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`COMMISSIONER FOR PATENTS
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`FILING DATE
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`RICHARDSON P.C.
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`FISH.
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`September 28, 2009“
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`Attorney Docket No.: 07917-045002
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`225 Franklin Street
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`DELAWARE
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`NEW YORK
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`SAN DIEGO
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`Box Patent Application
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`Commissioner for Patents
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`‘
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`Presented for filing is a new continuation patent application of:
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`I
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`Applicant: James G. Dobson and Michael F. Ethier
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`Title:
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`TREATMENT OF SKIN WITH ADENOSINE OR ADENOSINE
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`ANALOG
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`Enclosed are the following papers, includ1ng those requ1red to rece1ve a filmg date
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`TWIN CITIES
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`2: WASHINGTON, DC
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`35
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`£3
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`In addition to the above-listed pages, the following items are enclosed herewith:
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`FISH a;
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`' ZHARDSON P.C.
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`Commissioner for Patents
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`September 28, 2000
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`Page 2
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`This application is a continuation (and claims the benefit of priority under 35 USC
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`§120) of US. application Serial no. 09/179,006, filed October 26, 1998. The
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`disclosure of the prior application is considered part of (and is incorporated by
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`The prior application is assigned of record to University of Massachusetts,
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`a Massachusetts corporation, by virtue of an assignment record in the US. Patent and
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`Trademark Office on January 7, 1999 at Reel/Frame 9690/0305.
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`Please send all correspondence to:
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`If this application is found to be incomplete, or if a telephone conference would
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`Respectfully submitted,
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`Reg. No. 34,310
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`i
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`TREATMENT OF SKIN WITH ADENOSINE OR ADENOSINE ANALOG
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`Abstract of the Disclosure
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`Methods for enhancing the condition of non-diseased
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`skin by application of compositions containing adenosine or
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`an adenosine analog are disclosed. Also disclosed are
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`methods for increasing DNA synthesis or protein Synthesis in
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`dermal cells, and methods for increasing dermal cell size,
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`by application of compositions containing adenosine.,
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`227728.311
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`Vfififimfififlflflflfifl
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`-‘23 -
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`v'Attomey’sDockcu.
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`07917-045002/(UMMC 97-32)
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`APPLICATION
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`I
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`FOR
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`UNITED STATES LETTERS PATENT
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`TITLE:
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`TREATMENT OF SKIN WITH ADENOSINE OR
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`ADENOSINE ANALOG
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`APPLICANT:
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`James G. Dobson and Michael F. Ethier
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`m.*1,2?“
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`333£231113%?ifsif}!”3&3
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`' Date of Deposit
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`Signature
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`Typed or Printed Name of Person Signing Certificate
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`CERTIFICATE OF MAILING BY EXPRESS MAIL
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`ExpressMailLabelNo. 5412943’05'9LL5 -
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`I hereby certify under 37 CFR §l.10 that this correspOndenoe is being
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`deposited with the United States Postal Service as Express Mail Post
`Office to Addressee with sufficient postage on the date indicated below
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`and is addressed to the Commissioner \for Patents, » Washington,
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`DC. 20231.
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`ATTORNEY DOCKET NO: 07917/045002
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`PATENT
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`TREATMENT OF SKIN WITH ADENOSINE OR ADENOSINE ANALOG
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`gm N
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`S atement as to Federally Sponsored Research
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`Work on this invention was supported by funds from
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`the United States government
`(Public Health Service Grants
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`HL-22828 and AG—11491).
`The government therefore has certain
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`rights in this invention.
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`Field of the Invention
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`This invention relates to dermatology and cell
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`biology.
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`dermis.
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`Background of the Invention
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`Skin includes a surface layer, known as the
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`epidermis, and a deeper connective tissue layer, known as the
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`The epidermis undergoes continuous turnover as the
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`outermost cells are exfoliated and replaced by cells that
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`arise from inner dermal layers.
`The dermis is composed of a
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`variety of cell types,
`including fibroblasts.
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`Skin thickness begins to decline in humans after the age
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`of 20 as the dermis becomes thinner and the number of skin
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`fibroblasts declines. As skin ages, or is exposed to UV
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`light and other environmental insults, changes in the
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`underlying dermis can lead to the functional and
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`morphological changes associated with damaged skin.
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`Decreases in the abundance and function of products of the
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`fibroblasts, which include collagen and proteoglycans, are
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`believed to play major roles in wrinkled and damaged skin.
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`Summary of the Invention
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`We have disc0vered that adenosine stimulates DNA
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`synthesis,
`increases protein synthesis, and increases cell
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`size in cultures of human skin fibroblasts. Based on this
`discovery,
`the invention provides methods and compositions
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`for enhancing the condition of skin.
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`In general,
`the invention provides a method for
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`enhancing the condition of non-diseased skin of a mammal,
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`e.g., a human.
`The method includes topically applying a
`therapeutically effective amount of a composition including
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`adenosine or an adenosine analog to non-diseased skin of the
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`mammal.
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`V
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`The invention also provides a method for promoting
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`healing of broken, non-diseased skin in'a mammal by
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`topically administering a composition including a
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`therapeutically effective amount of adenosine or an
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`adenosine analog to the mammal.
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`Also included in the invention is a method for
`increasing DNA synthesis in a dermal cell of non-diseased
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`skin of a mammal.
`The method includes topically
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`administering a therapeutically effective amount of
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`adenosine or an adenosine analog to a region of non-diseased
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`skin of the mammal containing dermal cell.
`The adenosine is
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`added so that it does not cauSe proliferation of the dermal
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`cell.
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`The invention also features a method of increasing
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`protein synthesis in a dermal cell of non-diseased skin of a
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`The method includes topically administering a
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`composition including a therapeutically effective amount of
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`adenosine or an adenosine analog to a region of skin of the
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`mammal containing the dermal cell.
`The adenosine or
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`adenosine analog does not cause proliferation of the dermal
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`mammal.
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`cell.
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`11/156
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`Also provided in the invention is a method of
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`increasing cell size in a dermal cell in non-diseased skin
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`of a mammal, e.g., a human.
`The method includes topically
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`administering a composition including a therapeutically
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`effective amount of adenosine to a region of skin of the
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`mammal containing the dermal cell, wherein addition of the
`adenosine does not cause proliferation of the dermal cell,
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`wherein addition of the adenosine does not cause
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`proliferation of the dermal cell.
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`The invention also includes a method for enhancing
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`skin condition in a mammal, e.g., a human.
`The method
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`includes providing fibroblasts from the mammal ex vivo,
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`culturing the fibroblasts in the presence of adenosine, and
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`reintroducing the
`fibroblasts into the- mammal.
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`The therapeutically effective amount of adenosine
`used in the above-described methods is preferably‘lo'3 M to
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`10'7 M, more preferably 10‘4 M to 10'6 M, and most preferably'
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`about 10'4 M.
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`The composition used in the above-described methods-
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`The
`can include a second agent
`in addition to adenosine.
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`second agent can be, e.g. an agent that promotes binding of
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`adenosine or an adenosine analog to an adenosine receptor,
`an angiogenic factor such as vascular endothelial cell
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`growth factor (VEGF), basic fibroblast growth factor (BFGF),
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`an agent that itself enhances skin condition, such as
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`tretoinin or another known conditioning agent such as an
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`emollient, a humectant, or an occlusive agent.
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`In preferred embodiments of the invention,
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`adenosine or an adenosine analog does not promote skin cell
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`the
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`proliferation.
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`The invention also provides a composition including
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`about'lO'3 M to about 10‘7 M adenosine and a therapeutically
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`effective amount of an angiogenesis factor.
`In some
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`embodiments,
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`MI
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`5
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`10
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` 15
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`gf
`g;
`i:
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`"enhancement of skin condition"
`As used herein,
`means a noticeable decrease in the amount of wrinkling,
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`roughness, dryness,
`laxity, sallowness, or pigmentary
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`mottling in skin.
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`As used herein, a "therapeutically effective amount"
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`of adenosine or an adenosine analog means an amount that
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`enhances skin condition when applied to skin.
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`As used-henein, "non-diseased skin" means skin free
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`of any proliferative disorder observable by visual
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`inspection.
`‘
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`invention advantageously allows for
`The present
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`enhancement of skin condition. This results in skin that
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`shows a less wrinkled,
`rough, or dry complexion.
`For
`
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`example,
`the invention provides for enhancing the condition
`
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`of skin damaged due to exposure to the sun or skin whose
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`condition has deteriorated due to normal aging.
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`Unless otherwise defined, all technical and
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`scientific terms used herein have the same meaning as~
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`commonly understood by one of ordinary skill in the art to
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`which this invention belongs. Although methods and
`materials similar or equivalent to those described herein
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`can be used in the practice or testing of the present
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`invention, suitable methods and materials are described
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`below. All publications, patent applications, patents, and
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`other references mentioned herein are incorporated by
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`reference in their entirety.
`In case of conflict,
`
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`present specification,
`including definitions, will control.
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`In addition,
`the materials, methods, and examples are
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`illustrative only and not
`intended to be limiting.
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`the composition of the adenosine is about 10*
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`Other features and advantages of this invention will
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`be apparent from the following description of the preferredv
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`embodiments thereof, and from the claims.
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`. Brief Description of the Drawings
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`Figs. 1A and 18 are histograms showing the effect of
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`adenosine on [3H]thymidine incorporation in cultures of
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`normal human skin (Fig. 1A) and lung fibroblasts (Fig. 1B).
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`After incubation in serum-free medium for 24 hours, cells
`were exposed to 10‘4 M adenosine for 18 hours. Medium was
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`replaced with serum-free medium without adenosine, and
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`PHJthymidine was added. Results are expressed as percent
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`PHJthymidine incorporation compared to control cultures
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`without adenosine and are means 1 SEM for 4-5 experiments.
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`"*" denotes value was significantly different from control
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`value without adenosine.
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`Figs. 2A and 2B are histograms showing concentration
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`responses of adenosine-stimulated protein synthesis in human.
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`skin fibroblasts from a young (Fig. 2A) and aged (Fig. 2B)
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`donor. Cells were grown to 75% confluence. Medium was then
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`replaced with serum-free medium with or without adenosine.
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`After 48 hours, PHlphenylalanine incorporation was
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`determined as described. Results are expressed as
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`%[3H]phenylalanine incorporation compared to control
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`cultures without adenosine and are means iSEM for 6-25
`
`experiments.
`"*“ denotes value was significantly different
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`from control value without adenosine.
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`15
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`20
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`25
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`im$$§figi§§€§€3
`.fififilmifi
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`
`
`
`
`Detailed Description
`
`
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`
`
`The invention is suitable for treating skin of a
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`mammal, e.g., a human, for which promotion of fibroblast-
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`associated dermal functions is desired.
`For example,
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`3O
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`-5-
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`25
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`
`
`promotion of fibroblast-associated functions is desirable in
`enhancing the condition of aged skin, which is associated
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`with a decrease in dermal cell function and is characterized
`by increased dryness or roughness, or both.
`The method can
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`also be used on subjects having otherwise damaged skin,
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`e.g., wrinkled skin and skin with a non-proliferative
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`disorder.
`The method can may further be used
`prophylactically on a subject to minimize deterioration of
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`skin condition associated with aging or environmental
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`factors, such as photodamage.
`Adenosine and suitable adenosine analogs are
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`suitable for use in enhancing skin condition. Adenosine
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`analogs such as adenosine agonists, adenosine receptor
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`agonists, and compounds that increase intracellular or
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`extracellular adenosine levels are suitable for use in the
`
`invention;
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`Agonists of adenosine include 2’-deoxyadenosine;
`
`
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`2’,3’-isopropoylidene adenosine;
`toyocamycin; l-
`
`
`
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`methyladenosine; N-6-methyladenosine; adenosine N-oxide; 62
`
`
`
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`methylmercaptopurine riboside, 6-chloropurine riboside, S’-
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`adenosine.monophosphate, S’-adenosine diphoSphate, or S’-
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`
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`adenosine triphosphate. Adenosine receptor agonists include
`
`
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`l-Methylisoguanosine,
`phenylisopropyl-adenosine ("PIA"),
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`
`
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`ENBA (S(-), Ns-Cyclohexyladenosine (CHA), N5-
`
`
`
`Cyclopentyladenosine (CPA), 2-Chloro-Ng-
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`
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`cyclopentyladenosine, 2-chloroadenosine, and adenosine amine
`
`
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`
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`congener
`(ADAC), all of which are agonists for the adenosine
`A1 receptor. Other receptor agonists include 2-p-(2-
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`carboxy-ethyl) phenethyl-amino-S’-N-ethylcarboxamido-
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`adenosine (CGS-21680), N-ethylcarboxamido-adenosine (NECA)
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`and napthyl—substituted aralkoxyadenosine (SHA-082), S’(N-
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`Cyclopropyl)-carboxamidoadenosine, DPMA (PD 129,944),
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`Metrifudil, which are agonists for the adenosine A2
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`_ 5 _
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`receptor. Other adenosine receptor agonists include those
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`which preferentially bind the A1 receptor relative to the A2.
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`receptor, such as 2—Chloroadenosine, Ns-PhenyladenOSine, and
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`Ns-Phenylethyladenosine; and those which preferentially bind
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`the Ag receptor relative to the A1 receptor, such as 2-
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`Phenylaminoadenosine and MECA.‘
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`Also_suitable for use are Compounds that increase
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`intracellular adenosine Concentration by inhibiting the
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`cellular uptake of adenosine or the breakdown of adenosine.
`
`One pathway of adenosine metabolism is the conversion of
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`adenosine to inosine by adenosine deaminase. An example of
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`an adenosine deaminase inhibitor is erythro-9-(2—hydroxy—3-
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`nonyl) adenine ("EHNA").‘ Adenosine kinase inhibitors can
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`also be used. Adenosine kinase converts adenosine to
`
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`-
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`10
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`15
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`20
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`25
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`
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`
`
`adenosine monophosphate by adenosine kinase. An example of
`
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`an adenosine kinase inhibitor is iodotubercidin. Other
`suitable compounds include those that inhibit the
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`dipyridamole—sensitive nucleoside transporter, which exports
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`adenosine from the cytoplasm, and agents that promote the
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`activity of a 5’-nucleotidase, e.g.,
`the ATP-activated 5’-
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`nucleotidase, which forms adenosine.
`Compounds that
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`increase tissue adenosine and ATP levels include acadesine
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`(AICA-riboside), which is described in Gruber et al.,
`
`
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`Circulation 80:1400-1411 (1989).
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`__Adenosine can be also be administered with a second
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`compound.
`The second compound can enhance the action of
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`adenosine or the adenosine analog, e.g., by enhancing
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`binding of adenosine or an adenosine analog to an adenosine
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`receptor. An example of such a compound is PD 81,728, which
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`is described in Kollias-Baker et al. J. Pharmacol. Exp.
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`Ther. 281:761—68. Alternatively,
`the second agent can
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`itself act to enhance skin condition. Examples of these'
`
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`types of agents include tretinoin, a recognized skin
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`_ 7 -
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`(see, e.g., Olsen et al., J. Amer. Acad.
`conditioning agent
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`Dermatol. 37:217-26, 1997), an angiogenic factor such as
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`vascular endothelial cell growth factor (VEGF) or basic
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`fibroblast growth factor (BFGF), or a conditioning agent.
`
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`u The second compound can also be a conditioning agent
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`such as an emollient, humectant, or occlusive agent.
`
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`Numerous examples of particular conditioning agents are
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`provided in the CTFA Cosmetic Ingredient Handbook (Cosmetic
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`Toiletries and Fragrances Association, Washington, D.D.,
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`1988). ‘Emollients help to maintain the soft, smooth, and
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`pliable appearance of skin and function by remaining on the
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`Skin surface or in the stratum corneum to act as lubricants,
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`to reduce flaking, and to improve the skin’s appearance.
`Examples of emollients include acetyl trioctyl citrate,
`
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`cetyl alcohol, butyl myristate, cetyl alcohol, and mineral
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`oil.
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`Humectants act to increase the water content of the
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`top layers of the skin. Humectants include, e.g., acetamide
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`MEA, fructose, and xylitol. Occlusive agents inhibit the
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`evaporation of water from skin,
`thereby increasing the water
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`contend of the skin. Acetylated castor oil, mineral oil,
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`and lauryl stearate are examples of-occlusive agents.
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`A subject can be treated by applying adenosine or an
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`
`
`adenosine analog in a pharmaceutical composition in an
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`
`
`effective amount and for a period of time sufficient to
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`improve the condition of the skin.
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`The pharmaceutical composition may be formulated
`
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`
`
`using conventional methods to prepare pharmaceutically
`
`
`
`
`useful compositions.
`Such compositions preferably-include
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`
`
`at least one pharmaceutically acceptable carrier, such as
`
`
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`
`
`
`those described in Remington’s PharmaceutiCal Sciences (E.W.
`
`
`
`
`
`
`
`
`Martin).
`In addition,
`the compositions preferably include a
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`
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`pharmaceutically acceptable buffer, preferably phosphate
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`
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`- 8 -
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`together with a pharmaceutically acceptable
`buffered saline,
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`compound for adjusting isotonic pressure, such as, for
`example, sodium chloride, mannitol, or sorbitol.
`
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`Adenosine or an adenosine agonist can also be
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`provided in carriers and adjuvants such as ion exchangers,
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`alumina, aluminum stearate,
`lecithin, serum proteins, such
`
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`»as human serum albumin, buffer substances, such as
`phosphates, glycine, sorbic acid, potassium sorbate, partial
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`glyceride mixtures of saturated vegetable fatty acids,
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`water, salts or electrolytes, such as protamine sulfate,
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`disodium hydrogen phosphate, potassium hydrogen phosphate,
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`sodium chloride, zinc salts, colloidal silica, magnesium
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`trisilicate, polyvinyl pyrrolidone, cellulose-based
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`
`
`substances and polyethylene glycol. Adjuvants for topical
`or gel base