(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2008/0188441 A1
`Reinmuller et al.
`(43) Pub. Date:
`Aug. 7, 2008
`
`US 20080188441A1
`
`(54) COMPOSITION FORTREATING
`NFLAMMLATORY DISEASES
`
`(76) Inventors:
`
`Johannes Reinmuller, Wiesbaden
`(DE); Kay Dirting, Wiesbaden
`(DE)
`Correspondence Address:
`MILLEN, WHITE, ZELANO & BRANGAN, P.C.
`2200 CLARENDON BLVD., SUITE 1400
`ARLINGTON, VA 22201.
`
`21) Appl. No.:
`(21) Appl. No
`(22) PCT Filed:
`
`10/S86,345
`9
`Jan. 12, 2005
`
`(86). PCT No.:
`
`PCT/EP2005/000215
`
`S371 (c)(1),
`(2), (4) Date:
`
`Jul. 14, 2006
`
`(30)
`
`Foreign Application Priority Data
`
`Jan. 14, 2004 (DE) ...................... 10 2004 OO2 OO1.9
`
`Publication Classification
`
`(51) Int. Cl.
`(2006.01)
`A63L/728
`(2006.01)
`A6IP 700
`(2006.01)
`A6IP27/02
`(2006.01)
`A6IR 8/73
`(2006.01)
`A61O 19/00
`(52) U.S. Cl. .......................................................... 514/54
`
`ABSTRACT
`(57)
`The present invention relates to the use of hyaluronic acid for
`treating inflammatory diseases, in particular skin or mucous
`membrane diseases.
`
`Exhibit 1037
`Prollenium v. Allergan
`
`

`

`US 2008/0188441 A1
`
`Aug. 7, 2008
`
`COMPOSITION FOR TREATING
`NFLAMMATORY DISEASES
`
`0001. The present invention relates to the use of hyalu
`ronic acid for treating inflammatory diseases, in particular
`skin diseases or mucous membrane diseases.
`0002. A great number of skin diseases, in particular those
`of the atopic type, have not been explained causally. Com
`monly, these diseases are inflammatory reactions of the der
`mis and of the dermoepithelial transition Zone. It is known
`that in these diseases considerable shifts in the normal hyalu
`ronic acid content in the dermis and epidermis occur. The
`treatment of such diseases at present consists in various mea
`Sures, e.g. administration of fat-containing ointments, creams
`or lotions with addition of different active compounds. Most
`effectively, such inflammatory diseases, however, are treated
`with corticoid-containing preparations for external (topical)
`use. The adequately known local and systemic side effects of
`the corticoids (derivatives of the endogenous steroid hormone
`cortisol) are to be expected here. In the case of chronic use of
`the topical corticoid preparations, as a rule delayed conse
`quences occur, such as, for example, cutaneous atrophy.
`0003. Another means of treatment consists in the use of
`agents which attack cells of the immune system and inhibit
`the biosynthesis of immunomodulators, such as, for example,
`cyclosporin, tacrolism and pimecrolism. Substances having
`Such actions are also described as immunosuppressants,
`because they suppress the immune response of a bioorgan
`ism. Their use is thus considerably restricted, since an intact
`immune system is essential for a permanently satisfactory
`state of health. Use is thus suitable only in the case of severe
`symptoms and in physically mature individuals. Long-term
`risks and the risks of long-term use. Such as, for example,
`carcinogenicity, are completely unexplained.
`0004. There is therefore a need to develop new agents for
`treating inflammatory skin diseases or mucous membrane
`diseases, in which the disadvantages of the prior part can be at
`least partly avoided.
`0005 Surprisingly, it has been found that hyaluronic acid,
`a glycosaminoglycan, is outstandingly suitable for treating
`inflammatory skin diseases or mucous membrane diseases, in
`particular of inflammatory skin diseases of the atopic type.
`0006. One subject of the invention is thus the use of hyalu
`ronic acid for the production of a composition for preventing
`or treating inflammatory skin diseases or mucous membrane
`diseases.
`0007. A further subject of the invention is a process for
`preventing or treating an inflammatory skin or mucous mem
`brane disease, where a preparation is administered to a Sub
`ject to be treated, for example a human patient or alternatively
`an animal, which contains hyaluronic acid in an amount
`adequate for treating the disease.
`0008. The administration of hyaluronic acid can in prin
`ciple be carried out in any desired manner, provided this is
`Suitable for treating the respective disease. In many cases,
`local administration is carried out in the area of the diseased
`skin site, e.g. a lesion. Preferably, administration is carried
`out intradermally, e.g. by injection, or by topical application
`to the diseased skin site.
`0009 For the treatment of inflammatory skin diseases,
`hyaluronic acid is suitable both in uncrosslinked form and in
`crosslinked form or mixtures thereof. Uncrosslinked hyalu
`ronic acid is preferably selected from (i) long-chain hyalu
`
`ronic acid having an average molecular weight (weight-aver
`age) of at least 200 kD and (ii) short-chain hyaluronic acid
`having an average molecular weight (weight-average) up to
`50 kD or mixtures thereof.
`0010 Crosslinked hyaluronic acid can be, for example,
`covalently or noncovalently crosslinked. The preparation of
`crosslinked hyaluronic acid can be carried out per se in a
`known manner. Covalent crosslinkage can in general be car
`ried out here by crosslinking with bifunctional reactive
`agents, such as, for example, glutaraldehyde or carbodiimide,
`via bifunctional amino acids, e.g. lysine, protamines or albu
`mins. It is also possible, however, to produce crosslinkages by
`means of an amide, ester or ether bond for example. Further
`Suitable reagents for the covalent crosslinkage of hyaluronic
`acid are ethylene glycol diglycidyl ether or 1,4-butanediol
`diglycidyl ether, divinyl sulfone, photocrosslinking reagents,
`Such as ethyleosin, hydrazides, such as bishydrazide, trishy
`drazide and polyvalent hydrazide compounds. Furthermore,
`intra- or/and intermolecularly esterified hyaluronic acid
`derivatives can also be employed. A noncovalent crosslinkage
`using multivalent metal ions, such as, for example, iron, cop
`per, Zinc, calcium, magnesium, barium and other chelating
`metal ions is particularly preferred.
`0011
`Hyaluronic acid is commercially obtainable in the
`crosslinked State (e.g. Hylaform R), a crosslinked hyaluronic
`acid from Biomatrix, NJ. USA; for preparation see also U.S.
`Pat. No. 4,713,448, U.S. Pat. No. 4,605,691 APC(R) from
`Fidia, Incert(R) from Anika Therapeutics, Intergel(R) from
`LifeCore or Restylane from Q-Med).
`0012. In use, the molecular weight and, in the case of
`crosslinked hyaluronic acid products, the degree of crosslink
`age is of importance which, for example, is in the range from
`0.1% to 10%, without being restricted thereto. Generally, it is
`to be observed that with long-chain hyaluronic acid a lower
`degree of crosslinking Suffices in order to obtain a gelatinous
`matrix, whereas with short-chain hyaluronic acid a higher
`degree of crosslinkage is necessary in order to obtain compa
`rable properties.
`0013 The hyaluronic acid preparation according to the
`invention can be employed both in human medicine and in
`Veterinary medicine, for example for treating domestic ani
`mals or agricultural animals.
`0014. The pharmaceutical compositions according to the
`invention contain the hyaluronic acid preferably in amounts
`from 0.01 to 20% by weight, based on the total pharmaceu
`tical composition, in particular in an amount from 0.01 to 5%
`by weight and particularly preferably in an amount from 0.01
`to 1% by weight.
`0015. As pharmaceutical excipients, the pharmaceutical
`compositions according to the invention can contain, for
`example, agents for pH adjustment, stabilizing agents, anti
`oxidants, solubilizers, penetration-promoting agents, preser
`Vatives or/and gel-forming agents, such as are customarily
`used in Such compositions. They are used in the amounts
`customary in Such preparations.
`0016. In addition to the active compound hyaluronic acid,
`the pharmaceutical compositions according to the invention
`can optionally also contain still further pharmaceutical active
`compounds which are compatible with hyaluronic acid in the
`course of application, e.g. active compounds for the therapy
`of skin diseases (dermatoses), antimycotics, antibiotics (e.g.
`gentamycin, Vancomycin, penicillins or cephalosporins), Sul
`fonamides; disinfectants, hormones (e.g. corticoids) and hor
`mone derivatives (e.g. cortisol), local anesthetics (of the
`
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`US 2008/0188441 A1
`
`Aug. 7, 2008
`
`lidocaine or novocaine type), vasoactive Substances for vaso
`constriction (avoidance of hemorrhages), adrenalin, enzymes
`(such as, for example, hyaluronidase), interleukins, growth
`factors (e.g. EGF, PDGF or/and IGF), vitamins (e.g. vitamin
`D), skincare agents and/or circulation-promoting (hyperem
`izing) agents. The further active compounds can optionally be
`associated with the hyaluronic acid, e.g. by covalent or non
`covalent interactions.
`0017. Also of importance are additives, such as, for
`example, di- or trivalent metal ions, which can have a
`crosslinking and stabilizing action as a result of chelate for
`mation, which on the other hand can also accelerate the deg
`radation of the active hyaluronic acid.
`0018. In the tissue, the degradation of hyaluronic acid is
`carried out naturally by a large number of different hyalu
`ronidases or by oxygen free radicals. Therefore additives
`which have an inhibitory action on hyaluronidases (heparin,
`indomethacin or/and Salicylates) and those which prevent the
`oxidative degradation of hyaluronic acid in the tissue as “free
`radical traps” (vitamins A, E or/and C) are furthermore of
`importance.
`0019. A particularly preferred embodiment of the prepa
`ration according to the invention are mixtures of long-chain
`hyaluronic acid (? 200 kD) with short-chain hyaluronic acid
`(e.g. hexamers of the repetitive disaccharide units or larger
`units up to 50 kD) or alternatively mixtures of the aforemen
`tioned with crosslinked hyaluronic acid. Viscous injectable
`preparations result here, which are preferably introduced
`intradermally using injection needles (e.g. 30 gauge) or
`extensively by injection on the border of the dermoepidermal
`transition. The raising of isolated weals is also suitable
`according to the invention. The known local anesthetics can
`be added to the injectable hyaluronic acid preparations for
`minimization of the painfulness of the injection.
`0020. A further particularly preferred embodiment are
`mixtures of crosslinked hyaluronic acid and noncrosslinked
`hyaluronic acid.
`0021. Instead of the injection technique using needles, the
`preparations according to the invention can also be adminis
`tered extremely effectively by pressure injection. This pro
`cess is distinguished by extensive freedom from pain.
`0022. Further preparations according to the invention of
`the active compound are aqueous Solutions or emulsions for
`intravenous administration or for instillation into body cavi
`ties or hollow organs.
`0023. Since the barrier function of the dermoepithelial
`transition and of the deeper epidermal layers is disturbed by
`the inflammatory process of the entire skin in the case of one
`of the aforementioned diseases, the preparations according to
`the invention can also be applied topically, i.e. Superficially, to
`the skin in the form of ointments, creams, lotions, gels,
`sprays, tinctures, shampoos or occlusive films. A particular
`form of preparation within the meaning of the invention is a
`dry hyaluronic acid preparation in the form of a powder,
`which is used in particular for treating weeping eczema. The
`invention also relates to the introduction of the active com
`pounds in micro-encapsulated form or in the form of lipo
`Somes. A large number of Such topical preparations are
`known from the cosmetics field, these Substances being
`applied exclusively to healthy and intact skin.
`0024 Surprisingly, it has emerged that on use according to
`the invention of Such topical preparations on inflammatory
`skin, an exacerbation, for example, does not occur, but a
`regression of the inflammatory symptoms. If mucous mem
`
`branes of the airways have to be treated, aerosols can also be
`employed according to the invention as inhalation Solutions.
`0025. The compositions according to the invention can be
`prepared in a generally known manner, which is customary
`per se for the preparation of Such compositions. Here, the
`sequence of the mixing of the individual constituents is not
`critical as a rule.
`0026. The nature, dose and the frequency of the adminis
`tration of the composition according to the invention and the
`condition (e.g. Viscosity, degree of crosslinking, active com
`pound content etc.) depend in particular on the nature and
`severity of the disease and on the age of the patient and the
`place and the nature of the application, e.g. the condition and
`the sensitivity of the inflamed site. If the compositions
`according to the invention are administered in the form of
`topically applicable preparations, the administration as a rule
`conforms to the conditions customary for Such compositions.
`0027. The nature of the treatment and the frequency of
`application in particular also depend on the individual
`responses of the persons to be treated. Preferably, an appli
`cation of gels or solutions takes place at intervals of several
`days up to one or two months, in particular about one to two
`weeks.
`0028. The invention also comprises mixtures of hyalu
`ronic acid with other glycosaminoglycans in crosslinked
`or/and noncrosslinked form. For possible combinations and
`crosslinking possibilities, reference is made to EP-B-0619
`737, DE-A-102.9966 and WO 03/041723. Mixtures of hyalu
`ronic acid and heparin are preferred. Mixtures of hyaluronic
`acid and positively charged glycosaminoglycans, such as chi
`tosamine, are furthermore preferred.
`0029. The following skin diseases can be treated particu
`larly Successfully using the preparations according to the
`invention: atopic dermatitis and eczematous skin diseases,
`Such as seborrheic eczema and microbial eczema, pruritus,
`prurigo, urticaria, redlichen, psoriasis, Such as psoriasis Vul
`garis, vitiligo, rosacea, perioral dermatitis, acne Vulgaris or
`acne conglobata, and chronic and acute ulcerations of the
`skin. In addition, the composition is Suitable for Supportive
`treatment in mycoses, in particular in combination with an
`antimycotic.
`0030) Surprisingly, viral skin diseases which lead to wart
`formation can also be favorably influenced using the prepa
`rations according to the invention, such as, for example, Ver
`ruca Vulgaris, condylomas, such as, for example, Vulvar warts
`(Condylomata accuminata), or other pathological skin Symp
`toms caused by viruses of the papilloma group. Hyaluronic
`acid is preferably injected here at the base of such lesions on
`the dermoepidermal transition. The action of hyaluronic acid
`on herpes viruses was known (see patent application WO
`03/041723).
`0031. A further group of diseases of the mucous mem
`branes are “aphthae'. Painful vesicles are formed on the
`mucous membranes here. The cause of aphthae formation is
`hitherto unknown. The use according to the invention of
`hyaluronic acid in the case of aphthae lead to an immediate
`regression of the painfulness and to Subsequent healing of the
`aphthae.
`0032. The uses of hyaluronic acid for the prevention or
`treatment of diseases of mucous membranes or of body open
`ings which are lined with these is also expressly regarded as
`a subject of the invention. In this connection, Suitable gelati
`nous preparations can be instilled into appropriate cavities or
`the mucous membrane lesions can be lined submucosally by
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`

`

`US 2008/0188441 A1
`
`Aug. 7, 2008
`
`Suitable techniques. Treatment successes can be achieved, for
`example, in polypous mucous membrane diseases, such as
`nasal polyposis, or in inflammatory intestinal diseases. The
`Submucosal administration of the active compound can in this
`case also be carried out endoscopically.
`0033. The use of the preparation according to the inven
`tion extends not only to the introduction into dermis and
`epidermis. In particular cases, the application of the prepara
`tion according to the invention under the dermis can also be
`necessary and is thus a use within the meaning of the inven
`tion. The introduction of the active compound into closed
`body cavities. Such as, for example, chest and abdominal
`cavity, is also according to the invention.
`0034. A further subject of the invention is the use of a
`preparation which contains a mixture of crosslinked and non
`crosslinked hyaluronic acid for cosmetic or pharmaceutical
`uses, in particular for treating skin or soft tissue defects, and
`also wrinkles of the skin.
`0035. From the use of crosslinked hyaluronic acid for the
`lining of skin wrinkles and similar defects, the side effects
`known are inflammatory reactions which appear in the form
`of redness, Swelling, burning, itching and with the formation
`of small intradermal nodules. These side effects can be sup
`pressed according to the invention by admixing non
`crosslinked hyaluronic acid to the preparations of exclusively
`crosslinked hyaluronic acid. Admixtures of low molecular
`weight fractions up to about 500 kD have proven favorable
`here. The protective effect, however, can also be achieved
`using noncrosslinked hyaluronic acid above the molecular
`size mentioned, it also being possible to employ fractions up
`to 5 million D. Therefore, mixtures of crosslinked and non
`crosslinked hyaluronic acid for employment in the cosmetic
`or pharmaceutical treatment of wrinkles, soft tissue defects
`and for the augmentative treatment of soft tissues (e.g. lips)
`are likewise a subject of the invention. With regard to further
`preferred embodiments for this subject, reference is made to
`the details above.
`0036. The use according to the invention also includes the
`employment of hyaluronic acid on the conjunctiva of the eye
`and of the cornea, hitherto only the use of noncrosslinked
`hyaluronic acid after laser ablation of the cornea being
`known. It has been shown that crosslinked hyaluronic acid
`and mixtures of crosslinked and noncrosslinked hyaluronic
`acid can also be employed in manipulations, injuries and
`inflammations of the cornea. In the case of shaping treatments
`on the cornea of the eye, the employment of hyaluronic acid
`between the cornea and shaping dish for the purpose of an
`improvement of the visual power is also described as accord
`ing to the invention. In the implantation of plastic lenses into
`the eye for the elimination of cataract, at present non
`crosslinked hyaluronic acid is applied to the surface of the
`plastic lens for lubrication. The application of the preparation
`according to the invention, in particular of a mixture of non
`crosslinked and crosslinked hyaluronic acid, optionally in
`combination with a further glycosamino-glycan, Such as hep
`arin, is more advantageous as a result, in that the postopera
`tive inflammatory reaction is Suppressed long-term and thus
`the occurrence of “after-cataract’ is prevented. On the con
`junctiva of the eye, according to the invention all inflamma
`tory changes, that is inflammation of the conjunctiva or con
`
`junctivitis, are favorably influenced. With regard to further
`preferred embodiments for this subject, reference is made to
`the details above.
`
`USE EXAMPLES
`Example 1
`0037. A 30 year-old female patient having atopic derma
`titis was treated according to the invention by extensively
`introducing by injection 0.1 ml of a long-chain hyaluronic
`acid (Hyal System, Merz, Frankfurt/M) intradermally under
`atopic lesions in the area of the elbow. As early as 3 days after
`treatment, the previously excruciating itching had subsided.
`The original inflammatory symptoms were clearly declining.
`Example 2
`0038. In a 14 year-old, a virus wart on the right index
`finger was intralesionally infiltrated with 0.1 ml of
`crosslinked hyaluronic acid (Juvederm 18, LEADerm, Hall
`bergmoos). After 4 weeks, intact skin without wart attack
`existed in the treated region.
`Example 3
`0039. The attacked skin areas of a 20 year-old man with
`acne Vulgaris on the face were intradermally injected 0.75 ml
`deep with Hylaform. After 4 weeks, the acute inflammatory
`changes of the skin had disappeared. A fresh occurrence of
`the disease was able to be suppressed for 6 months.
`1. The use of hyaluronic acid in crosslinked form for the
`production of a composition for preventing or treating inflam
`matory skin or mucous membrane diseases.
`2. The use as claimed in claim 1, characterized in that a
`composition for local administration is produced.
`3. The use as claimed in claim 1 or, characterized in that a
`composition for intradermal administration, for administra
`tion to the border of the dermoepithelial transition or for
`topical administration is produced.
`4. The use as claimed in claim 1, characterized in that the
`degree of crosslinking is in the range from 0.1% to 10%.
`5. The use as claimed in claim 1, characterized in that the
`crosslinked hyaluronic acid is present in a mixture with
`uncrosslinked hyaluronic acid.
`6. The use as claimed in claim 5, characterized in that the
`uncrosslinked hyaluronic acid is selected from
`(i) long-chain hyaluronic acid having an average molecular
`weight (weight-average) of at least 200 kD and
`(ii) short-chain hyaluronic acid having an average molecu
`lar weight (weight-average) up to 50 kD or mixtures
`thereof.
`7. The use as claimed in claim 1, characterized in that the
`composition furthermore contains an inhibitor of hyaluronic
`acid degradation.
`8. The use as claimed in claim 9, characterized in that the
`inhibitor of hyaluronic acid degradation is selected from hep
`arin, indomethacin, salicylates, free radical traps, such as
`vitamin A, C or E, and mixtures thereof.
`9. The use as claimed in claim 1, characterized in that the
`hyaluronic acid is present as an injectable preparation, oint
`ment, cream, lotion, gel, spray, tincture, shampoo, occlusive
`film, powder or inhalable preparation.
`10. The use as claimed in claim 1, characterized in that the
`composition furthermore contains another glycosaminogly
`can in crosslinked or uncrosslinked form.
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`US 2008/0188441 A1
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`Aug. 7, 2008
`
`11. The use as claimed in claim 1, characterized in that the
`inflammatory skin or mucous membrane disease is selected
`from atopic dermatitis, eczemas, such as Seborrheic and
`microbial eczemas, pruritus, prurigo, urticaria, red lichen,
`psoriasis, such as psoriasis Vulgaris, vitiligo, viral skin dis
`eases which lead to wart formation, such as Verruca Vulgaris
`or Condylomata accuminata, rosacea, perioral dermatitis,
`acne. Such as acne Vulgaris or acne conglobata, polypous
`mucous membrane diseases, such as nasal polyposis, and
`inflammatory intestinal diseases, chronic or acute ulcerations
`of the skin, aphthae and mycoses.
`12. The use as claimed in claim 1 in human medicine.
`13. The use as claimed in claim 1 in veterinary medicine.
`14. A process for preventing or treating and inflammatory
`skin or mucous membrane disease, characterized in that a
`preparation is administered to a Subject to be treated, which
`contains hyaluronic acid in crosslinked form in an amount
`adequate for treating the disease.
`15. The use of hyaluronic acid in crosslinked form for the
`production of a composition for preventing or treating inflam
`matory diseases of the eye.
`
`16. The use as claimed in claim 15 for preventing or treat
`ing inflammatory diseases of the conjunctiva or cornea.
`17. The use as claimed in claim 15 for preventing or treat
`ing after-cataract or inflammation of the conjunctiva.
`18. The use as claimed in claim 15, characterized in that the
`crosslinked hyaluronic acid is present in a mixture with
`uncrosslinked hyaluronic acid.
`19. The use as claimed in claim 15, characterized in that the
`composition furthermore contains another glycos-aminogly
`can in crosslinked or uncrosslinked form.
`20. The use of a mixture of crosslinked and un-crosslinked
`hyaluronic acid for the production of a cosmetic or pharma
`ceutical composition for treating skin or soft tissue defects
`and skin wrinkles.
`21. The use as claimed in claim 20, characterized in that the
`composition furthermore contains another glycos-aminogly
`can in crosslinked or uncrosslinked form.
`
`c
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