The anti-inflammatory effects of antibiotics are under investigation and have been shown to inhibit matrix metalloproteinase function, subsequently reducing cathelicidin and inflammation.

[0014] Currently, in the United States, oral doxycycline is sold by Galderma Laboratories as a once-daily 40 mg capsule under the trade name ORACEA®, which was approved by the US FDA in 2006. ORACEA® is indicated only for the treatment of inflammatory lesions (papules and pustules) of rosacea in adults. However, ORACEA® is known to have side effects related to esophageal irritation and ulceration, which can be quite distressing for patients.

[0015] MINOCIN® is a capsule containing 50 mg, 75 mg, or 100 mg of minocycline and is approved for the treatment of a variety of infections caused by susceptible strains.

[0016] The use of minocycline at higher intensities is associated with adverse events related to vestibular control disorders, such as spatial disorientation, loss of coordination, or lightheadedness. A clear void exists in the area of ​​safe, commercially approved minocycline dosage forms for the treatment of inflammatory skin conditions, such as rosacea. Furthermore, there are no approved dosage forms of minocycline available for treating inflammatory skin conditions, such as rosacea.

[0017] There is a clear unmet need in the art to provide alternatives for the treatment of inflammatory skin conditions that increase the chances that a greater number of individuals will achieve effective treatment. In this regard, there is a need for methods of providing effective doses of minocycline for the treatment of inflammatory skin conditions that maximize therapeutic benefit while managing adverse effects.

[0018] In other words, there is a need to provide a minocycline dosage form for better compliance in treating inflammatory skin conditions that minimizes fluctuations or variability between peak and trough plasma or interstitial fluid levels of minocycline, thereby reducing side effects.

[0019] It is well known in the art that peak-to-trough fluctuations in drug concentrations critically affect clinical response, tolerability and ultimately the selection of the appropriate drug and dosage form required for the treatment of inflammatory skin conditions. Summary of the Invention [Problem to be solved by the invention]

[0020] Accordingly, the present application relates to a method of treating inflammatory skin conditions, such as rosacea, by administering a pharmaceutical composition comprising a reduced dose of minocycline, comprising a therapeutically effective amount of minocycline, to provide a desired plasma and / or interstitial fluid concentration of minocycline for treating said inflammatory skin condition. [Means for solving the problem]

[0021] The present application provides methods of treating inflammatory skin conditions, such as rosacea, by administering a pharmaceutical composition comprising a reduced dose of minocycline to provide an effective treatment for said inflammatory skin conditions.

[0022] The present application provides methods of treating inflammatory skin conditions, such as acne, by administering a pharmaceutical composition comprising a reduced dose of minocycline to provide an effective treatment for said inflammatory skin conditions.

[0023] The present application also provides a weight-independent dosing regimen for minocycline in a preferred pharmaceutical dosage form that includes a reduced dose of minocycline compared to other minocycline compositions for treating inflammatory skin conditions.

[0024] overview In one embodiment, the present application relates to a method of treating an inflammatory skin condition by administering a composition comprising a reduced dose of minocycline.

[0025] In one aspect, the present application relates to a method of treating an inflammatory skin condition selected from, but not limited to, rosacea, acne, atopic dermatitis, folliculitis, perioral dermatitis, photodamage, actinic keratosis, psoriasis, treatment of chronic wounds, bedsores, keratosis pilaris, surgical scars, acne scars, sebaceous cysts, inflammatory skin diseases, post-inflammatory hyperpigmentation, xerosis, pruritis, lichen planus, prurigo nodularis, eczema, and miliaria.

[0026] In another embodiment, the present application relates to a method of treating rosacea by administering a pharmaceutical composition comprising a reduced dose of minocycline.

[0027] In yet another embodiment, the present application relates to a method of treating acne by administering a pharmaceutical composition comprising a reduced dose of minocycline.

[0028] In another aspect of the above embodiment, the pharmaceutical composition of the present application comprises about 10 mg to 40 mg of minocycline.

[0029] In another embodiment, the present application relates to a method of treating an inflammatory skin condition by administering a pharmaceutical composition comprising an equivalent or reduced dose of minocycline compared to an oral doxycycline composition containing 40 mg of doxycycline.

[0030] In another embodiment, the present application relates to a method of treating rosacea by administering a pharmaceutical composition comprising an equivalent or reduced dose of minocycline compared to an oral doxycycline composition containing 40 mg of doxycycline.

[0031] In another embodiment, the present application relates to a method of treating acne by administering a pharmaceutical composition comprising an equivalent or reduced dose of minocycline compared to an oral doxycycline composition containing 40 mg of doxycycline.

[0032] In another aspect of the above embodiment, the present application relates to a method of treating an inflammatory skin condition by administering to a subject in need thereof an oral pharmaceutical composition comprising about 10 mg to 40 mg of minocycline, wherein said administration results in equivalent or improved efficacy compared to an oral doxycycline composition comprising 40 mg of doxycycline.

[0033] In another aspect of the above embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof an oral pharmaceutical composition comprising about 10 mg to 40 mg of minocycline, wherein said administration results in equivalent or improved efficacy compared to an oral doxycycline composition comprising 40 mg of doxycycline.

[0034] In certain embodiments, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject for whom treatment with an oral doxycycline composition comprising 40 mg of doxycycline is effective or ineffective, and administering an oral pharmaceutical composition comprising an equivalent or reduced dose of minocycline.

[0035] In another embodiment, the present application provides a method of treating rosacea in a subject in need thereof, comprising: (a) selecting a subject for whom treatment with an oral doxycycline composition containing 40 mg of doxycycline is ineffective, and administering an oral pharmaceutical composition containing an equivalent or reduced dose of minocycline; or (b) selecting a subject who would benefit from treatment with an oral doxycycline composition containing 40 mg of doxycycline, and administering an oral pharmaceutical composition containing a reduced dose of minocycline.

[0036] In some aspects of the above embodiments, the compositions of the present application comprise about 10 mg, about 20 mg, about 30 mg, or about 40 mg of minocycline.

[0037] In another aspect of the above embodiments, the method of treating rosacea reduces the severity of the rosacea compared to the severity of the rosacea before treatment as assessed using the Investigator's Global Assessment (IGA) scale.

[0038] In another aspect of the above embodiment, the method results in improved efficacy in at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of subjects as assessed by IGA score compared to pre-treatment IGA score.

[0039] In another aspect of the above embodiment, the method reduces the IGA score by at least about 25%, about 50%, about 75%, or about 100% when compared to the IGA score after administration of an oral doxycycline composition containing 40 mg of doxycycline.

[0040] In another aspect of the above embodiment, the method significantly reduces the number of inflammatory lesions compared to the number of inflammatory lesions before treatment.

[0041] In another aspect of the above embodiment, the method reduces the number of inflammatory lesions in the subject by at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90%, 95%, or 100% compared to the number of inflammatory lesions before treatment.

[0042] In another aspect of the above embodiment, the method reduces the number of inflammatory lesions by at least about 15%, about 30%, about 50%, or about 75% compared to the number of inflammatory lesions after administration of an oral doxycycline composition containing 40 mg of doxycycline.

[0043] In another aspect of the above embodiment, the compositions of the present application provide a maximum plasma concentration (C) of minocycline of about 500 ng / ml or less upon oral administration for about 3 weeks or less. maxSSP ) is shown.

[0044] In another aspect of the above embodiment, the compositions of the present application provide a plasma fluctuation index (FI) of about 0.9 to about 1.3 upon oral administration for about 3 weeks or less. SSP ) is shown.

[0045] In another aspect of the above embodiment, the compositions of the present application, upon oral administration for about three weeks or less, result in a plasma fluctuation index (FI) that is at least about 30% lower compared to oral administration of a doxycycline composition containing 40 mg of doxycycline. SSP )[(C maxSSP -C minSSP ) / C avgSSP ] is shown.

[0046] In another aspect of the above embodiment, the compositions of the present application, upon oral administration for about 3 weeks or less, result in a maximum plasma concentration (C) that is at least about 10% lower compared to oral administration of a doxycycline composition containing 40 mg of doxycycline. maxSSP ) is shown.

[0047] In another aspect of the above embodiment, the compositions of the present application, upon oral administration for about 3 weeks or less, produce a maximum plasma concentration (C) of 40 mg of doxycycline compared to oral administration of a doxycycline composition containing 40 mg of doxycycline. maxSSP ) shows a decrease of at least about 10% in the coefficient of variation (CV%).

[0048] In another aspect of the above embodiment, the compositions of the present application, when administered orally for about 3 weeks or less, result in a decrease in plasma minocycline exposure (AUC 0-tSSP ) shows a decrease of at least about 10% in the coefficient of variation (CV%).

[0049] In another aspect of the above embodiment, the compositions of the present application, upon oral administration for about 3 weeks or less, result in a plasma concentration ratio (C) that is at least about 30% lower than that of a doxycycline composition containing 40 mg of doxycycline.maxSSP :C maxP ) is shown.

[0050] In another aspect of the above embodiment, the compositions of the present application provide a plasma concentration ratio (C) of at least about 0.9 upon oral administration for about 3 weeks or less. maxSSP :C maxP ) is shown.

[0051] In another aspect of the above embodiment, the compositions of the present application, upon oral administration for about 3 weeks or less, result in a mean plasma concentration (C) of doxycycline that is at least about 20% lower compared to oral administration of a doxycycline composition containing 40 mg of doxycycline. avgSSP ) is shown.

[0052] In another aspect of the above embodiment, the compositions of the present application, upon oral administration for about three weeks or less, provide a ratio of minocycline exposure in interstitial fluid to plasma (AUC 0-tSSIF / AUC 0-tSSP ) is shown.

[0053] In another aspect of the above embodiment, the compositions of the present application, upon oral administration for about three weeks or less, provide a ratio of minocycline exposure in interstitial fluid to plasma (AUC 0-tSSIF / AUC 0-tSSP ) ratio.

[0054] In another aspect of the above embodiment, the compositions of the present application comprising a dose of about 10 mg to about 40 mg of minocycline, upon oral administration over a period of about 3 weeks or less, exhibit the following pharmacokinetic parameters as measured in plasma samples: (a) C of about 5 ng / ml / mg to about 12 ng / ml / mg maxSSP / D, or (b) AUC of about 60 ng / ml / mg to about 114 ng / ml / mg 0-tSSP / D.

[0055] In another aspect of the above embodiment, the compositions of the present application comprising a dose of minocycline of about 10 mg to about 40 mg, upon oral administration, exhibit the following pharmacokinetic parameters as measured in interstitial fluid samples: (a) C of about 1.8 ng / ml / mg to about 3 ng / ml / mg maxIF / D, or (b) AUC of about 25 ng / ml / mg to about 40 ng / ml / mg 0-tIF / D At least one of the following is shown.

[0056] In certain embodiments, the present application relates to a method of treating rosacea, comprising administering to a subject in need thereof a pharmaceutical composition comprising about 10 mg to about 40 mg of minocycline.

[0057] In certain aspects of the above embodiments, the pharmaceutical compositions of the present application are administered once daily.

[0058] In certain aspects of the above embodiments, the pharmaceutical compositions of the present application are administered twice daily.

[0059] In another aspect of the above embodiment, the pharmaceutical compositions of the present application are with or without food.

[0060] In another aspect of the above embodiment, the pharmaceutical composition of the present application is prepared in the form of an oral tablet, capsule, pill, mini-tablet, pellet, granule, powder, suspension or syrup.

[0061] In certain embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof an oral pharmaceutical composition comprising a reduced dose of minocycline, the method providing a weight-independent dosing regimen for minocycline.

[0062] In one embodiment, the present application relates to a method for preparing an oral pharmaceutical composition for treating an inflammatory skin condition in a subject in need thereof. In one embodiment, the method includes selecting and providing minocycline in a composition at an equivalent or reduced dose of minocycline compared to an oral doxycycline composition containing 40 mg of doxycycline. In one embodiment, the composition provides equivalent or improved efficacy compared to an oral doxycycline composition containing 40 mg of doxycycline. In certain embodiments, for example, the following are provided: (Item 1) 1. A method of treating an inflammatory skin condition in a subject in need thereof, comprising selecting and administering an oral pharmaceutical composition comprising an equivalent or reduced dose of minocycline compared to an oral doxycycline composition comprising 40 mg of doxycycline. (Item 2) 10. The method of claim 1, wherein the administration results in equivalent or improved efficacy compared to administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 3) Item 1. The method according to item 1, wherein the composition comprises about 10 mg to about 40 mg of minocycline. (Item 4) 10. The method of claim 1, wherein the composition comprises about 10 mg of minocycline. (Item 5) 10. The method of claim 1, wherein the composition comprises about 20 mg of minocycline. (Item 6) 10. The method of claim 1, wherein the composition comprises about 30 mg of minocycline. (Item 7) 10. The method of claim 1, wherein the composition comprises about 40 mg of minocycline. (Item 8) Item 1. The method according to item 1, wherein the inflammatory skin condition is selected from the group consisting of rosacea, acne, atopic dermatitis, folliculitis, perioral dermatitis, photodamage, actinic keratosis, psoriasis, chronic wound treatment, bedsores, keratosis pilaris, surgical scars, acne scars, sebaceous cysts, inflammatory skin diseases, post-inflammatory hyperpigmentation, xerosis, pruritus, lichen planus, prurigo nodularis, eczema, and miliaria. (Item 9) 9. The method of claim 8, wherein the inflammatory skin condition is rosacea. (Item 10) Item 10. The method of item 9, wherein the rosacea is selected from the group consisting of papulopustular rosacea, erythematotelangiectatic rosacea, nodular rosacea, ocular rosacea, acne rosacea, facial pyoderma, conglobata rosacea, mild rosacea, moderate rosacea, severe rosacea, mild to moderate rosacea, and moderate to severe rosacea. (Item 11) Item 10. The method of item 9, wherein the rosacea is characterized by inflammatory lesions. (Item 12) 10. The method of claim 9, wherein the rosacea is characterized by papules, pustules and / or nodules. (Item 13) 2. The method of claim 1, wherein the administration reduces the severity of rosacea compared to the severity of rosacea before the treatment as assessed using the Investigator Global Assessment (IGA) scale. (Item 14) 2. The method of item 1, wherein the administration reduces the IGA score by at least one grade compared to the IGA score before the treatment. (Item 15) 10. The method of claim 1, wherein the administration results in improved efficacy in at least about 15% of subjects as assessed by the IGA score compared to the IGA score before the treatment. (Item 16) 10. The method of claim 1, wherein the administration reduces the IGA score to a similar or greater extent compared to administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 17) The method according to item 5, wherein the administration reduces the IGA score to the same or a higher level compared to the administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 18) The method according to item 7, wherein the administration reduces the IGA score by at least about 25% compared to the IGA score after administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 19) The method according to item 1, wherein the administration reduces the severity of rosacea compared to the severity of rosacea before treatment when evaluated by counting the number of inflammatory lesions. (Item 20) The method according to item 1, wherein the administration reduces the number of inflammatory lesions compared to the number of inflammatory lesions before treatment. (Item 21) The method according to item 1, wherein the administration reduces the number of inflammatory lesions of the subject by at least about 15% compared to the number of inflammatory lesions of the subject before treatment. (Item 22) The method according to item 1, wherein the administration reduces the number of inflammatory lesions to the same or a higher level compared to the administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 23) The method according to item 5, wherein the administration reduces the number of inflammatory lesions to the same or a higher level compared to the administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 24) The method according to item 7, wherein the administration reduces the number of inflammatory lesions by at least about 15% compared to the number of inflammatory lesions after administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 25) The method according to item 1, wherein the composition exhibits a maximum plasma concentration (C maxSSP ) of minocycline of about 500 ng / ml or less by oral administration over about 3 weeks or less. (Item 26) The composition, when administered orally for about three weeks or less, results in a plasma fluctuation index (FI) that is at least about 30% lower than that of a doxycycline composition containing 40 mg of doxycycline. SSP )[(C maxSSP -C minSSP ) / C avgSSP Item 7. The method according to item 7, wherein (Item 27) The composition has a plasma fluctuation index (FI) of about 0.9 to about 1.3 after oral administration for about 3 weeks or less. SSP Item 1, the method according to item 1. (Item 28) The composition, upon oral administration for about three weeks or less, results in a maximum plasma concentration (C) that is at least about 10% lower than that of a doxycycline composition containing 40 mg of doxycycline. maxSSP Item 7. The method according to item 7, wherein (Item 29) The composition, when administered orally for about three weeks or less, produces a maximum plasma concentration (C) of 40 mg of doxycycline compared to oral administration of a doxycycline composition containing 40 mg of doxycycline. maxSSP 8. The method of claim 7, wherein the coefficient of variation (CV%) of the (Item 30) The composition, when administered orally for about 3 weeks or less, results in plasma minocycline exposure (AUC 0-tSSP 8. The method of claim 7, wherein the coefficient of variation (CV%) of the (Item 31) The composition, upon oral administration for about three weeks or less, provides a plasma concentration ratio (C) that is at least about 30% lower than that of a doxycycline composition containing 40 mg of doxycycline. maxSSP :C maxP Item 7. The method according to item 7, wherein (Item 32) The composition has a plasma concentration ratio (C) of at least about 0.9 upon oral administration for about three weeks or less.maxSSP : C maxP ) The method according to item 1, showing (Item 33) When the composition is administered orally over about 3 weeks or less, the average plasma concentration (C) is at least about 20% lower compared to the oral administration of a doxycycline composition containing 40 mg of doxycycline avgSSP ) The method according to item 7, showing (Item 34) When the composition is administered orally over about 3 weeks or less, the ratio of minocycline exposure in interstitial fluid to plasma (AUC 0-tSSIF / AUC 0-tSSP ) is at least about 10% higher compared to the oral administration of a doxycycline composition containing 40 mg of doxycycline. The method according to item 5, showing (Item 35) When the composition is administered orally over about 3 weeks or less, the ratio of minocycline exposure in interstitial fluid to plasma (AUC 0-tSSIF / AUC 0-tSSP ) is at least about 10% higher compared to the oral administration of a doxycycline composition containing 40 mg of doxycycline. The method according to item 7, showing (Item 36) The composition contains about 10 mg to about 40 mg of minocycline and, when administered orally over about 3 weeks or less, the following pharmacokinetic parameters when measured in plasma samples: (a) C of about 5 ng / ml / mg to about 12 ng / ml / mg maxSSP / D, and (b) AUC of about 60 ng / ml / mg to about 114 ng / ml / mg 0-tSSP / D, showing at least one of them. The method according to item 1, showing (Item 37) The composition contains about 10 mg to about 40 mg of minocycline and, when measured in interstitial fluid samples by oral administration, the following pharmacokinetic parameters: (a) C of about 1.8 ng / ml / mg to about 3 ng / ml / mg maxIF / D, and (b) AUC of about 25 ng / ml / mg to about 40 ng / ml / mg 0-tIF / D Item 1, the method according to item 1, wherein the method further comprises at least one of the following: (Item 38) 2. The method according to item 1, wherein the composition is in the form of a tablet, capsule, pill, mini-tablet, pellet, granule, dust, suspension or syrup. (Item 39) 10. The method of claim 1, wherein the composition is administered once or twice daily. (Item 40) 10. The method of claim 1, wherein the composition is administered with or without food. (Item 41) 1. A method of treating an inflammatory skin condition in a subject in need thereof, comprising: (a) selecting said subject for whom treatment with an oral doxycycline composition containing 40 mg of doxycycline is ineffective, and administering an oral pharmaceutical composition containing an equivalent or reduced dose of minocycline; or (d) selecting said subject for whom treatment with an oral doxycycline composition containing 40 mg of doxycycline would be beneficial, and administering an oral pharmaceutical composition containing a reduced dose of minocycline. A method comprising: (Item 42) 42. The method of claim 41, wherein the composition comprises about 10 mg to about 40 mg of minocycline. (Item 43) 42. The method of claim 41, wherein the composition comprises about 10 mg of minocycline. (Item 44) 42. The method of claim 41, wherein the composition comprises about 20 mg of minocycline. (Item 45) 42. The method of claim 41, wherein the composition comprises about 30 mg of minocycline. (Item 46) 42. The method of claim 41, wherein the composition comprises about 40 mg of minocycline. (Item 47) 42. The method of claim 41, wherein the inflammatory skin condition is selected from the group consisting of rosacea, acne, atopic dermatitis, folliculitis, perioral dermatitis, photodamage, actinic keratosis, psoriasis, treatment of chronic wounds, bedsores, keratosis pilaris, surgical scars, acne scars, sebaceous cysts, inflammatory skin diseases, post-inflammatory hyperpigmentation, xerosis, pruritus, lichen planus, prurigo nodularis, eczema, and miliaria. (Item 48) Item 48. The method of item 47, wherein the inflammatory skin condition is rosacea. (Item 49) Item 49. The method of item 48, wherein the rosacea is selected from the group consisting of papulopustular rosacea, erythematotelangiectatic rosacea, nodular rosacea, ocular rosacea, acne rosacea, facial pyoderma, confluent rosacea, mild rosacea, moderate rosacea, severe rosacea, mild to moderate rosacea, and moderate to severe rosacea. (Item 50) Item 49. The method of item 48, wherein the rosacea is characterized by inflammatory lesions. (Item 51) Item 49. The method of item 48, wherein the rosacea is characterized by papules, pustules and / or nodules. (Item 52) 42. The method of claim 41, wherein the administration reduces the severity of the rosacea compared to the severity of the rosacea before the treatment as assessed using the IGA scale. (Item 53) 42. The method of claim 41, wherein the administration reduces the IGA score by at least one grade compared to the IGA score before the treatment. (Item 54) 42. The method of claim 41, wherein the administration results in improved efficacy in at least about 15% of the subjects as assessed by the IGA score, compared to the IGA score before the treatment. (Item 55) 42. The method of claim 41, wherein the administration reduces the IGA score to a similar or greater extent compared to administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 56) 45. The method of claim 44, wherein the administration reduces the IGA score to a similar or greater extent compared to administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 57) 47. The method of claim 46, wherein said administering reduces the subject's IGA score by at least about 25% compared to the IGA score after administration of an oral doxycycline composition comprising 40 mg of doxycycline. (Item 58) 42. The method of claim 41, wherein the administration reduces the severity of the rosacea compared to the severity of the rosacea before the treatment, as assessed by counting the number of inflammatory lesions. (Item 59) 42. The method of claim 41, wherein said administering reduces the number of inflammatory lesions compared to the number of inflammatory lesions before said treatment. (Item 60) 42. The method of claim 41, wherein said administering reduces the number of inflammatory lesions in said subject by at least about 15% compared to the number of inflammatory lesions before said treatment. (Item 61) 42. The method of claim 41, wherein said administering reduces the number of inflammatory lesions by an amount equal to or greater than the reduction in the number of inflammatory lesions following administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 62) 45. The method of claim 44, wherein said administering reduces the number of inflammatory lesions by an amount equal to or greater than the reduction in the number of inflammatory lesions following administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 63) 47. The method of claim 46, wherein the administering reduces the number of inflammatory lesions by at least about 15% compared to the number of inflammatory lesions after administration of an oral doxycycline composition comprising 40 mg of doxycycline. (Item 64) The composition provides a maximum plasma concentration (C) of minocycline of about 500 ng / ml or less upon oral administration for about three weeks or less. maxSSP Item 42. The method according to Item 41, wherein (Item 65) The composition has a plasma fluctuation index (FI) of about 0.9 to about 1.3 after oral administration for about 3 weeks or less. SSP Item 42. The method according to Item 41, wherein (Item 66) The composition, when administered orally for about three weeks or less, results in a plasma fluctuation index (FI) that is at least about 30% lower than that of a doxycycline composition containing 40 mg of doxycycline. SSP )[(C maxSSP -C minSSP ) / C avgSSP Item 47. The method according to Item 46, wherein (Item 67) The composition, upon oral administration for about three weeks or less, results in a maximum plasma concentration (C) that is at least about 10% lower than that of a doxycycline composition containing 40 mg of doxycycline. maxSSP Item 47. The method according to Item 46, wherein (Item 68) The composition, when administered orally for about three weeks or less, produces a maximum plasma concentration (C) of 40 mg of doxycycline compared to oral administration of a doxycycline composition containing 40 mg of doxycycline. maxSSP 47. The method of claim 46, wherein the coefficient of variation (CV%) of the (Item 69) The composition, when administered orally for about 3 weeks or less, results in plasma minocycline exposure (AUC 0-tSSP 47. The method of claim 46, wherein the coefficient of variation (CV%) of the (Item 70) The composition, upon oral administration for about three weeks or less, provides a plasma concentration ratio (C) that is at least about 30% lower than that of a doxycycline composition containing 40 mg of doxycycline. maxSSP :C maxP Item 47. The method according to Item 46, wherein (Item 71) The composition has a plasma concentration ratio (C) of at least about 0.9 upon oral administration for about three weeks or less. maxSSP :C maxP Item 42. The method according to Item 41, wherein (Item 72) The composition, upon oral administration for at least three weeks, results in a mean plasma concentration (C) of doxycycline that is at least about 20% lower than that of a doxycycline composition containing 40 mg of doxycycline. avgSSP Item 47. The method according to Item 46, wherein (Item 73) The composition, upon oral administration for about 3 weeks or less, exhibits a ratio of minocycline exposure in interstitial fluid to plasma (AUC ) that is at least about 10% higher compared to oral administration of a doxycycline composition containing 40 mg of doxycycline. 0-tSSIF / AUC 0-tSSP Item 45. The method according to Item 44, wherein (Item 74) The composition, upon oral administration for about 3 weeks or less, exhibits a ratio of minocycline exposure in interstitial fluid to plasma (AUC ) that is at least about 10% higher compared to oral administration of a doxycycline composition containing 40 mg of doxycycline. 0-tSSIF / AUC 0-tSSP Item 47. The method according to Item 46, wherein (Item 75) The composition comprises about 10 mg to about 40 mg of minocycline and upon oral administration over a period of about 3 weeks or less, exhibits the following pharmacokinetic parameters when measured in plasma samples: (a) C of about 5 ng / ml / mg to about 12 ng / ml / mg maxSSP / D, and (b) AUC of about 60 ng / ml / mg to about 114 ng / ml / mg 0-tSSP Item 42. The method of item 41, wherein the compound is selected from the group consisting of methyl, ... (Item 76) The composition contains about 10 mg to about 40 mg of minocycline and, upon oral administration, exhibits the following pharmacokinetic parameters when measured in interstitial fluid samples: (a) C of about 1.8 ng / ml / mg to about 3 ng / ml / mgmaxIF / D, and (b) AUC of about 25 ng / ml / mg to about 40 ng / ml / mg 0-tIF / D Item 42. The method according to item 41, wherein the method comprises at least one of the following: (Item 77) 42. The method according to item 41, wherein the composition is in the form of a tablet, capsule, pill, mini-tablet, pellet, granule, dust, suspension or syrup. (Item 78) 42. The method of claim 41, wherein the composition is administered once or twice daily. (Item 79) 42. The method of claim 41, wherein the composition is administered with or without food. (Item 80) 1. A method for preparing an oral pharmaceutical composition for treating an inflammatory skin condition in a subject in need thereof, comprising selecting and providing minocycline in the composition at an equivalent or reduced dose compared to an oral doxycycline composition comprising 40 mg of doxycycline, wherein the composition provides equivalent or improved efficacy compared to the oral doxycycline composition comprising 40 mg of doxycycline. (Item 81) 81. The method of claim 80, wherein the composition comprises about 10 mg to about 40 mg of minocycline. (Item 82) 81. The method of claim 80, wherein the composition comprises about 10 mg of minocycline. (Item 83) 81. The method of claim 80, wherein the composition comprises about 20 mg of minocycline. (Item 84) 81. The method of claim 80, wherein the composition comprises about 30 mg of minocycline. (Item 85) 81. The method of claim 80, wherein the composition comprises about 40 mg of minocycline. (Item 86) 81. The method of item 80, wherein the inflammatory skin condition is selected from the group consisting of rosacea, acne, atopic dermatitis, folliculitis, perioral dermatitis, photodamage, actinic keratosis, psoriasis, treatment of chronic wounds, bedsores, keratosis pilaris, surgical scars, acne scars, sebaceous cysts, inflammatory skin diseases, post-inflammatory hyperpigmentation, xerosis, pruritus, lichen planus, prurigo nodularis, eczema, and miliaria. (Item 87) Item 87. The method of item 86, wherein the inflammatory skin condition is rosacea. (Item 88) Item 88. The method of item 87, wherein the rosacea is selected from the group consisting of papulopustular rosacea, erythematotelangiectatic rosacea, nodular rosacea, ocular rosacea, acne rosacea, facial pyoderma, confluent rosacea, mild rosacea, moderate rosacea, severe rosacea, mild to moderate rosacea, and moderate to severe rosacea. (Item 89) Item 88. The method of item 87, wherein the rosacea is characterized by inflammatory lesions. (Item 90) Item 88. The method of item 87, wherein the rosacea is characterized by papules, pustules and / or nodules. (Item 91) 81. The method of claim 80, wherein the administration reduces the severity of rosacea compared to the severity of rosacea before the treatment as assessed using the IGA scale. (Item 92) 81. The method of item 80, wherein the administration reduces the IGA score by at least one grade compared to the IGA score before the treatment. (Item 93) 81. The method of item 80, wherein the administration results in improved efficacy in at least about 15% of the subjects as assessed by the IGA score, compared to the IGA score before the treatment. (Item 94) 81. The method of claim 80, wherein the administration reduces the IGA score to a similar or greater extent compared to administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 95) 84. The method of claim 83, wherein the administration reduces the IGA score to a similar or greater extent compared to administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 96) 86. The method of claim 85, wherein said administering reduces the subject's IGA score by at least about 25% compared to the IGA score after administration of an oral doxycycline composition comprising 40 mg of doxycycline. (Item 97) 81. The method of claim 80, wherein the administration reduces the severity of rosacea compared to the severity of rosacea before the treatment, as assessed by counting the number of inflammatory lesions. (Item 98) 81. The method of claim 80, wherein said administering reduces the number of inflammatory lesions compared to the number of inflammatory lesions before said treatment. (Item 99) 81. The method of claim 80, wherein said administering reduces the number of inflammatory lesions in said subject by at least about 15% compared to the number of inflammatory lesions before said treatment. (Item 100) 81. The method of claim 80, wherein said administration reduces the number of inflammatory lesions to a similar or greater extent compared to administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 101) 84. The method of claim 83, wherein the administration reduces the number of inflammatory lesions to a similar or greater extent compared to administration of an oral doxycycline composition containing 40 mg of doxycycline. (Item 102) 86. The method of claim 85, wherein the administering reduces the number of inflammatory lesions by at least about 15% compared to the number of inflammatory lesions after administration of an oral doxycycline composition comprising 40 mg of doxycycline. (Item 103) The composition provides a maximum plasma concentration (C) of minocycline of about 500 ng / ml or less upon oral administration for about three weeks or less. maxSSP Item 80. The method according to Item 80, wherein (Item 104) The composition, when administered orally for about three weeks or less, results in a plasma fluctuation index (FI) that is at least about 30% lower than that of a doxycycline composition containing 40 mg of doxycycline. SSP )[(C maxSSP -C minSSP ) / C avgSSP Item 85. The method according to Item 85, wherein (Item 105) The composition has a plasma fluctuation index (FI) of about 0.9 to about 1.3 after oral administration for about 3 weeks or less. SSP Item 80. The method according to Item 80, wherein (Item 106) The composition, upon oral administration for about three weeks or less, results in a maximum plasma concentration (C) that is at least about 10% lower than that of a doxycycline composition containing 40 mg of doxycycline. maxSSP Item 85. The method according to Item 85, wherein (Item 107) The composition, when administered orally for about three weeks or less, produces a maximum plasma concentration (C) of 40 mg of doxycycline compared to oral administration of a doxycycline composition containing 40 mg of doxycycline. maxSSP 86. The method of claim 85, wherein the assay exhibits at least about a 10% reduction in the coefficient of variation (CV%) of the (Item 108) The composition, when administered orally for about 3 weeks or less, results in plasma minocycline exposure (AUC 0-tSSP 86. The method of claim 85, wherein the assay exhibits at least about a 10% reduction in the coefficient of variation (CV%) of the (Item 109) The composition, upon oral administration for about three weeks or less, provides a plasma concentration ratio (C) that is at least about 30% lower than that of a doxycycline composition containing 40 mg of doxycycline. maxSSP :C maxP Item 85. The method according to Item 85, wherein (Item 110) The composition has a plasma concentration ratio (C) of at least about 0.9 upon oral administration for about three weeks or less. maxSSP :C maxP Item 80. The method according to Item 80, wherein (Item 111) The composition, upon oral administration for about 3 weeks or less, results in a mean plasma concentration (C) of doxycycline that is at least about 20% lower than that of a doxycycline composition containing 40 mg of doxycycline. avgSSP Item 85. The method according to Item 85, wherein (Item 112) The composition, upon oral administration for about 3 weeks or less, exhibits a ratio of minocycline exposure in interstitial fluid to plasma (AUC ) that is at least about 10% higher compared to oral administration of a doxycycline composition containing 40 mg of doxycycline. 0-tSSIF / AUC 0-tSSP Item 84. The method according to Item 83, wherein (Item 113) The composition, upon oral administration for about 3 weeks or less, exhibits a ratio of minocycline exposure in interstitial fluid to plasma (AUC ) that is at least about 10% higher compared to oral administration of a doxycycline composition containing 40 mg of doxycycline. 0-tSSIF / AUC 0-tSSP Item 85. The method according to Item 85, wherein the ratio of (Item 114) The composition comprises about 10 mg to about 40 mg of minocycline and upon oral administration over a period of about 3 weeks or less, exhibits the following pharmacokinetic parameters when measured in plasma samples: (a) C of about 5 ng / ml / mg to about 12 ng / ml / mg maxSSP / D, and (b) AUC of about 60 ng / ml / mg to about 114 ng / ml / mg 0-tSSP Item 81. The method of item 80, wherein the method further comprises at least one of: (Item 115) The composition contains about 10 mg to about 40 mg of minocycline and, upon oral administration, exhibits the following pharmacokinetic parameters when measured in interstitial fluid samples: (a) C of about 1.8 ng / ml / mg to about 3 ng / ml / mg maxIF / D, and (b) AUC of about 25 ng / ml / mg to about 40 ng / ml / mg 0-tIF / D Item 81. The method according to item 80, wherein the method comprises at least one of the following: (Item 116) 81. The method according to item 80, wherein the composition is in the form of a tablet, capsule, pill, mini-tablet, pellet, granule, dust, suspension or syrup. (Item 117) 81. The method of claim 80, wherein the composition is administered once or twice daily. (Item 118) 81. The method of claim 80, wherein the composition is administered with or without food. [Brief explanation of the drawings]

[0063] [Figure 1] 1A and 1B show the mean plasma concentrations for ORACEA®, Example 1, and Example 3 on Days 1 and 21, respectively, when subjected to an open-label, six-cohort pharmacokinetic study.

[0064] [Figure 2] 2A and 2B show the mean interstitial fluid concentrations for ORACEA®, Example 1, and Example 3 on Days 1 and 21, respectively, when subjected to an open-label, six-cohort pharmacokinetic study.

[0065] [Figure 3] FIG. 3 shows the IGA "Treatment Success" for Example 1, Example 3, ORACEA®, and placebo when subjected to a 16-week, multicenter, randomized, double-blind, parallel-group, controlled study.

[0066] [Figure 4]FIG. 4 shows the change in papule, pustule, and nodule lesion counts for Example 1, Example 3, ORACEA®, and placebo during a 16-week, multicenter, randomized, double-blind, parallel-group, controlled study.

[0067] [Figure 5] FIG. 5 shows the change in total inflammatory lesions for Example 1, Example 3, ORACEA® and placebo during a 16-week multicenter, randomized, double-blind, parallel-group, controlled study. DETAILED DESCRIPTION OF THE INVENTION

[0068] Description of exemplary embodiments Details of one or more embodiments of the present invention are set forth in this document. Modifications to the embodiments described in this document, as well as other embodiments, will be apparent to those skilled in the art after studying the information provided in this document. The information provided in this document, and in particular the specific details of the exemplary embodiments described, are provided primarily for clarity of understanding, and no unnecessary limitations should be understood therefrom. In the event of a conflict, the specifics of this document, including definitions, will prevail.

[0069] Definitions: As used herein, the terms have the following meanings:

[0070] The present invention may comprise or consist essentially of the components of the present invention and other components or elements described herein. As used herein, "comprising" means the recited elements, or their structural or functional equivalents, plus any other element or elements not recited. The terms "having," "including," and "comprised of" are also to be construed as open-ended unless the context suggests otherwise. As used herein, "consisting essentially of" means that the invention may include components in addition to those recited in a claim, provided that the additional components do not materially alter the basic and novel characteristics of the claimed invention. As used herein, "consisting of" means that the invention excludes additional elements, steps, or ingredients not explicitly specified in the claim.

[0071] The terms "a" and "the," as used herein, are understood to encompass the plural and the singular, unless otherwise specifically referenced where necessary. For example, reference to "an excipient" includes reference to one or more of such excipients, and reference to "the vehicle" includes reference to one or more of such vehicles.

[0072] Terms such as "about," "up to," "generally," and the like should be construed as modifying a term or value as not absolute. Such terms will be defined by the context and the term they modify as understood by one of ordinary skill in the art. This includes, at a minimum, the degree of experimental error, technical error, and instrumental error that can be expected for a given experiment, technique, or device used to measure the value.

[0073] The term "about" is used to provide flexibility for the endpoints of a numerical range by indicating that a given value may be "slightly above" or "slightly below" the endpoint. As an example, a numerical range of "about 1 to about 5" should be interpreted to include not only the explicitly recited values ​​of about 1 to about 5, but also individual values ​​and subranges within the stated range. Thus, this numerical range includes individual values ​​such as 2, 3, and 4, and subranges such as 1-3, 2-4, and 3-5, as well as 1, 2, 3, 4, and 5 individually. This same principle applies to ranges reciting only a single numerical value as the minimum or maximum.

[0074] The terms "composition" and "formulation" refer to a mixture of two or more compounds, elements, or molecules. The terms may also be used to refer to a mixture of one or more active agents with a pharmaceutically acceptable vehicle or excipient. Additionally, the term "dosage form" may include one or more formulations or compositions provided in a form for oral administration, such as tablets, capsules, pills, minitablets, pellets, granules, powders, suspensions, syrups, etc., or mixtures thereof.

[0075] As used herein, the term "as needed" or "as needed" means that the subsequently described event or circumstance may or may not occur, or may or may not exist, and that the description includes cases where said event or circumstance occurs or exists, as well as cases where it does not occur or exist.

[0076] As used herein, the term "treatment" or "treating," including "alleviating," refers to curing or substantially curing a condition and improving at least one symptom of a condition, including prophylactic and therapeutic treatments. As would be recognized by one of ordinary skill in the art, if a treatment is administered before the clinical manifestation of a condition, the treatment is prophylactic (i.e., protects the subject from developing the condition). If a treatment is administered after the onset of a condition, the treatment is therapeutic (i.e., intended to diminish, ameliorate, control, alleviate, or maintain an existing condition and / or side effects associated with the condition). This term particularly relates to the medical management of a subject with the goal of substantially curing, ameliorating, stabilizing, or substantially preventing a condition, including, but not limited to, prophylactic treatment that prevents, prevents, forestalls, arrests, or delays something from occurring or reduces the severity of something that has occurred by prior action. Thus, the term treatment or treating includes, but is not limited to, inhibiting the progression of the target condition, arresting or preventing the occurrence of the target condition, reducing the severity of the target condition, ameliorating or alleviating the symptoms associated with the target condition, causing regression of the target condition or one or more symptoms associated with the target condition, and preventing the target condition or the occurrence of the target condition.

[0077] The term "minocycline," as used herein, is intended to include, but is not limited to, minocycline, its pharmaceutically acceptable salts, and both individual enantiomers of minocycline (dextrorotatory and levorotatory enantiomers) and their pharmaceutically acceptable salts in their substantially pure form, mixtures of minocycline enantiomers and their pharmaceutically acceptable salts (in any ratio), and active metabolites of minocycline and their pharmaceutically acceptable salts. The chemical name for minocycline is [4S-(4α,4aα,5aα,12aα)]-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-2-naphthacenecarboxamide. A solid form of minocycline can be used, or, for example, the minocycline can be amorphous or crystalline.

[0078] The term "doxycycline," as used herein, is intended to include, but is not limited to, doxycycline, its pharmaceutically acceptable salts, and both individual enantiomers of doxycycline in their substantially pure form and their pharmaceutically acceptable salts, mixtures of doxycycline enantiomers and their pharmaceutically acceptable salts (in any ratio), and pharmaceutically acceptable pharmacologically active derivatives of doxycycline, including the active metabolite of doxycycline and its pharmaceutically acceptable salts. The chemical name for doxycycline is (4S,4aR,5S,5aR,6R,12aR)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4H-tetracene-2-carboxamide. Solid forms of doxycycline may be used. Alternatively, for example, the doxycycline may be amorphous or crystalline.

[0079] The term "doxycycline composition," as used herein, includes oral doxycycline sold by Galderma Laboratories as a once-daily 40 mg capsule under the trade name ORACEA®, NDA number 050805 approved by the US FDA, and indicated solely for the treatment of inflammatory lesions (papules and pustules) of rosacea in adults. Doxycycline compositions include ORACEA®, or its pharmaceutical equivalent, or its therapeutic equivalent, or any of the products listed in Approved Drug Products, Inc. This includes drugs that have subsequently been approved or that have received marketing approval by the US FDA through an abbreviated new drug application (ANDA) filed by establishing bioequivalence, designated AB, evaluated by the US FDA in accordance with Therapeutic Equivalence Evaluations (34th edition).

[0080] The term "commercially available minocycline compositions," as used herein, includes oral minocycline sold by Medicis Pharmaceutical Corp. as a once-daily 45 mg tablet under the trade name SOLODYN®, with US FDA-approved NDA No. 050808, and indicated for the treatment of non-nodular, moderate to severe inflammatory lesions of acne vulgaris in patients 12 years of age and older. Commercially available minocycline compositions include SOLODYN®, or its pharmaceutical equivalents, or its therapeutic equivalents, or drugs subsequently approved for marketing by the US FDA through an abbreviated new drug application (ANDA) filed by establishing bioequivalence, as designated AB, as evaluated by the US FDA in accordance with Approved Drug Products with Therapeutic Equivalence Evaluations (34th edition).

[0081] The term "pharmaceutically acceptable salt," as used herein, includes salts that are suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, and the like, and are well known in the art. Salts can be prepared in situ during the final isolation and purification of the compounds of the present invention, or separately by reacting a pharmaceutically active substance having a free base functional group with a suitable organic or inorganic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, any of the salts or co-crystals of minocycline selected from hydrochloride, hydrobromide, sulfate, citrate, phosphate, maleate, formate, acetate, nitrate, mesylate, succinate, benzoate, and the like. The salt may be in solvate, hydrate, hemihydrate, or anhydrous form.

[0082] The term "therapeutically effective amount" as used herein refers to a predetermined amount of minocycline that is less than 45 mg. In some embodiments, the therapeutically effective amount of minocycline is about 44 mg, about 43 mg, about 42 mg, about 41 mg, about 40 mg, about 39 mg, about 38 mg, about 37 mg, about 36 mg, about 35 mg, about 34 mg, about 33 mg, about 32 mg, about 31 mg, about 30 mg, about 29 mg, about 28 mg, about 27 mg, about 26 mg, about 25 mg, about 24 mg, about 23 mg, about 22 mg, about 21 mg, about 20 mg, about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg, or about 10 mg. Such a therapeutically effective amount results in a plasma and / or interstitial fluid concentration of minocycline sufficient to treat inflammatory skin conditions. The specific amount of minocycline is expected to be low enough to avoid serious side effects. The effective amount of minocycline and the duration of treatment will depend on the age and health of the subject being treated, the severity of the condition, the nature of any concurrent therapy, and similar factors within the knowledge and expertise of the attending physician.

[0083] The term "reduced dose" refers to a dose of minocycline that contains less than 45 mg of minocycline. In some embodiments, the reduced dose of minocycline contains about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, or about 10 mg of minocycline. In some embodiments, the reduced dose of minocycline is about 44 mg, about 43 mg, about 42 mg, about 41 mg, about 40 mg, about 39 mg, about 38 mg, about 37 mg, about 36 mg, about 35 mg, about 34 mg, about 33 mg, about 32 mg, about 31 mg, about 30 mg, about 29 mg, about 28 mg, about 27 mg, about 26 mg, about 25 mg, about 24 mg, about 23 mg, about 22 mg, about 21 mg, about 20 mg, about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg, or about 10 mg of minocycline. The term "reduced dose" may also be used herein to refer to a comparison between minocycline and doxycycline. In this regard, minocycline provided in a reduced dose compared to doxycycline is a reduced mg amount. For example, minocycline less than 40 mg is a reduced dose compared to 40 mg of doxycycline. Similarly, the term "equivalent dose" can be used to refer to a comparison between minocycline and doxycycline. In this regard, minocycline provided in an equivalent dose compared to doxycycline is the same mg amount. For example, 40 mg of minocycline is a dose equivalent to 40 mg of doxycycline.

[0084] The term "sub-antimicrobial dose" refers to such an amount of This refers to an amount that does not have a significant antibacterial effect on the body when administered.

[0085] The term "inflammatory skin condition", as used herein, refers to conditions resulting in inflammatory lesions characterized by rosacea, acne, atopic dermatitis, folliculitis, perioral dermatitis, photodamage, actinic keratosis, psoriasis, chronic wound treatment, bedsores, keratosis pilaris, scars including surgical and acne scars, sebaceous cysts, inflammatory skin diseases, post-inflammatory hyperpigmentation, xerosis, pruritus, lichen planus, prurigo nodularis, eczema, or miliaria.

[0086] The term "rosacea," as used herein, includes skin conditions including inflammatory lesions (papulopustular rosacea—papules, pustules, and nodules), vascular instability and / or vascular ectasia (erythematotelangiectatic rosacea), edema, skin thickening and / or rhinophyma changes (proliferative rosacea), acne rosacea, or ocular changes (ocular rosacea), and the full spectrum of rosacea, including its causes, symptoms, and effects, as described by the National Rosacea Society, a United States 501(c)(3) organization.

[0087] The term "acne" as used herein includes all known types of acne, such as acne vulgaris, cystic acne, acne atrophica, bromoacne, chloracne, and genital acne. Acne congenita, cosmetic acne, detergent acne (acne detergicans), epidemic acne, seasonal acne (acne estivalis), acne fulminans, halogen acne, acne induralis, iodine acne, keloid Acne, mechanical acne, papular acne, pomade acne, premenstrual acne, pustular acne, acne scorbutica, acne scrofulosorum, urticarial acne, variola Skin conditions include acne, toxic acne, propionic acid acne, epidermolytic acne, gram-negative acne, steroid acne and nodulocystic acne.

[0088] The term "subject," as used herein, refers to a human individual who may or may not be afflicted with an inflammatory skin condition and who is the recipient of the oral pharmaceutical compositions described herein.

[0089] The term "patient," as used herein, refers to a human individual who is afflicted with an inflammatory skin condition and who is the recipient of an oral pharmaceutical composition described herein.

[0090] The term " efficacy " refers to the reduction or inhibition of the severity of inflammatory skin conditions such as rosacea, and the severity is evaluated by counting inflammatory lesions, including papules, pustules and / or nodules, before treatment begins, counting inflammatory lesions after treatment begins, and evaluating the change in investigator global assessment (IGA) score and / or the number of inflammatory lesions.If desired, efficacy can be quantified by the reduction of inflammatory lesion count from the baseline before treatment, by the improvement of IGA score from the baseline, or by both the reduction of inflammatory lesion count and IGA score.As used herein, the term " treatment success " can refer to the finding of efficacy.

[0091] The term "equivalent efficacy" refers to a comparative treatment using two different compositions that achieve substantially the same efficacy. For example, if treatment with two different compositions over the same period of time results in substantially the same reduction in lesion count, the compositions can be said to have equivalent or comparable efficacy.

[0092] The term " improved efficacy " refers to the comparative treatment using two different compositions, where the efficacy obtained by one composition is higher than that of the other composition.For example, if the treatment with the first composition and the second composition over the same period results in a greater reduction in the number of inflammatory lesions for the second composition than for the first composition, then the second composition is said to have improved efficacy compared to the first composition.

[0093] The term "substantially" can be used to modify a term or value so that the term or value is not absolute. This term is defined by the multiple contexts and multiple terms that it modifies, and these terms are as understood by those skilled in the art. This term is not completely and absolutely, but indicates approximation or a certain amount of deviation. For example, as those skilled in the art would recognize, when the term "substantially prevent" is used in connection with preventive treatment, it should not be understood as an absolute term that prevents all symptoms of any skin condition in a subject. Rather, when used in the context of preventive treatment, the term "substantially prevent" can refer to, for example, inhibiting the occurrence of a skin condition, limiting the severity of an existing skin condition, preventing the occurrence of a skin condition, etc., in a subject who may be susceptible to a skin condition but has not yet been diagnosed with a skin condition.

[0094] The term "Investigator Global Assessment (IGA) score" as used herein is determined by a trained medical professional who evaluates a subject's skin condition using a skin condition clinical global assessment. Typically, such a global assessment assigns a value to the degree of rosacea that the skin exhibits. In addition to the assessment made by the medical professional, the subject's own input and observation of their skin condition and answers to various questions (e.g., sensation of stinging or burning) also play a role in determining the assigned IGA score. For example, the IGA score for rosacea (Table 1) can range from 0 (none) to 1 (almost none) to 2 (mild) to 3 (moderate) to 4 (severe). [Table 1-1]

[0095] Reduction in inflammatory lesion count is determined at each study visit by, inter alia, absolute inflammatory lesion count or by percentage change in inflammatory lesion count. Improvement assessment includes grading or scoring of rosacea severity based on the total count or number of inflammatory lesions.

[0096] The term "moderate to severe rosacea" refers to at least about 10 papulopustular lesions before treatment. For example, a subject may have a rosacea IGA score of about 3 or about 4 and at least about 10, 12, 15, 20, 25 or more inflammatory papulopustular lesions before treatment. As used herein, a subject with "moderate rosacea" has a rosacea IGA score of about 3. As used herein, a subject with "severe rosacea" has a rosacea IGA score of about 4.

[0097] The term "interstitial fluid," as used herein, refers to extracellular fluid located outside blood vessels and in the spaces between tissue cells, and does not contain blood and blood cells, but may contain non-cellular blood components.

[0098] The term "steady state" as used herein refers to a concentration level of minocycline in which there is no further difference or minimal difference between the peak and trough concentrations of minocycline in plasma or interstitial fluid. Thus, in steady state, the plasma or interstitial fluid concentration level of minocycline does not substantially fluctuate within the dosing interval after repeated administration of the formulation. A steady state can be achieved in about 3 weeks or less by repeated administration of the pharmaceutical composition of the present invention containing minocycline once or twice daily. In certain circumstances, a steady state can be achieved in about 4 weeks.

[0099] "C maxP The term "maximum plasma concentration" refers to the maximum plasma concentration.

[0100] "C maxIF The term "maximum interstitial fluid concentration" refers to the maximum interstitial fluid concentration.

[0101] "C minP The term " refers to a minimum plasma concentration.

[0102] "C minIF The term "minimum interstitial fluid concentration" refers to the minimum interstitial fluid concentration.

[0103] "C maxSSPThe term "maximum plasma concentration achieved at steady state" refers to the maximum plasma concentration achieved at steady state.

[0104] "C maxSSIF The term "maximum interstitial fluid concentration achieved at steady state" refers to the maximum interstitial fluid concentration achieved at steady state.

[0105] "C minSSP The term "" refers to the minimum plasma concentration achieved at steady state.

[0106] "C minSSIF The term "minimum interstitial fluid concentration achieved at steady state" refers to the minimum interstitial fluid concentration achieved at steady state.

[0107] "C maxP / dose" or "C maxP The term " / D" refers to dose-normalized maximum plasma concentration.

[0108] "C maxIF / dose" or "C maxIF The term " / D" refers to dose-normalized maximum interstitial fluid concentration.

[0109] "C maxSSP / dose" or "C maxSSP The term " / D" refers to the dose-normalized maximum plasma concentration achieved at steady state.

[0110] "C maxSSIF / dose" or "C maxSSIF The term " / D" refers to the dose-normalized maximum interstitial fluid concentration achieved at steady state.

[0111] "C avgP The term "minocycline" refers to the average plasma concentration of minocycline within a 24-hour dosing interval exhibited by administration of the composition. avgP is calculated as follows:

number

[0112] "C avgIFThe term "" refers to the average interstitial fluid concentration of minocycline within a 24-hour dosing interval exhibited by administration of the composition. avgIF is calculated as follows:

number

[0113] "C avgSSP The term "minocycline" refers to the average plasma concentration of minocycline within a 24-hour dosing interval exhibited by administration of the composition. avgSS is calculated as follows:

number

[0114] "C avgSSIF The term "" refers to the average interstitial fluid concentration of minocycline within a 24-hour dosing interval exhibited by administration of the composition. avgSSIF is calculated as follows:

number

[0115] "AUC 0-tP The term " refers to the area under the plasma concentration-time curve, or minocycline exposure from time zero to time t, where "t" is the last sample collection time with a measurable drug concentration.

[0116] "AUC 0-tIF The term " refers to the area under the interstitial fluid concentration-time curve, or minocycline exposure from time zero to time t, where "t" is the last sample collection time with a measurable drug concentration.

[0117] "AUC 0-tSSP The term " refers to the area under the plasma concentration-time curve, or minocycline exposure from time zero to time t, where "t" is the last sample collection time with a measurable drug concentration at steady state.

[0118] "AUC 0-tSSIF The term " refers to the area under the interstitial fluid concentration-time curve, or minocycline exposure from time zero to time t, where "t" is the last sample collection time with a measurable drug concentration at steady state.

[0119] "AUC 0-tP / dose" or "AUC 0-tP The term " / D" refers to the area under the dose-normalized plasma concentration-time curve from time zero to time t, where "t" is the last sample collection time with a measurable drug concentration.

[0120] "AUC 0-tIF / dose" or "AUC 0-tP The term " / D" refers to the area under the dose-normalized interstitial fluid concentration-time curve from time zero to time t, where "t" is the last sample collection time with a measurable drug concentration.

[0121] "AUC 0-tSSP / dose" or "AUC 0-tSS The term " / D" refers to the area under the dose-normalized plasma concentration-time curve from time zero to time t, where "t" is the last sample collection time with a measurable drug concentration at steady state.

[0122] "AUC 0-tSSIF / dose" or "AUC 0-tSS The term " / D" refers to the area under the dose-normalized interstitial fluid concentration-time curve from time zero to time t, where "t" is the last sample collection time with a measurable drug concentration at steady state.

[0123] The term "coefficient of variation (CV)" refers to the ratio of the standard deviation obtained from clinical data to the mean. It indicates the degree of variability about the mean value of the study population. CV is expressed as a percentage (%); the lower the %CV, the more precise the data.

[0124] Volatility Index (FI P or FI SSP) or "Degree of Variability (DOF) P The term "variability index" refers to a measurement of the magnitude of fluctuation in drug plasma levels due to administration over the course of a dosing interval or at steady state. The closer the variability index is to 1, the greater the fluctuation over the course of the dosing period. Therefore, the FI P or FI SSP " indicates a reduction in the difference between peak and trough plasma levels, expressed as the ratio of the maximum concentration to the minimum concentration after administration according to the recommended dosing interval, calculated as follows: Volatility Index (FI P )=[C maxP -C minP ] / C avgP , or Volatility Index (FI SSP )=[C maxSSP -C minSSP ] / C avgSSP

[0125] Volatility Index (FI IF or FI SSIF ) or "Degree of Variability (DOF) IF The term "variability index" refers to the magnitude of variation in drug interstitial fluid levels with administration over the course of a dosing interval or at steady state. The closer the variability index is to 1, the less variability there is over the course of the dosing period. Thus, a reduced "FI" IF or FI SSIF " indicates a reduction in the difference between peak and trough interstitial fluid levels, expressed as the ratio of the maximum concentration to the minimum concentration after administration according to the recommended dosing interval, calculated as follows: Volatility Index (FI IF )=[C maxIF -C minP ] / C avgIF , or Volatility Index (FI SSIF )=[C maxSSIF -C minSSIF ] / C avgSSIF

[0126] Oral tetracycline compounds are known to treat inflammatory skin conditions such as rosacea.However, their higher dose and repeated administration with higher peak and trough plasma fluctuation index or fluctuation affect treatment regimen and increase the incidence of side effects.It has long been considered necessary to have treatment options with reduced dose, lower peak and trough plasma fluctuation index or fluctuation.

[0127] The presently disclosed invention is based, in part, on the surprising discoveries disclosed herein. Unexpectedly, minocycline exhibits comparative treatment results in percent reduction in lesion count for minocycline (approximately 40 mg), which is approximately 100% greater than that for doxycycline (40 mg) at an equivalent dose. Furthermore, the percent reduction in lesion count for minocycline (approximately 20 mg) at a half dose is equivalent to or greater than that for doxycycline (40 mg) at a full dose.

[0128] Furthermore, as demonstrated by comparative data, minocycline has improved efficacy for treating rosacea compared to doxycycline at equivalent doses, and equivalent efficacy at half the dose.

[0129] Thus, the present application relates to methods of treating inflammatory skin conditions with reduced doses of minocycline.

[0130] In certain embodiments, the present application relates to methods of treating inflammatory skin conditions, such as rosacea, with reduced doses of minocycline.

[0131] In certain embodiments, the present application relates to methods of treating inflammatory skin conditions, such as acne, with reduced doses of minocycline.

[0132] In another embodiment, the present application relates to a method of treating inflammatory skin conditions with reduced doses of minocycline that provide equivalent or improved efficacy compared to oral doxycycline compositions containing 40 mg of doxycycline.

[0133] In certain embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof an oral pharmaceutical composition comprising a reduced dose of minocycline, wherein said administration results in equivalent or improved efficacy compared to an oral doxycycline composition comprising 40 mg of doxycycline.

[0134] In certain embodiments, the present application relates to a method of treating an inflammatory skin condition by selecting and administering to a subject in need thereof an oral pharmaceutical composition comprising an equivalent or reduced dose of minocycline compared to an oral doxycycline composition comprising 40 mg of doxycycline.

[0135] In certain embodiments, the present application relates to a method of treating rosacea by selecting and administering to a subject in need thereof an oral pharmaceutical composition comprising an equivalent or reduced dose of minocycline compared to an oral doxycycline composition comprising 40 mg of doxycycline.

[0136] In some embodiments, the present application provides a method of treating an inflammatory skin condition in a subject, comprising: (a) selecting a subject for whom treatment with an oral doxycycline composition containing 40 mg of doxycycline is ineffective, and administering an oral pharmaceutical composition containing an equivalent or reduced dose of minocycline; or (b) selecting subjects who would benefit from treatment with an oral doxycycline composition containing 40 mg of doxycycline, and administering an oral pharmaceutical composition containing a reduced dose of minocycline; The present invention relates to a method, including:

[0137] In certain embodiments, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject for whom treatment with an oral doxycycline composition comprising 40 mg of doxycycline is ineffective, and administering an oral pharmaceutical composition comprising an equivalent or reduced dose of minocycline.

[0138] In certain embodiments, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject for whom treatment with an oral doxycycline composition comprising 40 mg of doxycycline is ineffective, and administering an oral pharmaceutical composition comprising an equivalent dose of minocycline.

[0139] In certain embodiments, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject for whom treatment with an oral doxycycline composition comprising 40 mg of doxycycline is ineffective, and administering an oral pharmaceutical composition comprising a reduced dose of minocycline.

[0140] In another embodiment, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject who would benefit from treatment with an oral doxycycline composition comprising 40 mg of doxycycline, and administering an oral pharmaceutical composition comprising an equivalent or reduced dose of minocycline.

[0141] In another embodiment, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject who would benefit from treatment with an oral doxycycline composition comprising 40 mg of doxycycline, and administering an oral pharmaceutical composition comprising an equivalent dose of minocycline.

[0142] In another embodiment, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject who would benefit from treatment with an oral doxycycline composition comprising 40 mg of doxycycline, and administering an oral pharmaceutical composition comprising a reduced dose of minocycline.

[0143] In yet another embodiment, the present application provides a method of treating rosacea in a subject in need thereof, comprising: (a) selecting a subject for whom treatment with an oral doxycycline composition containing 40 mg of doxycycline is ineffective, and administering an oral pharmaceutical composition containing an equivalent or reduced dose of minocycline; or (b) selecting subjects who would benefit from treatment with an oral doxycycline composition containing 40 mg of doxycycline, and administering an oral pharmaceutical composition containing an equivalent or reduced dose of minocycline; The present invention relates to a method, including:

[0144] In certain embodiments, the present application relates to a method of preparing an oral pharmaceutical composition for treating an inflammatory skin condition in a subject in need thereof, comprising selecting and providing minocycline in the composition at an equivalent or reduced dose compared to an oral doxycycline composition comprising 40 mg of doxycycline.

[0145] In certain embodiments, the present application relates to a method of preparing an oral pharmaceutical composition for treating rosacea in a subject in need thereof, comprising selecting and providing minocycline in the composition at an equivalent or reduced dose compared to an oral doxycycline composition comprising 40 mg of doxycycline.

[0146] In certain embodiments, the present application relates to a method of preparing an oral pharmaceutical composition for treating an inflammatory skin condition in a subject in need thereof, comprising selecting and providing minocycline in the composition at an equivalent or reduced dose compared to an oral doxycycline composition comprising 40 mg of doxycycline, wherein the composition provides equivalent or improved efficacy compared to an oral doxycycline composition comprising 40 mg of doxycycline.

[0147] In certain embodiments, the present application relates to a method of preparing an oral pharmaceutical composition for treating rosacea in a subject in need thereof, comprising selecting and providing minocycline in the composition at an equivalent or reduced dose compared to an oral doxycycline composition comprising 40 mg of doxycycline, wherein the composition provides equivalent or improved efficacy compared to an oral doxycycline composition comprising 40 mg of doxycycline.

[0148] In some aspects of the above embodiments, the pharmaceutical composition comprises less than 45 mg of minocycline.

[0149] In another aspect of the above embodiment, the pharmaceutical composition comprises about 10 mg to about 40 mg of minocycline.

[0150] In another aspect of the above embodiment, there is provided a method for preparing an oral pharmaceutical composition comprising minocycline, wherein the composition comprises from about 10 mg to about 40 mg of minocycline.

[0151] In another aspect of the above embodiment, the pharmaceutical composition comprises about 10 mg of minocycline.

[0152] In another aspect of the above embodiment, the pharmaceutical composition comprises about 20 mg of minocycline.

[0153] In another aspect of the above embodiment, the pharmaceutical composition comprises about 30 mg of minocycline.

[0154] In another aspect of the above embodiment, the pharmaceutical composition comprises about 40 mg of minocycline.

[0155] In certain embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof an oral pharmaceutical composition comprising a reduced dose of minocycline, wherein the composition exhibits a plasma concentration sufficient to reduce the severity of the inflammatory skin condition.

[0156] In certain embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof an oral pharmaceutical composition comprising a reduced dose of minocycline, wherein the composition exhibits a plasma concentration sufficient to reduce the severity of an inflammatory skin condition, such as rosacea.

[0157] In certain embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof an oral pharmaceutical composition comprising a reduced dose of minocycline, wherein the composition exhibits a plasma concentration sufficient to reduce the severity of an inflammatory skin condition, such as acne.

[0158] In certain aspects of the above embodiments, the present application provides a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the composition, upon administration, results in a maximum plasma concentration (C) of minocycline of about 500 ng / ml or less to reduce the severity of the inflammatory skin condition. maxP ) and the method.

[0159] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the composition, upon administration, results in a maximum plasma concentration (C) of minocycline of about 500 ng / ml or less to reduce the severity of rosacea. maxP ) and the method.

[0160] In certain aspects of the above embodiments, the present application provides a method of treating acne by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the composition, upon administration, results in a maximum plasma concentration (C) of minocycline of about 500 ng / ml or less to reduce the severity of acne. maxP ) and the method.

[0161] In certain aspects of the above embodiments, the present application provides a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the composition, upon administration, results in a maximum plasma concentration (C) of minocycline of about 500 ng / ml or less, about 450 ng / ml or less, about 440 ng / ml or less, or about 430 ng / ml or less to reduce the severity of the inflammatory skin condition. maxP ) and the method.

[0162] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the composition, upon administration, results in a maximum plasma concentration (C) of minocycline of about 500 ng / ml or less, about 450 ng / ml or less, or about 440 ng / ml or less, or about 430 ng / ml or less to reduce the severity of rosacea. maxP ) and the method.

[0163] In certain aspects of the above embodiments, the present application provides a method of treating acne by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the composition, upon administration, results in a maximum plasma concentration (C) of minocycline of about 500 ng / ml or less, about 450 ng / ml or less, about 440 ng / ml or less, or about 430 ng / ml or less to reduce the severity of acne. maxP ) and the method.

[0164] Oral tetracycline compounds are known to treat inflammatory skin conditions such as rosacea.However, their higher dose and repeated administration with higher peak and trough plasma fluctuation index or fluctuation, affect treatment regimen and increase the incidence of side effects.It has long been considered necessary to have treatment options with less peak and trough plasma fluctuation index or fluctuation.

[0165] Thus, the present application relates to methods of treating inflammatory skin conditions with a lower fluctuation index, which may result in a lower incidence of side effects.

[0166] In one embodiment, the present application provides a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition, upon oral administration, results in a lower plasma fluctuation index (FI P )[(C maxP -C minP ) / C avgP ], which relates to a method.

[0167] In one embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition, upon oral administration, results in a substantially lower plasma fluctuation index (FI P )[(C maxP -C minP ) / C avgP ], which relates to a method.

[0168] In one embodiment, the present application provides a method of treating acne by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition, upon oral administration, results in a substantially lower plasma fluctuation index (FI P )[(C maxP -C minP ) / C avgP ], which relates to a method.

[0169] In another embodiment, the present application provides a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition, upon oral administration, results in a lower plasma fluctuation index (FI SSP )[(C maxSSP -C minSSP ) / C avgSSP ], which relates to a method.

[0170] In another embodiment, the present application provides a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition provides a lower plasma fluctuation index (FI) upon oral administration for about three weeks or less. SSP )[(C maxSSP -C minSSP ) / C avgSSP ], which relates to a method.

[0171] In yet another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition provides a lower plasma fluctuation index (FI) upon oral administration for about three weeks or less. SSP )[(C maxSSP -C minSSP ) / C avgSSP ], which relates to a method.

[0172] In yet another embodiment, the present application provides a method of treating acne by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition results in a lower fluctuation index (FI) upon oral administration for about 3 weeks or less. SSP )[(C maxSSP -C minSSP ) / C avgSSP ], which relates to a method.

[0173] In another embodiment, the present application provides a method of treating an inflammatory skin condition by administering a pharmaceutical composition comprising a therapeutically effective amount of minocycline to a subject in need thereof, wherein the composition, upon oral administration for about three weeks or less, results in a lower Plasma Fluctuation Index (FI) compared to an oral doxycycline composition comprising 40 mg of doxycycline. SSP )[(C maxSSP -C minSSP ) / C avgSSP ], which relates to a method.

[0174] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition, upon oral administration for about three weeks or less, results in a lower Plasma Fluctuation Index (FI) compared to an oral doxycycline composition comprising 40 mg of doxycycline. SSP )[(C maxSSP -C minSSP ) / C avgSSP ], which relates to a method.

[0175] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition, upon oral administration for about three weeks or less, results in a plasma fluctuation index (FI) that is at least about 30% lower compared to an oral doxycycline composition comprising 40 mg of doxycycline. SSP )[(C maxSSP -C minSSP ) / C avgSSP ], which relates to a method.

[0176] In certain aspects of the above embodiments, there is provided a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration for at least three weeks or less results in a plasma fluctuation index (FI) that is at least about 20%, about 15%, or about 10% lower compared to an oral doxycycline composition comprising 40 mg of doxycycline.SSP )[(C maxSSP -C minSSP ) / C avgSSP ] shows the method.

[0177] In another aspect of the above embodiment, the present application provides a method of treating an inflammatory skin condition by administering a pharmaceutical composition comprising a therapeutically effective amount of minocycline to a subject in need thereof, wherein said administration results in a fluctuation index (FI) of about 0.9 to about 1.3. SSP ) and the method.

[0178] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering a pharmaceutical composition comprising a therapeutically effective amount of minocycline to a subject in need thereof, wherein said administration results in a fluctuation index (FI) of about 0.9 to about 1.3. SSP ) and the method.

[0179] In another aspect of the above embodiment, the present application provides a method of treating acne by administering a pharmaceutical composition comprising a therapeutically effective amount of minocycline to a subject in need thereof, wherein said administration results in a fluctuation index (FI) of about 0.9 to about 1.3. SSP ) and the method.

[0180] In another aspect of the above embodiment, the present application provides a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a fluctuation index (FI) of about 1.0. SSP ) and the method.

[0181] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a fluctuation index (FI) of about 1.0. SSP ) and the method.

[0182] In another aspect of the above embodiment, the present application provides a method of treating acne by administering a pharmaceutical composition comprising a therapeutically effective amount of minocycline to a subject in need thereof, wherein said administration for about 3 weeks or less results in a Fluctuation Index (FI) of about 1.0 to about 3. SSP ) and the method.

[0183] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a maximum plasma concentration (C) of 40 mg of doxycycline compared to an oral doxycycline composition comprising 40 mg of doxycycline. maxSSP ) exhibiting lower fluctuations in

[0184] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration reduces plasma minocycline exposure (AUC 0-tSSP ) exhibiting lower fluctuations in

[0185] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a maximum plasma concentration (C) of 40 mg of doxycycline compared to an oral doxycycline composition comprising 40 mg of doxycycline. maxSSP ) exhibiting at least about a 10% reduction in the coefficient of variation (CV%).

[0186] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a maximum plasma concentration (C) of 40 mg of doxycycline compared to an oral doxycycline composition comprising 40 mg of doxycycline. maxSSP) exhibiting at least about a 10%, about 15%, or about a 20% reduction in the coefficient of variation (CV%).

[0187] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration reduces plasma minocycline exposure (AUC 0-tSSP ) exhibiting at least about a 10% reduction in the coefficient of variation (CV%).

[0188] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration reduces minocycline exposure in plasma (AUC 0 mg) compared to an oral doxycycline composition comprising 40 mg doxycycline. 0-tSSP ) exhibiting at least about a 10%, about 15%, or about a 20% reduction in the coefficient of variation (CV%).

[0189] In one embodiment, the present application provides a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition achieves a steady-state maximum plasma concentration (Cmax) of minocycline upon oral administration for about three weeks or less. maxSSP ) and a method for maintaining the same.

[0190] In another embodiment, the present application provides a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition, upon oral administration for about 3 weeks or less, results in a steady-state maximum interstitial fluid concentration (C maxSSIF ) and a method for maintaining the same.

[0191] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition achieves a steady-state maximum plasma concentration (Cmax) of minocycline upon oral administration for about 3 weeks or less. maxSSP ) and a method for maintaining the same.

[0192] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition, upon oral administration for about 3 weeks or less, increases the steady-state maximum interstitial fluid concentration (C maxSSIF ) and a method for maintaining the same.

[0193] In another embodiment, the present application provides a method of treating acne by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition achieves a steady-state maximum plasma concentration (Cmax) of minocycline upon oral administration for about three weeks or less. maxSSP ) and a method for maintaining the same.

[0194] In another embodiment, the present application provides a method of treating acne by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition, upon oral administration for about three weeks or less, results in a steady-state maximum interstitial fluid concentration (C maxSSIF ) and a method for maintaining the same.

[0195] In yet another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition provides a plasma concentration ratio (C) of at least about 0.9 to about 1.3 upon oral administration for about three weeks or less. maxSSP :C maxP ) and the method.

[0196] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a plasma concentration ratio (C) of about 0.9. maxSSP :C maxP ) and the method.

[0197] In yet another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition, upon oral administration for about three weeks or less, results in an interstitial fluid concentration ratio (C) of at least about 0.7 to about 1.4. maxSSIF :C maxIF ) and the method.

[0198] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in an interstitial fluid concentration ratio (C) of about 1.0 over about 3 weeks or less of said administration. maxSSIF :C maxIF ) and the method.

[0199] In certain embodiments, the present application provides a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition achieves a desired steady-state maximum plasma concentration (C) for treating the inflammatory skin condition. maxSSP ) to bring about a method.

[0200] In one embodiment, the present application provides a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition achieves a steady-state maximum plasma concentration (C) of minocycline of about 500 ng / ml or less. maxSSP ) to bring about a method.

[0201] In certain embodiments, the present application provides a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition achieves a desired steady-state maximum interstitial fluid concentration (C) for treating the inflammatory skin condition. maxSSIF ) to bring about a method.

[0202] In another embodiment, the present application provides a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition maintains a steady-state maximum interstitial fluid concentration (C) of minocycline of about 200 ng / ml or less. maxSSIF ) to bring about a method.

[0203] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition achieves a steady-state maximum plasma concentration (C) of minocycline of about 500 ng / ml or less. maxSSP ) to bring about a method.

[0204] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition achieves a steady-state maximum plasma concentration (Cmax) of minocycline of about 500 ng / ml or less, about 450 ng / ml or less, about 400 ng / ml or less, about 350 ng / ml or less, or about 300 ng / ml or less. maxSSP ) to bring about a method.

[0205] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition maintains a steady-state maximum interstitial fluid concentration (C) of minocycline of about 200 ng / ml or less. maxSSIF ) to bring about a method.

[0206] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition maintains a steady-state maximum interstitial fluid concentration (C) of minocycline of about 200 ng / ml or less, about 180 ng / ml or less, about 170 ng / ml or less, about 160 ng / ml or less, or about 150 ng / ml or less. maxSSIF ) to bring about a method.

[0207] In one embodiment, the present application provides a method of treating an inflammatory skin condition by administering a pharmaceutical composition comprising a therapeutically effective amount of minocycline to a subject in need thereof, wherein said administration achieves a desired maximum plasma concentration (C) for treating said inflammatory skin condition on day 1. maxP ) to bring about a method.

[0208] In one embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a maximum plasma concentration (C) of minocycline of about 450 ng / ml or less on day 1. maxP ) to bring about a method.

[0209] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a maximum plasma concentration (C) of minocycline of about 450 ng / ml or less, about 440 ng / ml or less, or about 430 ng / ml or less on day 1. maxP ) to bring about a method.

[0210] In certain embodiments, the present application provides a method of treating an inflammatory skin condition by administering a pharmaceutical composition comprising a therapeutically effective amount of minocycline to a subject in need thereof, wherein said administration achieves a desired maximum interstitial fluid concentration (C) for treating said inflammatory skin condition on day 1. maxIF ) to bring about a method.

[0211] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a maximum interstitial fluid concentration (C) of minocycline of about 150 ng / ml or less on day 1. maxIF ) to bring about a method.

[0212] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a maximum interstitial fluid concentration (C) of minocycline of about 130 ng / ml or less, about 120 ng / ml or less, or about 110 ng / ml or less on day 1. maxIF ) to bring about a method.

[0213] In certain embodiments, the present application relates to a method of treating an inflammatory skin condition by administering a pharmaceutical composition comprising a therapeutically effective amount of minocycline to a subject in need thereof, wherein said administration for about three weeks or less maintains a desired plasma concentration of minocycline to treat said inflammatory skin condition.

[0214] In certain embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition maintains a desired plasma concentration of minocycline for treating the rosacea upon oral administration for about three weeks or less.

[0215] In certain embodiments, the present application relates to a method of treating acne by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition maintains a desired plasma concentration of minocycline for treating the acne upon oral administration for about three weeks or less.

[0216] In certain aspects of the above embodiments, a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition maintains a constant plasma concentration of about 500 ng / ml or less upon oral administration for about three weeks or less to treat the rosacea.

[0217] In another aspect of the above embodiment, a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition maintains a constant plasma concentration of about 500 ng / ml or less upon oral administration for about 3 weeks or less to treat the rosacea.

[0218] In certain embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition maintains a desired interstitial fluid concentration of minocycline for treating the rosacea upon oral administration for about three weeks or less.

[0219] In another aspect of the above embodiment, a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition maintains a constant interstitial fluid concentration of about 200 ng / ml or less of minocycline for treating the rosacea upon oral administration for about three weeks or less.

[0220] In another aspect of the above embodiment, there is provided a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein the composition, upon oral administration for about three weeks or less, results in a maximum interstitial fluid concentration (C) of about 200 ng / ml or less of minocycline for treating the rosacea. maxSSIF ) shows the method.

[0221] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a plasma minocycline exposure (AUC 0.01) of minocycline of about 4080 ng·hr / ml or less on day 1. 0-tP ) to bring about a method.

[0222] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in an interstitial fluid minocycline exposure (AUC) of about 1625 ng·hr / ml of minocycline or less on day 1. 0-tIF ) to bring about a method.

[0223] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state plasma minocycline exposure (AUC) of about 4550 ng·hr / ml of minocycline or less. 0-tSSP ) to bring about a method.

[0224] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state interstitial fluid minocycline exposure (AUC) of about 1845 ng·hr / ml of minocycline or less. 0-tSSIF ) to bring about a method.

[0225] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a mean plasma concentration (C) of minocycline of about 215 ng / ml or less on day 1. avgP ) to bring about a method.

[0226] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a mean interstitial fluid concentration (C) of minocycline of about 75 ng / ml or less on day 1. avgIF ) to bring about a method.

[0227] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a mean steady-state plasma concentration (C) of minocycline of about 245 ng / ml or less. avgSSP ) to bring about a method.

[0228] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a mean steady-state interstitial fluid concentration (C) of minocycline of about 90 ng / ml or less. avgSSIF ) to bring about a method.

[0229] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 20 mg of minocycline, wherein the composition, upon oral administration, provides a ratio of minocycline exposure in interstitial fluid to plasma (AUC ) that is at least about 10%, about 20%, about 30%, about 40%, or about 50% greater compared to oral administration of a doxycycline composition comprising 40 mg of doxycycline. 0-tIF / AUC 0-tP ) and the method.

[0230] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 20 mg of minocycline, wherein the composition, upon oral administration for about three weeks or less, provides a ratio of minocycline exposure in interstitial fluid to plasma (AUC ) that is at least about 10%, about 20%, about 30%, about 40%, or about 50% greater compared to oral administration of a doxycycline composition comprising 40 mg of doxycycline. 0-tSSIF / AUC 0-tSSP ) and the method.

[0231] In certain aspects of the above embodiments, there is provided a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 20 mg of minocycline, wherein the composition increases the ratio of minocycline exposure in interstitial fluid to plasma (AUC ) by at least about 35%, about 40%, about 45%, or about 50% upon oral administration. 0-tIF / AUC 0-tP ) shows the method.

[0232] In certain aspects of the above embodiments, there is provided a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 20 mg of minocycline, wherein the composition increases the ratio of minocycline exposure in interstitial fluid to plasma (AUC ) by at least about 35%, about 40%, about 45%, or about 50% upon oral administration for about 3 weeks or less. 0-tSSIF / AUC 0-tSSP ) shows the method.

[0233] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 30 mg of minocycline, wherein the composition, upon oral administration, provides a ratio of minocycline exposure in interstitial fluid to plasma (AUC ) that is at least about 10%, about 20%, about 30%, about 40%, or about 50% greater compared to oral administration of a doxycycline composition comprising 40 mg of doxycycline. 0-tIF / AUC 0-tP ) and the method.

[0234] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 30 mg of minocycline, wherein the composition, upon oral administration for about three weeks or less, provides a ratio of minocycline exposure in interstitial fluid to plasma (AUC ) that is at least about 10%, about 20%, about 30%, about 40%, or about 50% greater compared to oral administration of a doxycycline composition comprising 40 mg of doxycycline. 0-tSSIF / AUC 0-tSSP ) and the method.

[0235] In certain aspects of the above embodiments, there is provided a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 30 mg of minocycline, wherein the composition increases the ratio of minocycline exposure in interstitial fluid to plasma (AUC ) by at least about 35%, about 40%, about 45%, or about 50% upon oral administration. 0-tIF / AUC 0-tP ) shows the method.

[0236] In certain aspects of the above embodiments, there is provided a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 30 mg of minocycline, wherein the composition increases the ratio of minocycline exposure in interstitial fluid to plasma (AUC ) by at least about 35%, about 40%, about 45%, or about 50% upon oral administration for about 3 weeks or less. 0-tSSIF / AUC 0-tSSP ) shows the method.

[0237] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein the composition, upon oral administration, provides a ratio of minocycline exposure in interstitial fluid to plasma (AUC ) that is at least about 10%, about 20%, about 30%, about 40%, or about 50% greater compared to oral administration of a doxycycline composition comprising 40 mg of doxycycline. 0-tIF / AUC 0-tP) and the method.

[0238] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein the composition, upon oral administration for about three weeks or less, provides a ratio of minocycline exposure in interstitial fluid to plasma (AUC ) that is at least about 10%, about 20%, about 30%, about 40%, or about 50% greater compared to oral administration of a doxycycline composition comprising 40 mg of doxycycline. 0-tSSIF / AUC 0-tSSP ) and the method.

[0239] In certain aspects of the above embodiments, there is provided a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein the composition increases the ratio of minocycline exposure in interstitial fluid to plasma (AUC ) by at least about 35%, about 40%, about 45%, or about 50% upon oral administration. 0-tIF / AUC 0-tP ) shows the method.

[0240] In certain aspects of the above embodiments, there is provided a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein the composition increases the ratio of minocycline exposure in interstitial fluid to plasma (AUC ) by at least about 35%, about 40%, about 45%, or about 50% upon oral administration for about 3 weeks or less. 0-tSSIF / AUC 0-tSSP ) shows the method.

[0241] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 20 mg of minocycline, wherein the composition, upon oral administration, provides a mean interstitial fluid to plasma minocycline concentration ratio, or (CavgIF / C avgP ) and the method.

[0242] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 20 mg of minocycline, wherein the composition, upon oral administration for about three weeks or less, provides a mean interstitial fluid to plasma minocycline concentration ratio (C) that is at least about 10%, about 20%, about 30%, about 40%, or about 50% greater than oral administration of a doxycycline composition comprising 40 mg of doxycycline. avgSSIF / C avgSSP ) and the method.

[0243] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 20 mg of minocycline, wherein the composition, upon oral administration, increases the mean interstitial fluid to plasma minocycline concentration ratio, or (C avgIF / C avgP ) and the method.

[0244] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 20 mg of minocycline, wherein the composition increases the mean interstitial fluid to plasma minocycline concentration ratio, or (C) of at least about 30%, about 35%, about 40%, or about 45% upon oral administration for about 3 weeks or less. avgSSIF / C avgSSP ) and the method.

[0245] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 30 mg of minocycline, wherein the composition, upon oral administration, provides a mean interstitial fluid to plasma minocycline concentration ratio, or (C avgIF / C avgP ) and the method.

[0246] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 30 mg of minocycline, wherein the composition, upon oral administration for about three weeks or less, provides a mean interstitial fluid to plasma minocycline concentration ratio (C) that is at least about 10%, about 20%, about 30%, about 40%, or about 50% greater than oral administration of a doxycycline composition comprising 40 mg of doxycycline. avgSSIF / C avgSSP ) ratio.

[0247] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 30 mg of minocycline, wherein the composition, upon oral administration, increases the mean interstitial fluid to plasma minocycline concentration ratio, or (C avgIF / C avgP ) and the method.

[0248] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 30 mg of minocycline, wherein the composition increases the mean interstitial fluid to plasma minocycline concentration ratio, or (C) of at least about 30%, about 35%, about 40%, or about 45% upon oral administration for about three weeks or less. avgSSIF / C avgSSP) and the method.

[0249] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein the composition, upon oral administration, provides a mean interstitial fluid to plasma minocycline concentration ratio, or (C avgIF / C avgP ) and the method.

[0250] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein the composition, upon oral administration for about three weeks or less, provides a mean interstitial fluid to plasma minocycline concentration ratio (C) that is at least about 10%, about 20%, about 30%, about 40%, or about 50% greater than oral administration of a doxycycline composition comprising 40 mg of doxycycline. avgSSIF / C avgSSP ) ratio.

[0251] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein the composition, upon oral administration, increases the mean interstitial fluid to plasma minocycline concentration ratio, or (C avgIF / C avgP ) and the method.

[0252] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein the composition increases the mean interstitial fluid to plasma minocycline concentration ratio, or (C) of at least about 30%, about 35%, about 40%, or about 45% upon oral administration for about three weeks or less. avgSSIF / C avgSSP ) and the method.

[0253] In certain aspects of the above embodiments, the present application relates to a method of treating an inflammatory skin condition comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose comprises a lower dose of minocycline compared to commercially available minocycline compositions comprising 50 mg, 75 mg, or 100 mg minocycline compositions.

[0254] In certain aspects of the above embodiments, the present application relates to a method of treating rosacea comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose comprises a lower dose of minocycline compared to commercially available minocycline compositions comprising 50 mg, 75 mg, or 100 mg minocycline compositions.

[0255] In certain aspects of the above embodiments, the present application relates to a method of treating acne comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose comprises a smaller dose of minocycline as compared to a 50 mg, 75 mg, or 100 mg minocycline composition.

[0256] In certain aspects of the above embodiments, the present application relates to a method of treating an inflammatory skin condition, comprising administering to a subject in need thereof a pharmaceutical composition comprising a sub-antibacterial dose of minocycline.

[0257] In certain aspects of the above embodiments, the present application relates to a method of treating rosacea, comprising administering to a subject in need thereof a pharmaceutical composition comprising a sub-antibacterial dose of minocycline.

[0258] In certain aspects of the above embodiments, the present application relates to a method of treating acne comprising administering a sub-antibacterial dose of minocycline to a subject in need thereof.

[0259] In some aspects of the above embodiments, the sub-antimicrobial dose of minocycline is less than 45 mg. In other aspects, the sub-antimicrobial dose is less than about 40 mg. In other aspects, the sub-antimicrobial dose is less than about 30 mg. In other aspects, the sub-antimicrobial dose is less than about 20 mg.

[0260] In another aspect of the above embodiment, the present application relates to a method of treating an inflammatory skin condition comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose comprises a dose of minocycline less than 45 mg.

[0261] In another aspect of the above embodiment, the present application relates to a method of treating rosacea comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose comprises a dose of minocycline less than 45 mg.

[0262] In another aspect of the above embodiment, the present application relates to a method of treating acne comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose comprises a dose of minocycline less than 45 mg.

[0263] In another aspect of the above embodiments, the present application relates to a method of treating an inflammatory skin condition, comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, hi certain embodiments, the reduced dose comprises less than 45 mg of minocycline.

[0264] In another aspect of the above embodiment, the present application relates to a method of treating an inflammatory skin condition comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose comprises about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, or about 10 mg of minocycline.

[0265] In another aspect of the above embodiments, the present application relates to a method of treating rosacea, comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline. In some embodiments, the reduced dose comprises less than 45 mg, less than 40 mg, less than 35 mg, less than 30 mg, less than 25 mg, less than 20 mg, less than 15 mg, or less than 10 mg. In some embodiments, the reduced dose comprises about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, or about 10 mg of minocycline.

[0266] In another aspect of the above embodiment, the present application relates to a method of treating acne, comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline. In some embodiments, the reduced dose comprises less than 45 mg, less than 40 mg, less than 35 mg, less than 30 mg, less than 25 mg, less than 20 mg, less than 15 mg, or less than 10 mg. In some embodiments, the reduced dose comprises about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 15 mg, or about 10 mg of minocycline.

[0267] In another aspect of the above embodiment, the present application relates to a method of treating rosacea, comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose comprises from about 10 mg to about 40 mg of minocycline.

[0268] In another aspect of the above embodiment, the present application relates to a method of treating rosacea, comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose comprises from about 20 mg to about 40 mg of minocycline.

[0269] In another aspect of the above embodiment, the present application relates to a method of treating rosacea, comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose comprises about 20 mg of minocycline.

[0270] In another aspect of the above embodiment, the present application relates to a method of treating rosacea, comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose comprises about 30 mg of minocycline.

[0271] In another aspect of the above embodiment, the present application relates to a method of treating rosacea comprising administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose comprises about 40 mg of minocycline.

[0272] In certain aspects of the above embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof an oral pharmaceutical composition comprising about 20 mg of minocycline, wherein said administration provides equivalent efficacy compared to an oral doxycycline composition comprising 40 mg of doxycycline.

[0273] In another aspect of the above embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof an oral pharmaceutical composition comprising about 40 mg of minocycline, wherein said administration results in improved efficacy compared to an oral doxycycline composition comprising 40 mg of doxycycline.

[0274] In certain aspects of the above embodiments, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject for whom treatment with an oral doxycycline composition comprising 40 mg of doxycycline is ineffective or effective, and administering an oral pharmaceutical composition comprising less than 45 mg of minocycline.

[0275] In certain aspects of the above embodiments, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject for whom treatment with an oral doxycycline composition comprising 40 mg of doxycycline is ineffective or effective, and administering an oral pharmaceutical composition comprising about 10 mg or about 40 mg of minocycline.

[0276] In another aspect of the above embodiment, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject for whom treatment with an oral doxycycline composition comprising 40 mg of doxycycline is ineffective or effective, and administering an oral pharmaceutical composition comprising about 20 mg of minocycline.

[0277] In another aspect of the above embodiment, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject for whom treatment with an oral doxycycline composition comprising 40 mg of doxycycline is ineffective or effective, and administering an oral pharmaceutical composition comprising about 30 mg of minocycline.

[0278] In another aspect of the above embodiment, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject for whom treatment with an oral doxycycline composition comprising 40 mg of doxycycline is ineffective or effective, and administering an oral pharmaceutical composition comprising about 40 mg of minocycline.

[0279] In certain aspects of the above embodiments, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject for whom treatment with an oral doxycycline composition comprising 40 mg of doxycycline is ineffective or effective, and administering an oral pharmaceutical composition comprising less than 45 mg of minocycline.

[0280] In certain aspects of the above embodiments, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject who would benefit from treatment with an oral doxycycline composition comprising 40 mg of doxycycline, and administering an oral pharmaceutical composition comprising about 10 mg or about 40 mg of minocycline.

[0281] In another aspect of the above embodiment, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject who would benefit from treatment with an oral doxycycline composition comprising 40 mg of doxycycline, and administering an oral pharmaceutical composition comprising about 20 mg of minocycline.

[0282] In another aspect of the above embodiment, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject who would benefit from treatment with an oral doxycycline composition comprising 40 mg of doxycycline, and administering an oral pharmaceutical composition comprising about 30 mg of minocycline.

[0283] In another aspect of the above embodiment, the present application relates to a method of treating rosacea in a subject in need thereof, comprising selecting a subject who would benefit from treatment with an oral doxycycline composition comprising 40 mg of doxycycline, and administering an oral pharmaceutical composition comprising less than about 40 mg of minocycline.

[0284] In yet another aspect of the above embodiment, the present application provides a method of treating rosacea in a subject in need thereof, comprising: (a) selecting a subject for whom treatment with an oral doxycycline composition containing 40 mg of doxycycline is unsuccessful, and administering an oral pharmaceutical composition containing about 20 mg, about 30 mg, or about 40 mg of minocycline; or (b) selecting a subject who would benefit from treatment with an oral doxycycline composition comprising 40 mg of doxycycline, and administering an oral pharmaceutical composition comprising less than about 20 mg, about 30 mg, or about 40 mg of minocycline. The present invention relates to a method, including:

[0285] In yet another aspect of the above embodiment, the present application provides a method of treating rosacea in a subject in need thereof, comprising: (c) selecting a subject for whom treatment with an oral doxycycline composition containing 40 mg of doxycycline is ineffective, and administering an oral pharmaceutical composition containing about 20 mg, about 30 mg, or about 40 mg of minocycline; or (d) selecting a subject who would benefit from treatment with an oral doxycycline composition comprising 40 mg of doxycycline, and administering an oral pharmaceutical composition comprising about 20 mg, about 30 mg, or about 40 mg of minocycline. The present invention relates to a method, including:

[0286] In certain aspects of the above embodiments, the present application relates to a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose results in a desired plasma concentration of minocycline for treating the inflammatory skin condition.

[0287] In certain aspects of the above embodiments, the present application relates to a method of treating an inflammatory lesion by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose results in a desired interstitial fluid concentration of minocycline for treating the inflammatory lesion.

[0288] In another aspect of the above embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose results in a desired plasma concentration of minocycline to treat the rosacea.

[0289] In another aspect of the above embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose results in a desired interstitial fluid concentration of minocycline for treating the rosacea.

[0290] In another aspect of the above embodiment, the present application relates to a method of treating acne by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose results in a desired plasma concentration of minocycline to treat the acne.

[0291] In another aspect of the above embodiment, the present application relates to a method of treating acne by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose results in a sufficient interstitial fluid concentration of minocycline to treat the acne.

[0292] In another aspect of the above embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose comprises a dose of minocycline less than 45 mg to provide a steady-state maximum plasma concentration of minocycline of about 500 ng / ml or less to treat the rosacea.

[0293] In another aspect of the above embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a reduced dose of minocycline, wherein the reduced dose comprises a dose of minocycline less than 45 mg to produce a steady-state maximum interstitial fluid concentration of minocycline of about 200 ng / ml or less to treat the rosacea.

[0294] In certain aspects of the above embodiments, the present application provides a method of treating rosacea, comprising administering to a subject in need thereof a pharmaceutical composition comprising about 10 mg to about 40 mg of minocycline, wherein said administration to a subject results in the following pharmacokinetic parameters, as measured in plasma samples on day 1: (a) C of about 55 ng / ml to about 450 ng / ml maxP , (b) AUC from approximately 830 ng·hr / ml to approximately 4080 ng·hr / ml 0-tP ,or (c) C of about 30 ng / ml to about 215 ng / ml avgP The present invention relates to a method for producing at least one of the following:

[0295] In another aspect of the above embodiment, the present application provides a method of treating rosacea, comprising administering to a subject in need thereof a pharmaceutical composition comprising about 10 mg to about 40 mg of minocycline, The administration to subjects resulted in the following pharmacokinetic parameters as measured in interstitial fluid samples on Day 1: (a) C of about 14 ng / ml to about 150 ng / ml maxIF , (b) AUC from approximately 250 ng·hr / ml to approximately 1625 ng·hr / ml 0-tIF ,or (c) C of about 5 ng / ml to about 75 ng / ml avgIF The present invention relates to a method for producing at least one of the following:

[0296] In another aspect of the above embodiment, the present application provides a method of treating rosacea, comprising administering to a subject in need thereof a pharmaceutical composition comprising about 10 mg to about 40 mg of minocycline, wherein said administration to a subject results in the following steady-state pharmacokinetic parameters, as measured in plasma samples: (a) C of about 70 ng / ml to about 440 ng / ml maxSSP , (b) AUC from approximately 830 ng·hr / ml to approximately 4550 ng·hr / ml 0-tSSP ,or (c) C of about 40 ng / ml to about 245 ng / ml avgSSP The present invention relates to a method for producing at least one of the following:

[0297] In another aspect of the above embodiment, the present application provides a method of treating rosacea, comprising administering to a subject in need thereof a pharmaceutical composition comprising about 10 mg to about 40 mg of minocycline, wherein said administration to a subject results in the following steady-state pharmacokinetic parameters, as measured in interstitial fluid samples: (a) C of about 15 ng / ml to about 150 ng / ml maxSSIF , (b) AUC from approximately 375 ng·hr / ml to approximately 1845 ng·hr / ml 0-tSSIF ,or (c) C of about 8 ng / ml to about 90 ng / ml avgSSIF The present invention relates to a method for producing at least one of the following:

[0298] In another embodiment, the present application provides a method of treating rosacea by administering a pharmaceutical composition comprising about 20 mg of minocycline to a subject in need thereof, wherein said administration results in the following pharmacokinetic parameters as measured in plasma samples on day 1: (a) C of about 110 ng / ml to about 150 ng / ml maxP , (b) AUC of approximately 1210 ng·hr / ml to approximately 1625 ng·hr / ml 0-tP ,or (c) C of about 60 ng / ml to about 85 ng / ml avgP The present invention relates to a method for producing at least one of the following:

[0299] In another embodiment, the present application provides a method of treating rosacea by administering a pharmaceutical composition comprising about 20 mg of minocycline to a subject in need thereof, wherein said administration results in the following pharmacokinetic parameters as measured in interstitial fluid samples on Day 1: (a) C of about 37 ng / ml to about 60 ng / ml maxIF , (b) AUC from approximately 500 ng·h / ml to approximately 680 ng·h / ml 0-tIF ,or (c) C of about 22 ng / ml to about 30 ng / ml avgIF The present invention relates to a method for producing at least one of the following:

[0300] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 20 mg of minocycline, wherein said administration results in the following steady-state pharmacokinetic parameters as measured in plasma samples: (a) C of about 140 ng / ml to about 190 ng / ml maxSSP , (b) AUC of approximately 1660 ng·hr / ml to approximately 2245 ng·hr / ml 0-tSSP ,or (c) C of approximately 80 ng / ml to approximately 110 ng / ml avgSSP The present invention relates to a method for producing at least one of the following:

[0301] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 20 mg of minocycline, wherein said administration results in the following steady-state pharmacokinetic parameters as measured in interstitial fluid samples: (a) C of about 52 ng / ml to about 70 ng / ml maxSSIF , (b) AUC from approximately 745 ng·hr / ml to approximately 1010 ng·hr / ml 0-tSSIF ,or (c) C of about 32 ng / ml to about 43 ng / ml avgSSIF The present invention relates to a method for producing at least one of the following:

[0302] In another embodiment, the present application provides a method of treating rosacea by administering a pharmaceutical composition comprising about 30 mg of minocycline to a subject in need thereof, wherein said administration results in the following pharmacokinetic parameters as measured in plasma samples on day 1: (a) C of about 224 ng / ml to about 330 ng / ml maxP , (b) AUC of approximately 2215 ng·hr / ml to approximately 3107 ng·hr / ml 0-tP ,or (c) C of about 90 ng / ml to about 120 ng / ml avgP The present invention relates to a method for producing at least one of the following:

[0303] In another embodiment, the present application provides a method of treating rosacea by administering a pharmaceutical composition comprising about 30 mg of minocycline to a subject in need thereof, wherein said administration results in the following pharmacokinetic parameters as measured in interstitial fluid samples on Day 1: (a) C of about 70 ng / ml to about 95 ng / ml maxIF , (b) AUC from approximately 900 ng·hr / ml to approximately 1215 ng·hr / ml 0-tIF ,or (c) C of about 40 ng / ml to about 50 ng / ml avgIF The present invention relates to a method for producing at least one of the following:

[0304] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 30 mg of minocycline, wherein said administration results in the following steady-state pharmacokinetic parameters as measured in plasma samples: (a) C of about 215 ng / ml to about 290 ng / ml maxSSP , (b) AUC from approximately 2525 ng·hr / ml to approximately 3415 ng·hr / ml 0-tSSP ,or (c) C of about 140 ng / ml to about 180 ng / ml avgSSP The present invention relates to a method for producing at least one of the following:

[0305] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 30 mg of minocycline, wherein said administration results in the following steady-state pharmacokinetic parameters as measured in interstitial fluid samples: (a) C of about 80 ng / ml to about 110 ng / ml maxSSIF , (b) AUC from approximately 1025 ng·hr / ml to approximately 1385 ng·hr / ml 0-tSSIF ,or (c) C of about 50 ng / ml to about 65 ng / ml avgSSIF The present invention relates to a method for producing at least one of the following:

[0306] In another embodiment, the present application provides a method of treating rosacea by administering a pharmaceutical composition comprising about 40 mg of minocycline to a subject in need thereof, wherein said administration results in the following pharmacokinetic parameters as measured in plasma samples on day 1: (a) C of about 325 ng / ml to about 440 ng / ml maxP , (b) AUC of approximately 3115 ng·hr / ml to approximately 4080 ng·hr / ml 0-tP ,or (c) C of about 160 ng / ml to about 215 ng / ml avgP The present invention relates to a method for producing at least one of the following:

[0307] In another embodiment, the present application provides a method of treating rosacea by administering a pharmaceutical composition comprising about 40 mg of minocycline to a subject in need thereof, wherein said administration results in the following pharmacokinetic parameters as measured in interstitial fluid samples on Day 1: (a) C of about 95 ng / ml to about 150 ng / ml maxIF , (b) AUC from approximately 1200 ng·hr / ml to approximately 1625 ng·hr / ml 0-tIF ,or (c) C of about 55 ng / ml to about 75 ng / ml avgIF The present invention relates to a method for producing at least one of the following:

[0308] In another embodiment, the present application provides a method of treating rosacea by administering a pharmaceutical composition comprising about 40 mg of minocycline to a subject in need thereof, wherein said administration results in the following steady-state pharmacokinetic parameters as measured in plasma samples: (a) C of about 285 ng / ml to about 410 ng / ml maxSSP , (b) AUC of approximately 3365 ng·hr / ml to approximately 4550 ng·hr / ml 0-tSSP,or (c) C of about 175 ng / ml to about 245 ng / ml avgSSP The present invention relates to a method for producing at least one of the following:

[0309] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein said administration results in the following steady-state pharmacokinetic parameters as measured in interstitial fluid samples: (a) C of about 105 ng / ml to about 145 ng / ml maxSSIF , (b) AUC of approximately 1365 ng·hr / ml to approximately 1845 ng·hr / ml 0-tSSIF ,or (c) C of about 65 ng / ml to about 90 ng / ml avgSSIF The present invention relates to a method for producing at least one of the following:

[0310] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein said administration for about 3 weeks or less results in a plasma concentration ratio (C) of at least about 30% lower than an oral doxycycline composition comprising 40 mg of doxycycline. maxSSP :C maxP ) and the method.

[0311] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein said administration for about 3 weeks or less results in a plasma concentration ratio (C) that is at least about 30%, about 35%, about 40%, about 45%, or about 50% lower compared to an oral doxycycline composition comprising 40 mg of doxycycline. maxSSP :C maxP ) and the method.

[0312] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein said administration for about 3 weeks or less results in a mean plasma concentration (C) of minocycline that is at least about 20% lower compared to an oral doxycycline composition comprising 40 mg of doxycycline. maxSSP ) and the method.

[0313] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein said administration for about 3 weeks or less results in a mean plasma concentration (C) of minocycline that is at least about 20%, about 25%, about 30%, about 35%, or about 40% lower compared to an oral doxycycline composition comprising 40 mg of doxycycline. maxSSP ) and the method.

[0314] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 10 mg to about 40 mg of minocycline, wherein upon oral administration, the following pharmacokinetic parameters are achieved as measured in plasma samples: (a) C of about 5 ng / ml / mg to about 11 ng / ml / mg max / D, or (b) AUC of about 60 ng / ml / mg to about 102 ng / ml / mg 0-t / D The present invention relates to a method for manufacturing a semiconductor device, the method comprising:

[0315] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 10 mg to about 40 mg of minocycline, wherein oral administration over a period of about 3 weeks or less results in the following pharmacokinetic parameters, as measured in plasma samples: (a) C of about 5 ng / ml / mg to about 12 ng / ml / mg maxSSP / D, or (b) AUC of about 60 ng / ml / mg to about 114 ng / ml / mg 0-tSSP / D.

[0316] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 20 mg of minocycline, wherein upon oral administration, the following pharmacokinetic parameters are achieved as measured in plasma samples: (a) C of about 5.5 ng / ml / mg to about 7.5 ng / ml / mg maxP / D, or (b) AUC of about 60 ng / ml / mg to about 80 ng / ml / mg 0-tP / D The present invention relates to a method for producing a semiconductor device, the method comprising:

[0317] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 20 mg of minocycline, wherein oral administration over a period of about 3 weeks or less results in the following pharmacokinetic parameters as measured in plasma samples: (a) C of about 7 ng / ml / mg to about 9.5 ng / ml / mg maxSSP / D, or (b) AUC of about 80 ng / ml / mg to about 112 ng / ml / mg 0-tSSP / D.

[0318] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 30 mg of minocycline, wherein upon oral administration, the following pharmacokinetic parameters are achieved as measured in plasma samples: (c) C of approximately 8.3 ng / ml / mg to approximately 10.8 ng / ml / mg maxP / D, or (d) AUC of about 75 ng / ml / mg to about 100 ng / ml / mg 0-tP / D The present invention relates to a method for producing a semiconductor device, the method comprising:

[0319] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 30 mg of minocycline, wherein oral administration over a period of about 3 weeks or less results in the following pharmacokinetic parameters, as measured in plasma samples: (c) C of about 7 ng / ml / mg to about 9.5 ng / ml / mg maxSSP / D, or (d) AUC of about 85 ng / ml / mg to about 112 ng / ml / mg 0-tSSP / D.

[0320] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein upon oral administration, the following pharmacokinetic parameters are achieved as measured in plasma samples: (a) C of about 8 ng / ml / mg to about 11 ng / ml / mg maxP / D, or (b) AUC of about 75 ng / ml / mg to about 102 ng / ml / mg 0-tP / D The present invention relates to a method for producing a semiconductor device, the method comprising:

[0321] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein oral administration over a period of about 3 weeks or less results in the following pharmacokinetic parameters as measured in plasma samples: (a) C of about 7.2 ng / ml / mg to about 9.6 ng / ml / mg maxSSP / D, or (b) AUC of about 84 ng / ml / mg to about 114 ng / ml / mg 0-tSSP / D. C max / D - 10-40mg interstitial fluid Day 1 and steady state

[0322] In certain embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising minocycline at a dose of about 10 mg to about 40 mg, wherein upon oral administration, the following pharmacokinetic parameters are achieved as measured in interstitial fluid samples: (a) C of about 1.8 ng / ml / mg to about 3 ng / ml / mg maxIF / D, or (b) AUC of about 25 ng / ml / mg to about 40 ng / ml / mg 0-tIF / D The present invention relates to a method for producing a semiconductor device, the method comprising:

[0323] In another embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a dose of about 10 mg to about 40 mg of minocycline, wherein upon oral administration over a period of about 3 weeks or less, the following pharmacokinetic parameters are achieved as measured in interstitial fluid samples: (a) C of about 1.3 ng / ml / mg to about 3.6 ng / ml / mg maxSSIF / D, or (b) AUC of about 34 ng / ml / mg to about 46 ng / ml / mg 0-tSSIF / D.

[0324] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 20 mg of minocycline, wherein upon oral administration, the following pharmacokinetic parameters are achieved as measured in interstitial fluid samples: (a) C of about 1.8 ng / ml / mg to about 2.4 ng / ml / mg maxIF / D, or (b) AUC of about 25 ng / ml / mg to about 34 ng / ml / mg 0-tIF / D The present invention relates to a method for producing a semiconductor device, the method comprising:

[0325] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 20 mg of minocycline, wherein oral administration over a period of about 3 weeks or less results in the following pharmacokinetic parameters as measured in interstitial fluid samples: (a) C of about 2.6 ng / ml / mg to about 3.5 ng / ml / mg maxSSIF / D, or (b) AUC of about 37 ng / ml / mg to about 50 ng / ml / mg 0-tSSIF / D.

[0326] In certain aspects of the above embodiments, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 30 mg of minocycline, wherein upon oral administration, the following pharmacokinetic parameters are achieved as measured in interstitial fluid samples: (c) C of about 2.3 ng / ml / mg to about 3.0 ng / ml / mg maxIF / D, or (d) AUC of about 30 ng / ml / mg to about 40 ng / ml / mg 0-tIF / D The present invention relates to a method for producing a semiconductor device, the method comprising:

[0327] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 30 mg of minocycline, wherein oral administration over a period of about 3 weeks or less results in the following pharmacokinetic parameters as measured in interstitial fluid samples: (c) C of about 2.6 ng / ml / mg to about 3.5 ng / ml / mg maxSSIF / D, or (d) AUC of about 36 ng / ml / mg to about 44 ng / ml / mg 0-tSSIF / D.

[0328] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein upon oral administration, the following pharmacokinetic parameters are achieved as measured in interstitial fluid samples: (a) C of about 2.3 ng / ml / mg to about 3.1 ng / ml / mg maxIF / D, or (b) AUC of about 30 ng / ml / mg to about 40 ng / ml / mg 0-tIF / D The present invention relates to a method for producing a semiconductor device, the method comprising:

[0329] In another aspect of the above embodiment, the present application provides a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising about 40 mg of minocycline, wherein oral administration over a period of about 3 weeks or less results in the following pharmacokinetic parameters as measured in interstitial fluid samples: (a) C of about 2.6 ng / ml / mg to about 3.6 ng / ml / mg maxSSIF / D, or (b) AUC of about 34 ng / ml / mg to about 46 ng / ml / mg 0-tSSIF / D.

[0330] In certain aspects of the above embodiments, the present application relates to methods of treating inflammatory skin conditions or lesions resulting from one or more of rosacea, acne vulgaris, atopic dermatitis, folliculitis, perioral dermatitis, photodamage, actinic keratosis, psoriasis, chronic wound treatment, bedsores, keratosis pilaris, scars including surgical and acne scars, sebaceous cysts, inflammatory skin diseases, post-inflammatory hyperpigmentation, xerosis, pruritus, lichen planus, prurigo nodularis, eczema, or miliaria.

[0331] In certain aspects of the above embodiments, there is provided a method of treating rosacea by administering an oral pharmaceutical composition comprising a reduced dose of minocycline to a subject in need thereof, wherein the rosacea is papulopustular rosacea, acne rosacea, erythematotelangiectatic rosacea, nodular rosacea, ocular rosacea, acne rosacea, facial pyoderma, bulbar rosacea, mild rosacea, moderate rosacea, severe rosacea, mild to moderate rosacea, or moderate to severe rosacea.

[0332] In certain aspects of the above embodiments, a method of treating acne by administering an oral pharmaceutical composition comprising a reduced dose of minocycline to a subject in need thereof, wherein the acne is acne vulgaris, cystic acne, atrophic acne, bromine acne, chlorine acne, acne conglobata, cosmetic acne, detergent acne, epidemic acne, seasonal acne, acne fulminans, halogen acne, acne indureus, iodine acne, keloid acne, mechanical acne, papular acne, pomade acne, premenstrual acne, pustular acne, scurvy acne, scrofulous acne, urticarial acne, acne variola, toxic acne, propionibacterial acne, epidermolytic acne, gram-negative acne, steroid-induced acne, and nodulocystic acne.

[0333] In another aspect of the above embodiment, a method of treating rosacea by administering an oral pharmaceutical composition comprising a reduced dose of minocycline to a subject in need thereof, wherein the rosacea is characterized by inflammatory lesions.

[0334] In another aspect of the above embodiment, a method of treating rosacea by administering an oral pharmaceutical composition comprising a reduced dose of minocycline to a subject in need thereof, wherein the rosacea is characterized by papules, pustules, and / or nodules.

[0335] In certain aspects of the above embodiments, the present application relates to a method of treating an inflammatory skin condition by administering a pharmaceutical composition comprising a therapeutically effective amount of minocycline in a dose of less than 45 mg to a subject in need thereof, wherein the inflammatory skin condition comprises rosacea.

[0336] In certain aspects of the above embodiments, the application relates to a method of treating an inflammatory skin condition by administering a pharmaceutical composition comprising a therapeutically effective amount of minocycline at a dose of less than 45 mg to a subject in need thereof, wherein the inflammatory skin condition is selected from the group consisting of papulopustular rosacea, erythematotelangiectatic rosacea, nodular or ocular rosacea, acne rosacea, facial pyoderma, bulbar rosacea, mild rosacea, moderate rosacea, severe rosacea, mild to moderate rosacea, and moderate to severe rosacea.

[0337] In certain aspects of the above embodiments, the present application relates to a method of treating an inflammatory skin condition by administering a pharmaceutical composition comprising a therapeutically effective amount of minocycline in a dose of less than 45 mg to a subject in need thereof, wherein the inflammatory skin condition comprises acne.

[0338] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration significantly reduces the severity of the rosacea compared to the severity of the rosacea before treatment.

[0339] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration significantly reduces the severity of the rosacea compared to the severity of the rosacea before treatment, and wherein said severity of the rosacea is assessed using the IGA scale.

[0340] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration significantly reduces the IGA score compared to the IGA score before treatment.

[0341] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration significantly reduces an IGA score compared to an IGA score of a placebo composition.

[0342] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration reduces the subject's IGA score by at least one grade compared to the IGA score before treatment.

[0343] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration reduces the subject's IGA score by at least one grade compared to the IGA score of a placebo composition.

[0344] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration reduces the subject's IGA score by at least one grade compared to the IGA score about 1 to 16 weeks prior to treatment.

[0345] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration results in improved efficacy in at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75% of subjects as assessed by IGA score compared to the IGA score before treatment.

[0346] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration results in improved efficacy in at least about 15% of subjects as assessed by IGA score compared to the IGA score before treatment.

[0347] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration results in improved efficacy in at least about 30% of subjects as assessed by IGA score compared to the IGA score before treatment.

[0348] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration reduces the subject's IGA score by at least one grade compared to the IGA score of an oral doxycycline composition comprising 40 mg of doxycycline.

[0349] In certain aspects of the above embodiments, a method of treating rosacea by administering about 10 mg to about 40 mg of minocycline, wherein said administration reduces IGA score to a similar or greater extent compared to administration of an oral doxycycline composition comprising 40 mg of doxycycline.

[0350] In some aspects of the above embodiments, a method of treating rosacea by administering about 20 mg of minocycline, wherein said administration reduces IGA scores to a similar or greater extent compared to administration of an oral doxycycline composition comprising 40 mg of doxycycline.

[0351] In certain aspects of the above embodiments, a method of treating rosacea by administering about 30 mg to about 40 mg of minocycline, wherein said administration reduces the subject's IGA score by at least about 25%, about 50%, about 75%, or about 100% compared to the IGA score of an oral doxycycline composition comprising 40 mg of doxycycline.

[0352] In certain aspects of the above embodiments, a method of treating rosacea by administering about 30 mg to about 40 mg of minocycline, wherein said administration reduces the subject's IGA score by at least about 25% compared to the IGA score of an oral doxycycline composition comprising 40 mg of doxycycline.

[0353] In certain aspects of the above embodiments, a method of treating rosacea by administering about 40 mg of minocycline, wherein said administration reduces the subject's IGA score by at least about 25%, about 50%, about 75%, or about 100% compared to the IGA score of an oral doxycycline composition comprising 40 mg of doxycycline.

[0354] In certain aspects of the above embodiments, a method of treating rosacea by administering about 40 mg of minocycline, wherein said administration reduces the subject's IGA score by at least about 25% compared to the IGA score of an oral doxycycline composition comprising 40 mg of doxycycline.

[0355] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration significantly reduces the severity of rosacea compared to the severity of rosacea before treatment, wherein said severity of rosacea is assessed by counting the number of inflammatory lesions.

[0356] In some aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration significantly reduces the number of inflammatory lesions compared to the inflammatory lesions before treatment.

[0357] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration significantly reduces the number of inflammatory lesions compared to inflammatory lesions of a placebo composition.

[0358] In certain aspects of the above embodiments, there is provided a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration reduces the number of inflammatory lesions in a subject by at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% compared to the number of inflammatory lesions before treatment.

[0359] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration reduces the number of inflammatory lesions in a subject by at least about 15% compared to the number of inflammatory lesions before treatment.

[0360] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration reduces the number of inflammatory lesions in a subject by at least about 30% compared to the number of inflammatory lesions before treatment.

[0361] In certain aspects of the above embodiments, a method of treating rosacea by administering a reduced dose of minocycline, wherein said administration reduces the number of inflammatory lesions in a subject by at least about 50% compared to the number of inflammatory lesions before treatment.

[0362] In some aspects of the above embodiments, there is provided a method of treating rosacea by administering about 10 mg to about 40 mg of minocycline, wherein said administration reduces the number of inflammatory lesion scores compared to administration of an oral doxycycline composition comprising 40 mg of doxycycline. of inflammatory lesions score) to the same or a greater extent.

[0363] In some aspects of the above embodiments, a method of treating rosacea by administering about 20 mg of minocycline, wherein said administration reduces the number of inflammatory lesion scores to a similar or greater extent compared to administration of an oral doxycycline composition comprising 40 mg of doxycycline.

[0364] In some aspects of the above embodiments, a method of treating rosacea by administering about 30 mg to about 40 mg of minocycline, wherein said administration reduces inflammatory lesions by at least about 25%, about 50%, about 75%, or about 100% compared to the number of inflammatory lesions in an oral doxycycline composition comprising 40 mg of doxycycline.

[0365] In some aspects of the above embodiments, a method of treating rosacea by administering about 30 mg to about 40 mg of minocycline, wherein said administration reduces inflammatory lesions by at least about 50% compared to the number of inflammatory lesions in an oral doxycycline composition comprising 40 mg of doxycycline.

[0366] In some aspects of the above embodiments, a method of treating rosacea by administering about 30 mg to about 40 mg of minocycline, wherein said administration reduces inflammatory lesions by at least about 75% compared to the number of inflammatory lesions in an oral doxycycline composition comprising 40 mg of doxycycline.

[0367] In some aspects of the above embodiments, a method of treating rosacea by administering about 30 mg to about 40 mg of minocycline, wherein said administration reduces inflammatory lesions by at least about 100% compared to the number of inflammatory lesions in an oral doxycycline composition comprising 40 mg of doxycycline.

[0368] In some aspects of the above embodiments, a method of treating rosacea by administering about 40 mg of minocycline, wherein said administration reduces inflammatory lesions by at least about 25%, about 50%, about 75%, or about 100% compared to the number of inflammatory lesions of an oral doxycycline composition comprising 40 mg of doxycycline.

[0369] In some aspects of the above embodiments, a method of treating rosacea by administering about 40 mg of minocycline, wherein said administration reduces inflammatory lesions by at least about 50% compared to the number of inflammatory lesions of an oral doxycycline composition comprising 40 mg of doxycycline.

[0370] In some aspects of the above embodiments, a method of treating rosacea by administering about 40 mg of minocycline, wherein said administration reduces inflammatory lesions by at least about 75% compared to the number of inflammatory lesions of an oral doxycycline composition comprising 40 mg of doxycycline.

[0371] In some aspects of the above embodiments, a method of treating rosacea by administering about 40 mg of minocycline, wherein said administration reduces inflammatory lesions by at least about 100% compared to the number of inflammatory lesions of an oral doxycycline composition comprising 40 mg of doxycycline.

[0372] In certain aspects of the above embodiments, the present application relates to a method of treating an inflammatory skin condition by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline in a dose of less than 45 mg, wherein the composition is administered orally.

[0373] In certain aspects of the above embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline in a dose of less than 45 mg, wherein the composition is administered orally.

[0374] In certain aspects of the above embodiments, the present application relates to a method of treating acne by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline in a dose of less than 45 mg, wherein the composition is administered orally.

[0375] In certain aspects of the above embodiments, the present application relates to a method of treating rosacea by administering a pharmaceutical composition comprising minocycline at a dose of about 40 mg to a subject in need thereof, wherein the composition is administered orally.

[0376] In certain aspects of the above embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising minocycline at a dose of about 35 mg, wherein the composition is administered orally.

[0377] In certain aspects of the above embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising minocycline at a dose of about 30 mg, wherein the composition is administered orally.

[0378] In certain aspects of the above embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising minocycline at a dose of about 25 mg, wherein the composition is administered orally.

[0379] In one embodiment, the present application relates to a method of treating rosacea by administering a pharmaceutical composition comprising minocycline at a dose of about 20 mg to a subject in need thereof, wherein the composition is administered orally.

[0380] In one embodiment, the present application relates to a method of treating rosacea by administering a pharmaceutical composition comprising minocycline at a dose of about 15 mg to a subject in need thereof, wherein the composition is administered orally.

[0381] In one embodiment, the present application relates to a method of treating rosacea by administering a pharmaceutical composition comprising minocycline at a dose of about 10 mg to a subject in need thereof, wherein the composition is administered orally.

[0382] In certain aspects of the above embodiments, the pharmaceutical compositions of the present application are administered once daily.

[0383] In another embodiment, the present application relates to a method of treating rosacea by administering a pharmaceutical composition comprising a therapeutically effective amount of minocycline in a dose of less than 45 mg to a subject in need thereof, wherein the composition is administered once daily.

[0384] In certain aspects of the above embodiments, the pharmaceutical compositions of the present application are administered twice daily.

[0385] In another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline in a dose of less than 45 mg, wherein the composition is administered twice daily.

[0386] In another aspect of the above embodiment, the pharmaceutical compositions of the present application are with or without food.

[0387] In another embodiment, the present application relates to a method of treating rosacea by administering a pharmaceutical composition comprising a therapeutically effective amount of minocycline in a dose of less than 45 mg to a subject in need thereof, wherein the composition is administered with or without food.

[0388] In certain embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof an oral pharmaceutical composition comprising a reduced dose of minocycline, the method providing a weight-independent dosing regimen for minocycline.

[0389] In certain aspects of the above embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline in a dose of less than 45 mg, wherein the composition is orally administered in the form of an oral tablet, capsule, pill, mini-tablet, pellet, granule, powder, suspension, syrup, or the like.

[0390] In certain embodiments, the present application relates to a method of treating an inflammatory skin condition by administering a pharmaceutical composition comprising minocycline or a pharmaceutically acceptable salt thereof to a subject in need thereof and measuring plasma and / or interstitial fluid concentrations of minocycline in the subject.

[0391] As will be appreciated by those skilled in the art, depending on the circumstances, minocycline plasma and / or interstitial fluid concentrations may be measured once daily, more than once daily, or less than once daily during the entire course of treatment of a subject or a portion of the course of treatment. In some embodiments, for example, a subject may be measured for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks.

[0392] In some embodiments, the method may include monitoring the measurements until a maximum steady-state plasma and / or interstitial fluid concentration of minocycline is achieved and maintained for a specified period of time. In some embodiments, once steady-state minocycline has been achieved and maintained for a specified period of time, the dose of minocycline may be maintained for the duration of the course of treatment.

[0393] In some embodiments, the method may include identifying a maximum steady-state plasma concentration. In some embodiments, the method may further include determining whether the maximum steady-state plasma concentration is less than or equal to about 500 ng / ml.

[0394] As will be recognized by those skilled in the art, depending on the circumstances, it may be beneficial to use the plasma and / or interstitial fluid concentrations of minocycline to determine certain parameters. For example, in some embodiments, it may be useful to calculate a variability index as defined herein. In some embodiments, it may be useful to monitor the variability index. In some embodiments, it may be useful to determine whether the variability index is about 1.0. In some embodiments, it may be useful to calculate any variation in the variability index from a first time point during treatment to one or more additional time points during treatment. In some embodiments, it may be useful to determine whether the variability index varies by less than about 30, 20, or 10%.

[0395] In one embodiment, the present application relates to a pharmaceutical composition comprising minocycline for treating an inflammatory skin condition in a subject in need thereof, wherein the pharmaceutical composition is in the form of an oral tablet, capsule, pill, mini-tablet, pellet, granule, dust, suspension, or syrup.

[0396] In certain embodiments, the present application relates to a pharmaceutical composition comprising minocycline for treating rosacea in a subject in need thereof, wherein the pharmaceutical composition is in the form of an oral tablet, capsule, pill, mini-tablet, pellet, granule, powder, suspension, or syrup.

[0397] In certain embodiments, the present application relates to a pharmaceutical composition comprising minocycline for treating acne in a subject in need thereof, wherein the pharmaceutical composition is in the form of an oral tablet, capsule, pill, mini-tablet, pellet, granule, dust, suspension, or syrup.

[0398] In certain aspects of the above embodiments, the minocycline pharmaceutical composition is in the form of a matrix composition, wherein the minocycline is uniformly distributed in a matrix of one or more pharmaceutically acceptable excipients.

[0399] In another aspect of the above embodiment, the minocycline pharmaceutical composition is in the form of a gastroretentive system that is designed to be retained in the stomach for an extended period of time and release minocycline in the upper part of the gastrointestinal (GI) tract. Various approaches or systems for extending gastric retention time include floating drug delivery systems, including mucoadhesive or bioadhesive systems, high-density systems, expandable or swelling systems, and gas-generating systems.

[0400] In yet another aspect of the above embodiment, the minocycline pharmaceutical composition is in the form of an osmotic drug delivery system, said system comprising a minocycline layer having a water-swellable polymer (osmogen) and a push layer.

[0401] In another aspect of the above embodiment, the minocycline pharmaceutical composition is in the form of a modified-release composition, said composition comprising an immediate-release (IR) portion and / or an extended-release (ER) portion containing minocycline along with one or more pharmaceutically acceptable excipients.

[0402] In certain embodiments, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum plasma concentration of minocycline of about 500 ng / ml or less, and wherein said composition comprises an immediate-release (IR) portion and / or an extended-release (ER) portion containing minocycline along with one or more pharmaceutically acceptable excipients.

[0403] In certain aspects of the above embodiments, the pharmaceutical compositions of the present application comprise a therapeutically effective amount of minocycline for a subject in need thereof.

[0404] In another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum plasma concentration of minocycline of about 500 ng / ml or less, and wherein said composition comprises: (i) about 0 to about 100 percent minocycline in an immediate-release (IR) portion; (ii) about 0 to about 100 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0405] In another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum interstitial fluid concentration of minocycline of about 200 ng / ml or less, and wherein said composition comprises: (i) about 0 to about 100 percent minocycline in an immediate-release (IR) portion; (ii) about 0 to about 100 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0406] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum plasma concentration of minocycline of about 500 ng / ml or less, and wherein said composition comprises: (i) about 0 to about 100 percent minocycline in an immediate-release (IR) portion; (ii) about 0 to about 100 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0407] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum plasma concentration of minocycline of about 500 ng / ml or less, and wherein said composition comprises: (i) about 30 percent minocycline in an immediate-release (IR) portion; (ii) about 70 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0408] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum plasma concentration of minocycline of about 500 ng / ml or less, and wherein said composition comprises: (i) about 25 percent minocycline in an immediate-release (IR) portion; (ii) about 75 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0409] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum plasma concentration of minocycline of about 500 ng / ml or less, and wherein said composition comprises: (i) about 20 percent minocycline in an immediate-release (IR) portion; (ii) about 80 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0410] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum plasma concentration of minocycline of about 500 ng / ml or less, and wherein said composition comprises: (i) about 40 percent minocycline in an immediate-release (IR) portion; (ii) about 60 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0411] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum plasma concentration of minocycline of about 500 ng / ml or less, and wherein said composition comprises: (i) about 50 percent minocycline in an immediate-release (IR) portion; (ii) about 50 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0412] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum plasma concentration of minocycline of about 500 ng / ml or less, and wherein said composition comprises: (i) about 60 percent minocycline in an immediate-release (IR) portion; (ii) about 40 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0413] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum plasma concentration of minocycline of about 500 ng / ml or less, and wherein said composition comprises: (i) about 70 percent minocycline in an immediate-release (IR) portion; (ii) about 30 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0414] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum plasma concentration of minocycline of about 500 ng / ml or less, and wherein said composition comprises: (i) about 75 percent minocycline in an immediate-release (IR) portion; (ii) about 25 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0415] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum plasma concentration of minocycline of about 500 ng / ml or less, and wherein said composition comprises: (i) about 80 percent minocycline in an immediate-release (IR) portion; (ii) about 20 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0416] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum interstitial fluid concentration of minocycline of about 200 ng / ml or less, and wherein said composition comprises: (i) about 0 to about 100 percent minocycline in an immediate-release (IR) portion; (ii) about 0 to about 100 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0417] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum interstitial fluid concentration of minocycline of about 200 ng / ml or less, and wherein said composition comprises: (i) about 30 percent minocycline in an immediate-release (IR) portion; (ii) about 70 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0418] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum interstitial fluid concentration of minocycline of about 200 ng / ml or less, and wherein said composition comprises: (i) about 25 percent minocycline in an immediate-release (IR) portion; (ii) about 75 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0419] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum interstitial fluid concentration of minocycline of about 200 ng / ml or less, and wherein said composition comprises: (i) about 40 percent minocycline in an immediate-release (IR) portion; (ii) about 60 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0420] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum interstitial fluid concentration of minocycline of about 200 ng / ml or less, and wherein said composition comprises: (i) about 20 percent minocycline in an immediate-release (IR) portion; (ii) about 80 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0421] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum interstitial fluid concentration of minocycline of about 200 ng / ml or less, and wherein said composition comprises: (i) about 50 percent minocycline in an immediate-release (IR) portion; (ii) about 50 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0422] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum interstitial fluid concentration of minocycline of about 200 ng / ml or less, and wherein said composition comprises: (i) about 70 percent minocycline in an immediate-release (IR) portion; (ii) about 30 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0423] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum interstitial fluid concentration of minocycline of about 200 ng / ml or less, and wherein said composition comprises: (i) about 75 percent minocycline in an immediate-release (IR) portion; (ii) about 25 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0424] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum interstitial fluid concentration of minocycline of about 200 ng / ml or less, and wherein said composition comprises: (i) about 80 percent minocycline in an immediate-release (IR) portion; (ii) about 20 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0425] In yet another embodiment, the present application relates to a method of treating rosacea by administering to a subject in need thereof a pharmaceutical composition comprising a therapeutically effective amount of minocycline, wherein said administration results in a steady-state maximum interstitial fluid concentration of minocycline of about 200 ng / ml or less, and wherein said composition comprises: (i) about 60 percent minocycline in an immediate-release (IR) portion; (ii) about 40 percent minocycline in an extended-release (ER) portion; and (iii) one or more pharmaceutically acceptable excipients.

[0426] In certain aspects of the above embodiments, the immediate release (IR) portion and / or the extended release (ER) portion are present in the form of granules, pellets, beads, prills, mini-tablets, powders, etc., or mixtures thereof.

[0427] In certain embodiments, the present application relates to a method of preparing a pharmaceutical composition comprising a therapeutically effective amount of minocycline.

[0428] In another embodiment, the present application relates to a method of preparing a pharmaceutical composition comprising a therapeutically effective amount of minocycline in a dose of less than 45 mg, wherein the composition is administered orally.

[0429] In another aspect of the above embodiment, the method comprises a conventional method for preparing oral pharmaceutical compositions, including but not limited to wet or dry granulation using a fluid bed granulator or a high shear mixer granulator, direct compression, extrusion-spheronization, melt granulation / extrusion, spray drying, spray congealing, freeze drying or any other conventional method known in the art.

[0430] In certain aspects of the above embodiments, the method comprises coating or layering minocycline onto an inert core with a coating or layering material comprising minocycline and / or other suitable pharmaceutical excipients, such as a binder, plasticizer, or disintegrant, on the inert core.

[0431] Coating or layering methods include any method known in the art, such as, but not limited to, spraying a suspension or dispersion of the coating material containing minocycline in a conventional coating pan or fluidized bed apparatus (e.g., Wurster or Glatt), followed by drying the core. Alternatively, the coating material may also be applied by powder coating, in which the core is maintained in a tacky state and a mixture of coating material is continuously or periodically added to adhere to the tacky core, followed by drying the coated core when the desired coating is achieved.

[0432] "Inert core", as used herein, refers to a pharmaceutically acceptable inert base commonly used in the field of formulations, including but not limited to powders or multiparticulates, such as granules, pellets, beads, prills, beadlets, microcapsules, millispheres, nanocapsules, nanospheres, microspheres or minitablets, which comprises at least one pharmaceutically acceptable excipient selected from the group comprising water-soluble, water-insoluble, water-swellable or non-water-swellable materials, such as starch, sugar, microcrystalline cellulose, vegetable gums, waxes, etc.

[0433] The inert cores can also be prepared by techniques known to those skilled in the art, such as wet granulation, dry granulation, or extrusion-spheronization, etc. The inert cores have a diameter ranging from about 125 to about 600 microns.

[0434] Suitable solvent(s) used in the preparation of the minocycline solution are selected from, but not limited to, water, methanol, ethanol, n-propanol, isopropanol, dichloromethane, acetone, absolute alcohol, and the like, or mixtures thereof.

[0435] Suitable examples of binder(s) that can be used in the present application include, but are not limited to, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, propylene glycol, pregelatinized starch, oxides such as polyethylene oxide, and the like, or mixtures thereof. The binder may be a combination of two or more types, for example, hydroxypropyl cellulose and hydroxypropyl methylcellulose. The binder used in the present application has a viscosity of about 5 centipoise to about 15 centipoise.

[0436] In another aspect of the above embodiment, the extended release (ER) portion coats the immediate release (IR) portion with one or more release modifying polymers. It is prepared by

[0437] In another aspect of the above embodiment, the present application relates to a method for preparing a pharmaceutical composition of minocycline comprising an extended-release (ER) portion, wherein the ER coating layer has a thickness of 200 μm or less.

[0438] Suitable examples of release-modifying polymers that can be used in the present application include, but are not limited to, unsubstituted alkyl celluloses or cellulose ethers such as ethyl cellulose; and substituted alkyl celluloses or cellulose ethers such as hydroxyalkyl celluloses and carboxyalkyl celluloses, for example, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethylethyl cellulose, and carboxymethyl cellulose; acrylic and methacrylic acid polymers and copolymers, for example, methyl methacrylate, ethoxyethyl methacrylate, ethyl acrylate, aminoalkyl methacrylate copolymers, poly(acrylic acid), poly(methacrylic acid), polyacrylamide, and glycidyl methacrylate copolymers; polyalkylene oxides, for example, polyethylene oxide and polypropylene oxide, and copolymers of ethylene oxide and propylene oxide; polyvinyl alcohol, gums, synthetic resins, etc., or mixtures thereof. The release-modifying polymer may be present in an amount ranging from about 5% to about 45% w / w of the composition.

[0439] In another embodiment, the pharmaceutical composition of minocycline of the present application may comprise one or more pharmaceutically acceptable excipients selected from a glidant, a glidant, an anti-adherent, a plasticizer, a disintegrant or an opacifier, etc., or mixtures thereof.

[0440] Lubricants, glidants, or anti-adherents may be used interchangeably in the compositions of the present application and may be selected from, but are not limited to, metal stearates such as magnesium stearate, calcium stearate, and zinc stearate; stearic acid, hydrogenated vegetable oils, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycol, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, tricalcium phosphate, and the like, or mixtures thereof. The amount of such agents may range from about 0.1% w / w to about 10% w / w of the composition.

[0441] The plasticizer used in the pharmaceutical composition of the present application may be used in the coating layer to increase the flexibility and strength of the coating / layer, and suitable plasticizers may be selected from, but are not limited to, propylene glycol, polyethylene glycol, triethyl citrate, acetyltriethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, tributyl citrate, or mixtures thereof. The plasticizer may be present in an amount ranging from about 0.1% to about 20% w / w of the composition.

[0442] The disintegrant used in the pharmaceutical composition of the present application may be selected from, but is not limited to, crospovidone, sodium starch glycolate, croscarmellose sodium, croscarmellose potassium, croscarmellose calcium, carboxymethylcellulose, pregelatinized starch, carboxymethyl starch, etc., or mixtures thereof. The disintegrant may be present in an amount of 1% to 20% by weight of the composition.

[0443] In certain aspects of the above embodiments, the method for preparing a pharmaceutical composition comprising a dose of minocycline of about 10 mg to about 40 mg includes the steps of: (i) preparing an immediate-release (IR) portion; and / or (ii) preparing an extended-release (ER) portion; (iii) combining the IR and / or ER portions with one or more pharmaceutically acceptable excipients; and (iv) filling the mixture of (iii) into capsules or compressing it into tablets.

[0444] In certain aspects of the above embodiments, the method for preparing a pharmaceutical composition comprising a dose of minocycline less than 45 mg includes the steps of: (i) preparing an immediate-release (IR) portion; and / or (ii) preparing an extended-release (ER) portion; (iii) combining the IR and / or ER portions with one or more pharmaceutically acceptable excipients; and (iv) filling the mixture of (iii) into capsules or compressing it into tablets.

[0445] In certain aspects of the above embodiments, the method comprises combining the IR and ER moieties in a ratio of about 0:100, about 10:90, about 20:80, about 30:70, about 40:60, about 50:50, about 60:40, about 70:30, about 75:25, about 80:20, about 90:10, or about 100:0.

[0446] In certain aspects of the above embodiments, the method for preparing a pharmaceutical composition comprising a dose of minocycline less than 45 mg includes the steps of: (i) preparing an immediate-release (IR) portion; and / or (ii) preparing an extended-release (ER) portion; (iii) combining the IR and / or ER portions in a ratio of about 0:100 to about 100:0 with one or more pharmaceutically acceptable excipients; and (iv) filling the mixture of (iii) into capsules or compressing it into tablets.

[0447] In certain aspects of the above embodiments, the method for preparing a pharmaceutical composition comprising a dose of minocycline less than 45 mg includes the steps of: (i) preparing an immediate-release (IR) portion; and / or (ii) preparing an extended-release (ER) portion; (iii) combining the IR and ER portions in a ratio of about 20:80 with one or more pharmaceutically acceptable excipients; and (iv) filling the mixture of (iii) into capsules or compressing it into tablets.

[0448] In certain aspects of the above embodiments, the method for preparing a pharmaceutical composition comprising a dose of minocycline less than 45 mg includes the steps of: (i) preparing an immediate-release (IR) portion; and / or (ii) preparing an extended-release (ER) portion; (iii) combining the IR and ER portions in a ratio of about 25:75 with one or more pharmaceutically acceptable excipients; and (iv) filling the mixture of (iii) into capsules or compressing it into tablets.

[0449] In certain aspects of the above embodiments, the method for preparing a pharmaceutical composition comprising a dose of minocycline less than 45 mg includes the steps of: (i) preparing an immediate-release (IR) portion; and / or (ii) preparing an extended-release (ER) portion; (iii) combining the IR and ER portions in a ratio of about 30:70 with one or more pharmaceutically acceptable excipients; and (iv) filling the mixture of (iii) into capsules or compressing it into tablets.

[0450] In certain aspects of the above embodiments, the method for preparing a pharmaceutical composition comprising a dose of minocycline less than 45 mg includes the steps of: (i) preparing an intragranular portion; and / or (ii) preparing an extragranular portion; (iii) mixing (i) and (ii) with suitable pharmaceutically acceptable excipients; (iv) compressing the mixture of (iii) into tablets; and (v) optionally coating the tablets of (iv) with a suitable coating material.

[0451] In certain embodiments, pharmaceutical compositions comprising minocycline may also be co-administered (simultaneously or sequentially) with one or more valuable pharmaceutical agents that are in a commercially available dosage form or that can be developed into a pharmaceutically acceptable dosage form suitable for treating an inflammatory skin condition or related disease state.

[0452] In another embodiment, the pharmaceutical composition comprising minocycline is mixed at a speed of 100 rpm, USP Dissolution studies can be performed in 500 ml of pH 2.1 simulated gastric fluid, pH 4.5 acetate buffer, and pH 6.8 phosphate buffer at 37° C. for up to 3 hours using a Type I apparatus.

[0453] Examples of pharmaceutical agents that may be co-administered are selected from, but are not limited to, systemic and topical antibiotics such as tetracycline, minocycline, doxycycline, metronidazole, erythromycin, and clindamycin; or retinoids such as tretinoin (vitamin A or retinoic acid), isotretinoin (13-cis-retinoic acid), acitretin, and the like, or mixtures thereof.

[0454] The present application is further illustrated by examples, which are presented as mere examples of the above-mentioned pharmaceutical compositions and do not limit the scope of the present application. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application. The present invention is hereinafter illustrated by reference to the following examples. However, those skilled in the art will recognize that the specific methods and results discussed are merely examples of the present invention and should not be construed as limiting the present application. The following examples may include compilations of data that are representative data collected at various times during the course of development and experimentation related to the present invention. [Example]

[0455] Examples 1 to 5

[0456] Pharmaceutical compositions containing 40 mg, 30 mg, 20 mg, or 10 mg of minocycline were prepared. Further details regarding the exemplary compositions used for these non-limiting examples are provided in Table 1. [Table 1-2] [Table 1-3]

[0457] procedure: An exemplary composition can be prepared using the following procedure. a. For exemplary compositions 1-4 as shown in Table 1, drug dispersions were prepared by mixing minocycline hydrochloride, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyethylene glycol, and talc in water and layering onto inert cores to obtain drug-loaded pellets. b. For Exemplary Composition 5 as shown in Table 1, the drug and microcrystalline cellulose were wet granulated. The wet mass was then extruded and the extrudate was spheronized to prepare drug pellets. c. A barrier coating solution was prepared by dissolving the hydroxypropyl methylcellulose, followed by adding the polyethylene glycol and talc with stirring. d. A modified release coating solution was prepared by dissolving the required amounts of ethyl cellulose and hydroxypropyl methyl cellulose in isopropyl alcohol, followed by the addition of triethyl citrate. e. The immediate release (IR) portion was prepared by coating the barrier coating solution prepared in step (c) onto the drug-loaded portion of step (a) or step (b). f. The extended release (ER) portion was prepared by coating the modified release coating solution prepared in step (d) onto the drug-loaded portion of step (a) or step (b), followed by an outer top coating or seal coating. g. The required amount of outer top coating portion and barrier coating portion was mixed with talc and filled into empty hard gelatin capsule shells of the required size and packaged in a suitable pharmaceutical storage bottle.

[0458] Example 6

[0459] Exemplary pharmaceutical compositions containing minocycline were prepared as shown in Table 2. [Table 2]

[0460] procedure: An exemplary composition can be prepared using the following procedure. a. The indicated amounts of minocycline hydrochloride, microcrystalline cellulose, hydroxypropyl cellulose, polyethylene oxide and croscarmellose sodium were sieved through a suitable sieve. b. The blend of step (a) was lubricated using sodium stearyl fumarate to prepare the bioadhesive portion. c. The required amounts of minocycline hydrochloride, microcrystalline cellulose, hydroxypropyl methylcellulose, polyethylene oxide and croscarmellose sodium were sieved through a suitable sieve. d. The blend of step (c) was lubricated with sodium stearyl fumarate to prepare the modified release portion. e. The lubricated blend of step (b) was compressed onto the drug-loaded modified-release and bioadhesive portion into a bilayer tablet.

[0461] (Examples 7 to 8)

[0462] Exemplary pharmaceutical compositions containing minocycline were prepared as shown in Table 3. [Table 3]

[0463] procedure: An exemplary composition can be prepared using the following procedure. a. The required amounts of minocycline hydrochloride, microcrystalline cellulose and / or polyethylene oxide were sieved through a suitable sieve. b. The required amounts of microcrystalline cellulose, colloidal silicon dioxide and sodium stearyl fumarate were sieved through a suitable sieve. c. A solution of hydroxypropyl methylcellulose was prepared in a mixture of isopropyl alcohol and water. d. The powder mass of step (a) was granulated with the solution of step (c). e. The granules of step (d) were dried in a suitable dryer and the dried granules were passed through a suitable sieve. f. Example 7: The dried granules of step (e) were lubricated by mixing with the powder mass of step (b) and compressed into tablets. g. Example 8: The dried granules of step (e) were lubricated by mixing with the powder mass of step (b), compressed into tablets, and subsequently coated with an outer top coating composition as described in Examples 1-5.

[0464] Example 9

[0465] The pharmacokinetic parameters of the pharmaceutical compositions as shown in Examples 1 and 3 were investigated by using an open-label, six-cohort pharmacokinetic study. A total of 24 healthy human subjects were randomized into six groups and orally administered a single dose of the compositions of Examples 1 and 3 and 40 mg doxycycline capsules, ORACEA®. Subjects received treatment on Day 1, followed by sampling, and continued self-administration for the next 19 days. At steady-state levels on Day 21, subjects were dosed under supervision, followed by sampling, and discharged 24 hours later. Plasma and interstitial fluid sampling was performed, and the results are shown in Tables 4, 5, 6, 7, and 8 below. [Table 4] [Table 5] [Table 6] [Table 7] [Table 8]

[0466] Example 10

[0467] The pharmaceutical compositions shown in Examples 1 and 3 were investigated in a 16-week, multicenter, randomized, double-blind, parallel-group, controlled study to evaluate their efficacy. Subjects at least 18 years of age diagnosed with papulopustular rosacea were randomized into four different treatment groups (50 subjects in each of Groups 1-4). Each subject was assigned to one of the treatment groups and received a single oral dose of Example 1 (Group 1) or Example 3 (Group 2); ORACEA® 40 mg doxycycline capsules (Group 3); or placebo capsules (Group 4) for 16 weeks. Subject visits were scheduled at screening, baseline (Day 1), and Weeks 4, 8, 12, and 16.

[0468] Clinical evaluation of efficacy was based on the proportion of subjects with IGA "treatment success (reduction in IGA grade)" and reduction in total inflammatory lesion count (sum of papules, pustules, and nodules) from baseline (day 1) to weeks 4, 8, 12, and 16. The results are shown in Table 9 (IGA "treatment success"), Table 10 (total inflammatory lesion change), Table 11 (P value), and Figures 6, 7, and 8 below. [Table 9] [Table 10] [Table 11]

Claims

[Claim 1] The invention as described in the drawings.

Images