U.S. patent application number 11/776669 was filed with the patent office on 2008-07-31 for method for the treatment of acne.
This patent application is currently assigned to MEDICIS PHARMACEUTICAL CORPORATION. Invention is credited to Kuljit Bhatia, Bhiku Patel, R. Plott, Mitchell Wortzman.
Application Number | 20080182825 11/776669 |
Document ID | / |
Family ID | 37568356 |
Filed Date | 2008-07-31 |
United States Patent
Application |
20080182825 |
Kind Code |
A2 |
Wortzman; Mitchell ; et
al. |
July 31, 2008 |
METHOD FOR THE TREATMENT OF ACNE
Abstract
A method for treatment of acne with tetracyclines is provided. A
lower sustained dose and no loading dose is employed, with an
optional once-a-day dosing regimen.
Inventors: |
Wortzman; Mitchell;
(Scottsdale, AZ) ; Plott; R.; (Briscoe, TX)
; Bhatia; Kuljit; (Nesconset, NY) ; Patel;
Bhiku; (Chandler, AZ) |
Correspondence
Address: |
MARLIN J MESSICK
1553 FOREST AVENUE
SARALAND
AL
36571
US
|
Assignee: |
MEDICIS PHARMACEUTICAL
CORPORATION
8125 North Hayden Road
Scottsdale
AZ
85258
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20070270390 A1 |
November 22, 2007 |
|
|
Family ID: |
37568356 |
Appl. No.: |
11/776669 |
Filed: |
July 12, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11/166,817 |
Jun 24, 2005 |
|
|
|
11776669 |
Jul 12, 2007 |
|
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Current U.S.
Class: |
514/152 |
Current CPC
Class: |
A61P 31/02 20180101;
A61P 17/10 20180101; A61K 31/65 20130101 |
Class at
Publication: |
514/152 |
International
Class: |
A61K 31/65 20060101
A61K031/65; A61P 17/10 20060101 A61P017/10 |
Claims
1. An oral dosage form comprising: an antibiotically effective dose
of an oral minocycline; and a pharmaceutically suitable delivery
vehicle having a fast dissolving carrier and a slow dissolving
carrier, wherein said fast dissolving carrier and said slow
dissolving carrier of said vehicle are at a weight ratio of about
0.3 to about 0.5; wherein the oral dosage form for administration
once a day provides a patient with about 0.5 mg/kg/day to about 1.5
mg/kg/day of said oral minocycline; wherein said vehicle
continuously releases, without an initial load dose, said oral
minocycline at a rate so that C.sub.max is reached at about 2.75 to
about 4 hours after administration.
2. The oral dosage form of claim 1, wherein said oral minocycline
is minocycline as hydrochloride.
3. The oral dosage form of claim 1, wherein the ratio of fast
dissolving carrier to slow dissolving carrier is about 0.35 to
about 0.45.
4. The oral dosage form of claim 1, wherein the ratio of fast
dissolving carrier to slow dissolving carrier is about 0.36 to
about 0.40.
5. The oral dosage form of claim 1, wherein said fast dissolving
carrier comprises lactose monohydrate.
6. The oral dosage form of claim 1, wherein said slow dissolving
carrier is selected from the group consisting of polyvinyl
pyrrolidone, polyvinyl acetate, microcrystalline cellulose, methyl
cellulose, ethyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, magnesium stearate, and calcium
stearate.
7. The oral dosage form of claim 1, wherein said slow dissolving
carrier comprises hydroxypropylmethyl cellulose.
8. The oral dosage form of claim 1, wherein said slow dissolving
carrier is present at about 23.5% to about 27.0% by weight of said
oral dosage form.
9. The oral dosage form of claim 1, wherein said slow dissolving
carrier is present at: 23.5% by weight of said oral dosage form
when said oral dosage form comprises 135 mg of said oral
minocycline; or 27.0% by weight of said oral dosage form when said
oral dosage form comprises 45 mg of said oral minocycline.
10. The oral dosage form of claim 1, wherein said oral dosage form
is formulated to release said oral minocycline at a rate so that
C.sub.max is reached at about 3.0 to about 3.75 hours after
administration.
11. The oral dosage form of claim 1, wherein said oral dosage form
is a tablet or caplet comprising 45 mg or 135 mg of said oral
minocycline.
12. The oral dosage form of claim 1, further comprising an
intragranular fast dissolving carrier.
13. The oral dosage form of claim 12, wherein said slow dissolving
carrier encapsulates said intragranular fast dissolving
carrier.
14. The oral dosage form of claim 1, further comprising a
coating.
15. An oral dosage form comprising: an antibiotically effective
dose of an oral minocycline; and a pharmaceutically suitable
delivery vehicle having a fast dissolving carrier and a slow
dissolving carrier, wherein said fast dissolving carrier and said
slow dissolving carrier of said vehicle are at a weight ratio of
about 0.3 to about 0.5; wherein the oral dosage form for
administration once a day provides a patient with about 0.5
mg/kg/day to about 1.5 mg/kg/day of said oral minocycline; wherein
said vehicle continuously releases, without an initial load dose,
said oral minocycline at a rate of either about 25 to about 52%
within about 1 hour, about 53 to about 89% within about 2 hours,
and at least about 90% within about 4 hours, or about 30 to about
52% within about 1 hour, about 53 to about 84% within about 2
hours, and at least about 85% within about 4 hours.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 11/166,817 filed on Jun. 24, 2005 the entire disclosure of
which is incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates to the treatment of acne vulgaris,
commonly known simply as "acne." Acne is a disease of the skin in
which the pilosebaceous structures of the skin become inflamed,
leading to the formation of comedones, pustules and nodules. Acne
can lead to permanent scarring in severe cases.
[0003] It is generally believed that acne arises when
hyperkeratosis of the pilosebaceous structure wholly or partially
blocks the opening of the structure, resulting in comedones filled
with sebum, keratin, and Propionibacterium acnes. These lesions are
commonly identified as acne. P. acnes naturally occurs in normal
skin, but is especially and characteristically present in acne
lesions. It is believed that metabolic byproducts and waste from P.
acnes within the pilosebaceous structures cause or contribute to
the inflammation of acne lesions.
[0004] Conventional acne treatments have taken many forms. Topical
keratolytic agents, such as salicylic acid are sometimes used.
Keratolytic agents are thought to encourage the opening up of
blocked pilosebaceous structures, thereby reducing conditions that
are favorable to inflammation. Benzoyl peroxide, an anti-microbial,
remains a popular and effective treatment. Topical antibiotics,
such as clindamycin, which are effective against P. acnes, have
also been used with a view towards preventing the formation of
metabolic byproducts from this organism. Topical retinoids such as
tretinoin have also been used in the treatment of acne.
[0005] Systemic (i.e. non-topical) treatments for acne include the
use of oral antibiotics in more serious cases. These treatments are
directed towards the reduction in the amount P. acnes in the skin,
especially the pilosebaceous structures, and seek to reduce the
inflammation caused by waste materials and metabolic byproducts
from these organisms. Tetracycline antibiotics are most commonly
used for this purpose. These include tetracycline, minocycline and
doxycycline. Erythromycinis also sometimes used.
[0006] Standard oral minocycline therapy for acne in pediatric
patients calls for the administration of a 4 mg/kg initial loading
dose, and a 2 mg/kg dose every 12 hours thereafter. This results in
a dose of 6 mg/kg on the first day of treatment and a 4 mg/kg dose
each day thereafter. In adults, a 200 mg initial dose is followed
by a 100 mg dose every 12 hours thereafter. In a typical patient,
this results in about a 4.5 mg/kg dose on the first day of
treatment, and 3.0 mg/kg dose each day thereafter.
[0007] In cases where acne does not respond to oral antibiotic
treatment, oral isotretinoin is sometimes used. While effective,
isotretinoin is also powerfully teratogenic, and women of
childbearing age are required to use multiple methods of
contraception while taking the drug.
[0008] While oral tetracycline antibiotics remain a highly favored
and widely used treatment for more serious cases of acne, it is not
without side effects. Vestibular side effects, including extreme
dizziness and concomitant nausea, can be so severe as to result in
discontinuance of tetracycline therapy. Long term use can sometimes
result in vaginal candidisis, esophageal erosions and in antibiotic
resistant infections.
[0009] Some recent research has indicated that very low doses of
oral tetracycline can result in some improvement of acne even
though the dose of tetracycline is too low to have an antibiotic
effect. This observation has been attributed to an
anti-inflammatory effect of tetracycline compounds. This effect has
been reported to have been observed even where a chemically
modified tetracycline that have no antibiotic properties are used.
The use of tetracycline antibiotics at a dose too low to have an
antibiotic effect or the use of modified tetracycline having no
antibiotic properties as treatments for acne has never been
approved by any drug regulatory agency.
SUMMARY OF THE INVENTION
[0010] According to the present invention, a method is provided for
the treatment of acne in which an antibiotically effective dose of
an oral tetracycline, such as minocycline, is provided. This dose
is approximately 1 milligram per kilogram of body weight (1 mg/kg),
without an initial loading dose of antibiotic. This antibiotic
dosing regimen has been found to be as effective as a conventional
dosing regimen incorporating a significant initial loading dose and
higher subsequent doses. However, the dosing method of the current
invention produces far fewer side effects.
[0011] In another aspect of this invention, the oral tetracycline
is provided in a dosage form that provides for the continued
release of the antibiotic between doses, as opposed to an immediate
or nearly immediate release of the drug.
DETAILED DESCRIPTION OF THE INVENTION
[0012] According to the present invention, acne vulgaris is treated
by the use of an oral tetracycline antibiotic, preferably
minocycline. This antibiotic is administered in an antibiotically
effective amount of approximately 1.0 milligram per kilogram of
body weight per day (1.0 mg/kg/day). While this may be accomplished
by the use of divided doses, it is preferred that the tetracycline
antibiotic be delivered in a single daily dose. This treatment
regime is initiated without a loading dose, and is continued until
resolution or substantial resolution of the patient's acne. The
course of treatment typically lasts 12 to up to 60 weeks, but will
be adjusted according to the disease status and other medical
conditions of each patient in the exercise of ordinary good
clinical judgment by the patient's health care provider.
[0013] Controlled, double-blinded studies were undertaken to
determine the effectiveness of this invention. Treatment of 473
patients with acne was undertaken according to the present
invention. Placebos were provided to 239 patients. The
effectiveness of the invention in treating acne vulgaris is shown
in Table 1. TABLE-US-00001 TABLE 1 Total Lesion Counts Total
Lesions Total Lesions (as Percent of Baseline) Baseline (mean)
169.3 100 Day 28 (mean) 134.0 78 Day 56 (mean) 119.3 69 Day 84
(mean) 112.3 66 Inflammatory Lesion Counts Inflammatory
Inflammatory Lesions (as Lesions Percent of Baseline) Baseline
(mean) 77.4 100 Day 28 (mean) 52.1 66 Day 56 (mean) 44.3 56 Day 84
(mean) 41.9 53
[0014] While effective as a treatment for acne, this resulted in
almost no side effects above those observed with a placebo, as
shown in Table 2. TABLE-US-00002 TABLE 2 % Subjects with Adverse
Events Minocycline Placebo At least One Adverse Event 56.2 54.1 At
Least One Serious 0.4 0 Adverse Event Blood/Lymphatic System 0.3
0.3 Disorders Cardiac Disorders 0.3 0 Ear and Labyrinth Disorders
3.6 3.3 Endocrine Disorders 0.3 0 Eye Disorders 2.2 2.7
Gastrointestinal Disorders 21.2 26.1 General Disorders and 13.8
10.4 Administrative Site Conditions Immune System Disorders 0.7 2.5
Infections and Infestations 9.3 11.0 Laboratory Blood 0.7 1.1
Abnormalities Metabolism and Nutrition 0.6 0.3 Disorders
Musculoskeletal and 4.6 3.6 Connective Disorders Neoplasms Benign,
0.1 0 Malignant and Unspecified Nervous System Disorders 29.2 25.8
Psychiatric Disorders 6.4 7.1 Renal and Urinary Disorders 0.3 0.5
Reproductive System and 0.7 0.3 Breast Disorders Respiratory,
Thoracic and 5.3 6.9 Mediastinal Disorders Skin and Subcutaneous
8.6 7.1 Tissue Disorders Vascular Disorders 1.0 0.3
[0015] The effectiveness of this invention can be seen by comparing
the above efficacy data with published data on the effectiveness of
conventional tetracycline treatments for acne in the reduction of
total acne lesions and in the reduction of inflammatory lesions.
See, e.g. Hersel & Gisslen, "Minocycline in Acne Vulgaris: A
Double Blind Study," Current Therapeutic Research, 1976.
[0016] Because of the variations in body weight encountered in
clinical practice, in the actual practice of this invention it is
not practical to provide every patient with exactly 1 mg/kg/day of
oral tetracycline antibiotic. However, it is acceptable to
approximate this dose by providing the patient with from 0.5 to 1.5
mg/kg/day although from 0.7 to 1.3 mg/kg/day is preferred, and 1.0
mg/kg/day is ideal.
[0017] While it can be effective to provide the oral tetracycline
antibiotic in divided doses taken over the course of a day (e.g.
twice or three times a day), it is preferable to provide the oral
tetracycline antibiotic in a dosage form that releases the
antibiotic slowly during the course of a day so that once-a-day
dosing is possible. While delayed release dosage forms are known in
the art, the formulation of them is far from predictable and the
selection of a specific delayed release formulation is accomplished
more by trial and error than by mathematical prediction based on
known properties of delay release agents. No delayed release
product useful in the present invention has been known
heretofore.
[0018] It has been discovered that the ratio of fast dissolving
carriers to slow dissolving carriers in the core caplet is
important in obtaining a dissolution profile that enables
once-a-day dosing in accordance with the present invention. By
keeping the ratio of these components within a certain range, one
may obtain this result.
[0019] The fast dissolving carrier is any binder, vehicle, or
excipient that quickly dissolves in an aqueous physiological
medium, such as gastric fluid, thereby tending to quickly release
the active ingredient. Lactose, its salts and hydrates are good
examples of such components. It has been observed that sometimes a
portion of the fast dissolving components are formulated in a
manner that results in the complete or partial encapsulation or
inclusion or coating of these fast-dissolving materials in granules
of slow-dissolving materials. These encapsulated materials are
excluded from the calculation of the above mentioned ratio of
fast-dissolving to slow dissolving components.
[0020] A slow dissolving carrier is any binder, vehicle, or
excipient that dissolves slowly over the course of hours and
perhaps a day, thereby slowing the release of the active
ingredient. Examples of such components are polyvinyl pyrrolidone,
polyvinyl acetate, microcrystalline cellulose, methyl cellulose,
ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl
cellulose, or waxy or lipid-based tableting agents such as
magnesium stearate or calcium stearate. Outer "enteric" coatings
are excluded from this amount when calculating the above-mentioned
ratio.
[0021] Insoluble carriers are binders, vehicles, or excipients that
are practically insoluble in physiological fluids, such as gastric
fluid, and includes compounds, such as silicon dioxide and
talc.
[0022] While the exact formulation of these dosage forms can vary,
it has been observed that it is advantageous to formulate them so
that the ratio of fast dissolving carriers to slow dissolving
carriers is from 0.30 to 0.50, and preferably from 0.35 to 0.45. A
ratio of about 0.36 to 0.40 is particularly preferable.
[0023] Dosage forms, such as capsules, tablets, and caplets that
release 25 to 52% of the antibiotics within 1 hour, 53 to 89% in 2
hours, and at least 90% within 4 hours are suited to the once-a-day
dosage regimen contemplated by the current inventories. More
preferably, 30 to 52% of the antibiotic is released within 1 hour,
53 to 84% within 2 hours, and at least 85% within 4 hours.
[0024] Alternatively, the oral tetracycline antibiotic may be
delivered in a dosage form that releases the antibiotic in such a
way that the maximum blood concentration of the antibiotic
(C.sub.max) is reached at about 3.5 hours after administration
(T.sub.max). In actual practice of the invention, the C.sub.max
should be reached between 2.75 and 4.0 after administration, more
preferably between 3.0 and 3.75 after administration.
[0025] As examples of such a once-a-day formulation, one may use
the following: TABLE-US-00003 Quantity Component (mg) 135 mg Caplet
Minocycline (as 145.8 hydrochloride) (dry weight) Lactose 107.4
Monohydrate (intragranular) Lactose 43.8 Monohydrate
(extragranular) Total Lactose 151.2 Monohydrate HPMC 94 Silicon
Dioxide 3 Mg. Stearate 6 45 mg Caplet Minocycline (as 48.6
hydrochloride) (dry weight) Lactose 192.2 Monohydrate
(intragranular) Lactose 42.2 Monohydrate (extragranular) Total
Lactose 234.40 Monohydrate HPMC 108 Silicon Dioxide 3 Mg. Stearate
6
[0026] Each of these components is combined in a conventional
fashion, compressed in a tabletting apparatus, and then provided in
a conventional manner with a suitable coating, such as, without
limitation Opadry II and optional coloring.
* * * * *