.
`
`United States Patent [19]
`Kochinke et a1,
`'
`
`US005338548A
`
`[11] Patent Number:
`[45] Date of Patent:
`
`5,338,548
`Aug. 16, 1994
`
`[54] METHOD FOR INCREASING THE
`STORAGE STABILITY 01:
`PHYSOSTIGMINE
`
`[75] Inventors: Frank Kochinke; Richard W. Baker,
`both of Fremont, Calif.
`_
`_
`_
`[73] Asslgneez Pharmetrix Corporahon, Menlo
`Park, Cahf-
`
`_
`
`[21] APPl' No" 201m”
`22 F1 :
`F . 17
`[
`]
`led
`eh
`' 1993
`Related us. Application Data
`
`[63]
`
`Continuation of Ser. No. 487,546, Mar. 2, 1990, aban
`doned.
`
`[51] Int. Cl.5 ............................................ .. A61F 13/00
`[52] US. Cl. ........................ .. 424/449; 424/448
`[58] Field of Search .............................. .. 424/448, 449
`[5 6]
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,765,985 8/1988 Leeson et a1. ..................... .. 424/449
`4,788,063 l1/1988 Fisher .................... .. 424/449
`4,837,025 6/1989 Guillemet et a1. .
`.. 424/486
`4,839,174 6/1989 Baker 6181. ..... ..
`.. 424/486
`4,867,982 9/1989 Campbell et a1. . . . . .
`. . . . .. 424/449
`4,869,909 9/1989 Takahashietal.
`.... .. 424/486
`4,880,690 ll/1989 Szycher et a1.
`.... .. 424/486
`4,908,213 3/1990 Govil etal.
`.... .. 424/449
`4,911,707 3/1990 Heiber et a1. ..
`.... .. 424/449
`
`5,064,654 11/1991 Berner . . . . . . . . . . .
`
`. . . . .. 424/448
`
`5,089,267 2/1992 Hille e161. ........................ .. 424/449
`.
`Primary Examiner—Gabr1el1e Phelan
`Attorney, Agent, or Fzrm-Townsend and Townsend
`Khourie and Crew
`
`[57]
`
`ABSTRACT
`
`This Patent relates a method for increasing the storage
`Stability of physostigmine free base and physostigmine
`analogs by incorporating the free base into a polymer
`matrix. Chemically compatible enhancers and adjuvants
`do not interfere with the stabilization of the free bases.
`
`4,559,054 12/1985 Bruck ................................ .. 424/449
`
`6 Claims, 2 Drawing Sheets
`
`PHYSOSTIGMINE STORAGE STABILITY
`_
`Q
`ACIDIFIED WATER
`
`‘
`
`,3 I00
`Q
`z
`
`.
`
`I; 80
`
`8 Z 60"
`
`-
`
`.
`
`I- ,
`Z ,
`
`O
`O
`
`LU
`
`g 40
`c_9
`% m 20
`
`I
`m
`
`-
`
`NEUTRAL WATER
`
`O
`
`1
`
`1
`
`.
`
`I
`
`.
`
`l
`
`.
`
`|
`
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`
`O
`
`6O
`4O
`20
`STORAGE TIME (DAYS)
`
`80
`
`I00
`
`NOVARTIS EXHIBIT 2037
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`IPR2014-00550
`Page 1 of 8
`
`

`
`US. Patent
`
`Aug. 16, 1994
`
`Sheet 1 of 2
`
`5,338,548
`
`
`PEAK
`
`HEIGHT (ARBITRARY UNITS)
`
`FIG IA. 0
`o
`
`l0
`5
`RETENTlON TIME (MIN)
`
`l5
`
`
`PEAK
`
`HEIGHT (ARBITRARY UNITS)
`
`()1
`
`FIG’ ,5‘ 0o
`
`IO
`5
`RETENTION TIME (MIN)
`
`15
`
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`
`

`
`US. Patent
`
`Aug.16, 1994
`
`Sheet 2 of2
`
`'
`
`5,338,548
`
`,3 I00
`g}
`Q
`5 80-
`O:
`I-
`Z
`
`Z
`
`-
`
`-
`
`8 Z 60"
`
`O
`Q
`
`..
`
`PHYSOSTIGMINE STORAGE STABILITY
`0
`ACIDIFIED WATER
`
`NEUTRAL WATER
`
`LL!
`
`2 40
`g
`% w “20 -
`
`)
`I
`a.
`
`..
`
`O
`
`4
`
`I
`
`n
`
`I
`
`|
`
`l
`
`-
`
`I
`
`l
`
`O
`
`6O
`4O
`20
`STORAGE TIME (DAYS)
`
`80
`
`I00
`
`FIG. 2.
`
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`
`

`
`1
`
`5,338,548
`
`METHOD FOR INCREASING THE STORAGE
`STABILITY OF PHYSOSTIGMINE
`
`This is a continuation of application Ser. No.
`07/487,546 ?led 2 Mar. 1990 now abandoned.
`
`5
`
`FIELD OF THE INVENTION
`This invention is directed to devices and methods for
`the percutaneous administration of physostigmine and
`its closely related chemical analogs.
`
`2
`Myasthenia gravis is a neuromuscular disease charac
`terized by weakness and marked fatigability of skeletal
`muscles. Its clinical manifestations were described be
`fore the turn of the century, but it was not until the early
`1930s that physostigmine was used in the management
`of this disease. The observation that physostigmine
`gave rise to increased strength of muscular contraction
`and the similarity between the symptoms of myasthenia
`gravis and curare poisoning in animals, suggested that
`physostigmine, an agent then known to antagonize cu
`rare, might be of therapeutic value for this disease. This
`observation led to the use of physostigmine in the treat
`ment of myasthenia gravis.
`Tardive dyskinesia is a disease characterized by ab
`normal, involuntary movements, usually of oral and
`facial musculature but often involving the trunk and
`extremities. Typical of oral and facial movements are
`puffing of the cheeks, grimacing, protrusion and licking
`of the tongue, and incessant blinking of the eyes. The
`abnormal movements are rhythmic and repetitive and
`may interfere with speech, salivation, chewing, and
`swallowing. Patients, many times, are not aware of the
`symptoms. Tardive dyskinesia is usually irreversible
`and considered to be incurable at the present time.
`Therefore, prevention of the manifestations of this dis
`ease is considered to be the only known effective
`method for dealing with the problem. Tardive dyskine
`sia is most frequently found in geriatric patients who
`have been taking neuroleptic drugs. All neuroleptic
`drugs may cause tardive dyskinesia. However, the low
`dose, high potency drugs which produce the greatest
`degree of blockage, and thus a greater degree of pyra
`midal side effects are the most likely to cause tardive
`dyskinesia. Such high potency drugs include the pheno
`thiazines, the thioxanthenes, the butyrophenones, the
`benxodiazepines and the dihydroindolones. In recent
`years, the greater use of psychotropic drugs has aggra
`vated the incidence of tardive dyskinesia. The increas
`ing use of neuroleptic drugs in geriatric care facilities
`has resulted in dramatic increase in the incidence of
`tardive dyskinesia. See Geriatrics, Volume 34, Number
`7, pages 59-66, July 1979, by Harcourt Brace Jovano
`vich, Inc. An investigation in the use of anticholinergic
`drugs reported in American Journal of Psychiatry, Vol
`ume 134, Number 7, July 1979, pages 769-774 indicates
`that the use of physostigmind and choline have positive
`therapeutic effects on tardive dyskinesia. Although the
`data presented is not unequivocal, tests have shown that
`physostigmine injections reduce tardive dyskinesia in
`from 20% to 80% of the patients suffering from tardive
`dyskinesia. Continuous and permanent drug therapy is
`necessary to control tardive dyskinesia.
`Senile dementia of the Alzheimer’s type (SDAT) is a
`progressive, incurable, and irreversible disease charac
`terized by long term memory impairment. Studies in
`humans and animals have implicated cholinergic pro
`cesses in memory functioning. Investigations with anti
`cholinergics and cholinomimetics indicate that ?uctua
`tions in cholinergic activity can profoundly affect stor
`age and retrieval of information in memory. Davis, et al.
`in a study by reported in Science, Volume 201, p.272
`(1978) concluded that physostigmine signi?cantly en
`hanced storage of information into long-term memory.
`This study moreover indicates that retrieval of informa
`tion from long-term memory was also improved by
`physostigmine therapy.
`Treatment of tardive dyskinesia, wide angle glau
`coma, SDAT, and the like, by injection of physostig
`
`25
`
`BACKGROUND OF THE INVENTION
`Acetylcholine (ACh), an essential neurotransmitter,
`occurs both within the brain and in the peripheral para
`sympathetic nervous system. Impulses conducted along
`muscle ?bers or axons depend upon the formation of
`ACh at the synaptic junction for transmission of the
`impulse to other ?bers or axons. Acetylcholine’s func
`tion as a transmitter is terminated (switched off) when it
`is converted to choline and acetic acid by the enzyme
`acetylcholinesterase (AChE). Modern biophysical
`methods have revealed that the amount of time con
`sumed for the process of conversion of ACh to choline
`and acetic acid is less than one thousandth of a second.
`Drugs that have the ability to inhibit or inactivate
`AChE are called anticholinesterases or AChE inhibi
`tors. As a result of AChE inhibition, acetylcholine ac
`cumulates in the synaptic cleft; since ACh is not
`Switched off, impulses are transmitted to the affected
`site for a longer period of time than would otherwise
`occur and results in a stronger or more prolonged neu
`romuscular action. Since these ACh parasympathetic
`synapses are widely distributed in the brain and periph
`eral nervous syslem, it is not surprising that AChE
`inhibitors produce a wide variety of effects on both the
`brain and body.
`Physostigmine is one of the naturally occurring ace
`tylcholinesterase inhibitorsl It has been isolated from
`the dry, ripe seed of the calabar or ordeal bean, a peren
`40
`nial plant (Physostigma venenosum), found in the Cala
`bar region of Nigeria, West Africa. Also called Esre
`nut, chop nut or bean of Etu Esre, calabar bean was
`used as an ordeal poison. As a test of guilt, the suspect
`was forced to ingest a quantity of calabar beans. If he
`45
`died, his guilt was proved. If the accused was con?dent
`of his innocence and ate the beans rapidly, the chances
`were high that he would regurgitate the beans and sur
`vive the ordeal. (It is reported that proof of guilt or
`innocence was not always left to chance. Apparently, a
`50
`placebo was given to those prejudged to be innocent by
`the tribal elders in order to avoid any potential miscar
`riages of tribal justice), see Plants in the Development on
`Modern Medicine, Swain, T. ed., Harvard University
`Press, p. 303-360 (1972). Physostigmine, isolated from
`the calabar bean, was introduced into medicine for the
`treatment of wide angle glaucoma in 1877 by Laqueur.
`Glaucoma is a disease characterized by an increase in
`intraocular pressure that, if suf?ciently high and persis
`tent, can lead to damage to the optic disc and result in
`permanent blindness. Wide angle glaucoma, or chronic,
`simple glaucoma occurs when the meshwork of pores of
`small diameter involved in the out?ow of the aqueous
`humor lose their tone. Wide angle glaucoma has a grad
`ual, insidious onset and is generally not amenable to
`surgical improvement. In this type of glaucoma, control
`of ocular pressure is only possible with continuous and
`permanent drug therapy.
`
`55
`
`60
`
`65
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`5,338,548
`3
`mine is not practical therapy. Physostigmine exhibits a
`short half-life (about 1 to 2 hours) due to rapid metabo
`lism following systemic administration. Thus, treatment
`would require injections of physostigmine every 30
`minutes to 1 hour at a minimum, to maintain efficacious
`blood levels. Additionally, physostigmine has a narrow
`therapeutic window which necessitates constant patient
`monitoring for safety in order to avoid side effects
`which limit physostigmine’s systemic use. Recently,
`physostigmine has been formulated into tablets for oral
`dosage. Determination of drug blood levels for multiple
`oral doses show typical variations in blood concentra
`tion ranging from a maxima above the required level
`(and possibly in the toxic range) to a minima which may
`be below the effective dose. The dysfunctions men
`tioned above, as well as many others, are more preva
`lent among the elderly. This population group endures
`more memory impairment and physical disability than
`other age groups and consistent therapy is necessarily
`more difficult to attain. Percutaneous administration of
`physostigmine has many advantages over systemic ther
`apy. It is well known that patient compliance is im
`proved where therapy can be attained with fewer num
`bers of drug applications within a twenty-four hour
`period. Transdermal administration offers the possibil
`ity that application of an appropriate device need occur
`but once in a twenty four hour period. Therapy can be
`terminated by removal of the transdermal device. Sta
`ble blood levels can be obtained using dose-controlled
`devices, thus limiting the toxic side effects caused by
`overdosing and the lack of effect due to underdosing.
`Pharmacologically active agents with short metabolic
`lifetimes are particularly suited to transdermal methods
`of drug delivery.
`The literature is ?lled with descriptions of trans
`dermal devices for the slow or sustained or controlled
`release of medicaments. These devices may take the
`form of monolithic reservoir devices, osmotically
`driven devices, membrane controlled devices, enhancer
`controlled devices, microencapsulated drugs, bioeroda
`ble devices and almost every conceivable combination
`of the above. For a general review of the art see, “Con
`trolled Release of Biologically Active Agents”, R. W.
`Baker, John Wiley and Sons, 1987. All of the dosing
`methods and devices used in drug therapy carry an
`implicit and many times unstated assumption, that the
`drug released has not been altered upon storage in any
`way to significantly decrease its efficacy or accumulate
`undesirable or unacceptable break-down products. It is
`well known that most free base alkaloids are not stable
`against air oxidation, actinic radiation, heat etc. Physo
`stigmine free base is a particularly labile compound
`because its two basic tertiary amine groups facilitate
`hydrolysis of its phenolic carbanilide group. Once hy
`drolysis has taken place, contact with atmospheric oxy
`gen will rapidly oxidize the phenolic hydroxyl group to
`the highly colored ortho-quinone, rubreserine, see,
`Studies on Physostigmine and related substances, IV
`Chemical Studies on Physostigmine Breakdown Products
`and Related Epinephrine Derivatives, S. Ellis, J. Phar
`macol. Exp. Then, 79 (1943) pp 364-372. See Reaction
`I. Consequently, chemicals of this class are commonly
`stored and administered as their salts. For example,
`because physostigmine is difficult to store as its free
`base, the salicylate salt is sold as a commercial prepara
`tion with the admonition that solutions should be kept
`well closed in light-resistant, alkali-free glass containers
`and used within a week of opening. The practitioner is
`
`60
`
`15
`
`25
`
`30
`
`35
`
`45
`
`55
`
`65
`
`4
`cautioned to discard the preparation if it is discolored.
`In almost all cases, the free base is preferred for trans
`dermal permeation because the free base will quickly
`cross the stratum corneum skin barrier while the salt
`form is poorly, if at all, transported and absorbed. Many
`approaches have been tried to solve this con?icting
`problem of storage vs permeability. For example, Ba
`nerje, in US. Pat. No. 4,692,462, binds the free base of
`drug on an ion exchange resin and relies upon the ab
`sorption of an equilibrium concentration of the free base
`form of the drug by the skin for utility. Lee and Yum in
`Us. Pat. No. 4,781,924, store a variety of basic drugs in
`their salt form in combination with a dry basic com
`pound. Upon moisture absorption, a solution is formed
`which permits the reaction between the alkaline com
`pound and the salt form of the organic base, liberating
`the free base. The free base migrates through the device
`to the skin surface where it rapidly permeates the skin
`barrier. These inventions serve to illustrate the lengths
`to which those skilled in the art have gone in order to
`contain the therapeutic agent in its stable form as the
`salt, and administer the drug in its most biologically
`useful form, the free base. 'The foregoing discussion
`illustrates the need and value of a device or method that
`contains the target drug in its most active and bioavaila
`ble form (free base) while maintaining adequate storage
`stability.
`Conventional wisdom has indicated that effective
`protection against the deleterious effects of oxygen and
`moisture could not be achieved by employing the vari
`ous polymers as monolithic matrices for sensitive drugs.
`Diffusion of atmospheric oxygen and water vapor are
`thought to be so high that drugs sensitive to hydrolysis
`or oxidation, stored for any signi?cant length of time
`under ambidnt conditions, would be quickly converted
`to the expected degradation products. Comequently,
`past efforts toward dealing with the problem of drug
`instability have been dedicated to converting the target
`drug into a chemical form that has adequate storage
`stability.
`
`OBJECTS OF THE INVENTION
`It is the object of this invention to disclose a novel
`means for increasing the storage lifetime of drugs.
`It is another object of this invention to disclose a
`novel means for increasing the storage lifetime of phy
`sostigmine free base and its closely related analogs.
`It is another object of this invention to disclose novel
`transdermal devices for the release of physostigmine
`free base and its closely related analogs.
`It is another object of this invention to disclose de
`vices and methods for controlled release of compounds
`effective in the treatment of memory impairment, glau
`coma, tardive dyskinesia and myasthenia gravis.
`It is another object of this invention to provide a
`means for treatment of disorders resulting from a defi
`ciency of acetylcholine.
`It is a further object of this invention to provide a
`means for symptomatic treatment of disorders resulting
`from a de?ciency of acetylcholine.
`Further objects of the invention will be apparent
`from the description of the invention to those skilled in
`the art.
`
`SUMMARY OF THE INVENTION
`The present invention stabilizes compounds contain
`ing chemically labile functional groups, such as physo
`
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`5,338,548
`5
`6
`stigmine free base, by incorporating them into a mono
`types. Many of the physical and chemical properties of
`lithic polymer matrix.
`a polyurethane are determined by the ratio of hard to
`The effective compounds include physostigmine free
`soft segments as well as the choice of polyol and poly
`base and physostigmine derivatives. Physostigmine free
`isocyanate reactants. Linear polyurethanes are typically
`base and physostigmine free base derivatives may be
`made by the prepolymer route, reacting a hydroxy-ter
`represented by formula I as follows:
`minated compound with a diisocyanate according to
`the reaction:
`
`0
`
`/"\
`
`N
`1
`
`O
`
`R4
`
`.
`
`CH3
`
`15
`
`In formula 1, R1, R2, R3 and R4 independently repre~
`sent H or lower alkyl groups.
`Chemically similar functional groups are de?ned as
`hydrolytically, oxidatively or hydrolytically and oxida
`tively unstable moieties.
`“Monolith” as used herein means a single-phase com
`bination of chemical and polymeric carrier.
`
`where R is a polyether, polyester, polycarbonate or
`hydrocarbon.
`The product of this reaction is an isocyanate termi
`nated prepolymer. This prepolymer is then further re
`acted (two shot process) with a lower molecular weight
`diol (chain extender) such as l,4-butane diol to produce
`linear, thermoplastic and solvent soluble elastomers.
`Alternatively, all the reactants can be combined in a
`single step (one shot process) to produce the desired
`product. Polyether soft segmented polyurethanes have
`better hydrolysis resistance than polyester based poly
`urethanes but have less oxidative resistance and lower
`tensile strength; polycarbonate based soft segmented
`polyurethanes normally occupy a middle ground in
`physical and chemical properties between the polyether
`and polyester types. Hydrocarbon based polyols are
`available and can be used to prepare polyurethanes with
`superior oxidative and hydrolysis resistance. Aromatic,
`aliphatic and alicyclic polyisocyanates offer differing
`degrees of ultra-violet and moisture resistance biocom
`patibility. Thus, one of ordinary skill in the art of poly
`urethane synthesis can select appropriate monomers for
`synthesis to overcome speci?c application problems.
`Polyether, polycarbonate and hydrocarbon type poly
`urethanes are preferred for biomedical use, because, in
`general, they are more inert than polyester types. Poly
`urethane polymers are available in grades approved for
`medical use from Dow Chemical, Midland, Mich. under
`the trade name Pellethane TM 2363 and from Therme
`dics Corporation, Woburn, Massa. under the name of
`Tecco?ex TM EG-80A and Tecco?ex TM EG-6OD.
`Different hardnesses are available; the softer grades are
`generally preferred in the context of the present inven
`tion, because they are easier to dissolve.
`Other polymers that can be used as the polymer ma
`trix material include ethylene vinyl acetate copolymers.
`These polymers are commercially available (Elvax ®,
`DuPont Corporation; Ultrathene ®, USI Chemicals,
`etc.) in a wide variety of grades from 2% to more than
`50% vinyl acetate content. Generally, the permeability
`of the polymer is increased with increasing vinyl acetate
`content, see Controlled Release of Biologically Active
`Agents, Baker, R. W., John Wiley & Sons, pp 161-165.
`Thus, by choosing the appropriate vinyl acetate content
`and film thickness, an appropriate release characteristic
`may be obtained. Other useful matrix materials include
`polyether polyamide block copolymers such as those
`available from Atochem Inc. under the trade name
`Pebax ®. Also useful are silicone based polymers of the
`types available from Dow Corning, General Electric,
`etc. In general, rubbery polymers are preferred for this
`application, although glassy polymers such as polyvinyl
`chloride or ethyl cellulose could be used if supplied as
`plasticized by the drug or an added pharmacologically
`acceptable plasticizer such as dioctyl phthalate, polye
`thyleneglycol, butyl sebacate or the like. The patch may
`be assembled by any of the techniques known in the art
`
`25
`
`35
`
`40
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`Physostigmine free base is known to be hydrolyti
`cally and oxidatively unstable. It has been discovered
`that when physostigmine free base is contained in a
`polymer matrix, its stability is markedly increased. A
`number of techniques may be used to obtain a drug in
`polymer matrix, including extrusion of blends of poly
`mer and drug (where temperature and shear stability
`permit), powder compaction, solution methods and the
`like. In a most elementary embodiment, preparation of a
`drug loaded matrix is achieved by ?rst dissolving both
`physostigmine free base and a polymer in an appropri
`ate solvent followed by solution casting. When a clear
`solution is obtained, the preparation can be cast onto a
`protective backing by any of the known techniques for
`casting solvent based polymer ?lms, and the solvent
`allowed to evaporate. After evaporation, a thin adhe
`sive ?lm is cast onto the matrix, or double-sided medical
`adhesive tape is attached. The adhesive is covered by a
`release liner, and patches are cut out by punching. The
`?nished patches may be heat sealed into foil pouches,
`45
`and stored until needed. The physostigmine free base
`matrix comprises solid physostigmine free base dis
`persed in a polymer matrix. The inventors offer the
`following interpretation of the observed phenomenon
`for the purposes of explanation without intending to be
`bound. Since the degradation of physostigmine like
`compounds require reaction with water and oxygen,
`polymers with low moisture absorption and low oxygen
`and moisture transmission prevent degradation by ex
`clusion of an essential reagent for the degradation reac
`tion. Preferably, the polymer should have moisture
`absorption of less than 5 wt % at 100% relative humid
`ity at 20° C. In order to prevent premature degradation
`caused by processing and not the result of polymer
`matrix control, oxygen and moisture should be ex
`cluded during the processing of the free base into the
`?nished patch including thorough drying of the poly
`mer before use, conducting the manufacturing opera
`tions under and inert atmosphere and sealing the ?n
`ished patches under an inert atmosphere. One of the
`preferred polymers is of the polyurethane type. Poly
`urethanes are usually synthesized using polyisocyanates
`(hard segment) and polyols (soft segment) of various
`
`65
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`
`8
`ever, the drug in neutral solution degrades rapidly with
`more than half of the initial drug gone within 30 days
`under the same storage conditions. Repetition of these
`experiments using ethanol and isopropyl myristate as
`solvents showed the rate of degradation to be slower
`than with unbuffered water but faster than with acidi
`?ed water. In ethanol solution, 5% of the physostigmine
`free base was lost after 7 days and 10% after 27 days. At
`this rate of degradation, a patch would have lost 72% of
`its active ingredient in one year and 92% in two years.
`
`5,338,548
`7
`for laminating patches. Typically the ?rst step in prepa
`ration of the patch is to prepare a solution of the poly
`mer matrix material. Solvents that may be used to dis
`solve polyurethane include tetrahydrofuran (T HF),
`Fischer Scienti?c, Spring?eld, N.J., dimethylsulfoxide
`(DMSO), and dimethylformamide (DMF). Tetrahydro
`furan is the preferred solvent, because it has been ap
`proved for use with medical materials so long as the
`residue remaining in the material after drying does not
`exceed 1.5%. Typically the percentage by weight of
`polyurethane in the solution will be in the range 5% to
`about 35%, depending on the solvent and the polyure
`thane grade. Using THF, it is possible to prepare casting
`solutions with relatively high concentrations, typically
`around 20 to 25%, of a soft grade polyurethane. The
`harder grades are more difficult to dissolve. It is usually
`desirable to make the concentration of polyurethane as
`high as possible. The solution as cast is closer in thick
`ness to the ?nished ?lm. Also, concentrated solutions
`are more viscous, and it has been found that, in general,
`better containment of physostigmine free base is
`achieved with ?lms cast from viscous solutions. Solid
`physostigmine free base is added to the polymer solu
`tion, and the mixture is stirred until complete solution is
`achieved. The percentage of physostigmine free base in
`the solution may be varied according to the desired
`loading of the ?nished matrix. The physostigmine free
`base content of the ?nished matrix may vary widely,
`from around 3% to about 30%. Loading above 30%
`may be achieved, but because of the potency and toxic
`ity of physostigmine, highly concentrated matrices do
`not offer advantages that outweigh the hazards associ
`ated with potential for accidentally overdosing physo
`stigmine.
`Physostigmine free base in polyurethane was chosen
`as a model compound for the examples given, but one of
`ordinary skill in the art can apply the general principles
`and methods to other analogous chemicals.
`
`10
`
`20
`
`25
`
`30
`
`35
`
`EXAMPLE 1
`Stability of Physostigmine Free Base in Aqueous
`,
`Solution
`Relative stability of physostigmine free base in neu
`tral or alkaline solution was determined as follows.
`Methanolic solution of physostigmine free base was
`45
`acidi?ed with a few drops of hydrochloric acid to lower
`the pH to about 3-6. Aliquots of this solution were
`analyzed immediately and after one or two hours when
`the solution became pink due to accumulation of the
`degradation product rubreserine. Analysis was per
`formed using HPLC Nova Pak 4-C18 column and a
`mobile phase consisting of:
`348.0 g Water
`650.0 g Methanol
`12.0 g Citric Acid
`0.63 g 85% Phosphorous Acid
`0.96 g Sodium pentasulphonate
`
`55
`
`50
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`The chromatogram of physostigmine free base imme
`diately before signi?cant degradation is shown in FIG.
`1a, the appearance of degradation products of the pink
`solution that appear after one or two hours is shown in
`FIG. 1b.
`In the same manner, stability of physostigmine free
`base in neutral or slightly acidi?ed water was deter
`mined and is shown in FIG. 2. At room temperature,
`pH 3, the drug is more stable, and slightly pink; how
`
`60
`
`65
`
`EXAMPLE 2
`Stability of Physostigmine Free Base in Polymer Matrix
`Increased stability of physostigmine free base in poly
`mer matrices over solutions is shown in the following
`experiments. Patches containing physostigmine free
`base in a polymer matrix were prepared by dissolving
`18 g of a polyether based polyurethane produced by
`Dow under the name Pellethane TM grade 2363-80AE,
`2.0 g physostigmine free base and 2.0 g isopropyl myris
`tate in 80 g THF. The solution was allowed to stand
`until clear. A second identical lot of polymer/drug
`solution was prepared containing 0.02 g of acetyl cys
`tine. Clear solutions were cast onto the reverse side of a
`polyester-based release liner available from 3M Com
`pany of Minneapolis under the trade name Scotch TM
`1002. After evaporation of the THF solvent, the liquid
`cast ?lm of 2000 um produced a dry matrix ?lm
`200-230 nm thick. Patches with an area of 7.9 cm2 were
`out from these laminated structures, packaged in poly
`ethylene foil pouches and stored at room temperature
`and at 45° C.
`Three patches from each lot were tested for physo~
`stigmine free base content immediately after manufac
`ture and after 7 and 25 days of storage at room tempera
`ture and at 45° C. Once the backing was removed from
`the patch, the drug-containing ?lm was weighed and
`then dissolved in 25 g of THF, followed by dilution
`with 25 g on methanol. Precipitated Pellethane TM was
`?ltered from the solution before injection into the
`HPLC. Average amounts of physostigmine free base
`recovered from the patches, with and without acetyl
`cysteine, are given in Table 1. Theoretical drug loadings
`were 17.2 and 16.2 mg for the stabilized and unstabilized
`patches, respectively. Scatter in the weight data can be
`attributed to variation in ?lm weights and analytical
`errors amounting to as much as 110%.
`TABLE I
`Stability of Physostigmine Free Base Patches with and
`without Preservatives (n = 3)
`Weight of Physostigmine free base Recovered (mg)
`No Preservative
`With Preservative
`Room
`Room
`Temperature
`Temperature
`17.2
`16.2
`
`Storage
`Time
`(days)
`Theoretical
`Loading
`0
`7
`25
`
`45° C.
`17.2
`
`45° C.
`16.2
`
`15.0
`16.5
`16.8
`
`15.0
`16.8
`18.5
`
`15.1
`17.3
`16.8
`
`15.1
`16.8
`16.8
`
`Within the limits of error, there was no measurable
`physostigmine free base loss during these tests either at
`room temperature or at 45° C. Patches stored for 25
`days at 45° C. appeared slightly discolored; however,
`no additional peaks were observed in the HPLC analy
`sis of these patches.
`
`NOVARTIS EXHIBIT 2037
`Noven v. Novartis and LTS Lohmann
`IPR2014-00550
`Page 7 of 8
`
`

`
`5
`
`9
`EXAMPLE 3
`In Vivo Test of Physostigmine Free Base Patches
`Pellethane TM 2363-80AE (24.4 g) was added to a
`solution of 101.3 g of THF containing 2.903 g of physo
`stigmine free base and 2.951 g of isopropyl myristate
`and stirred until a clear solution was formed. After
`evaporation of the THF solvent, the liquid cast ?lm of
`2000 um produced a dry matrix ?lm 180-230 pm thick.
`A solution of Avery adhesive 460, containing 10 wt %
`isopropyl myristate was cast on the drug/ polymer ma
`trix ?lm to produce an adhesive layer approximately
`801 pm thick. The ?lm was ?nally overlaid with a re
`lease liner ?lm 1022 available from 3M Company and
`patches with an area of 7.92 cm2 were cut from the
`laminated structure. These patches were weighed, heat
`sealed into polyethylene-foil pouches and stored until
`use.
`The patches were then placed on the skin of rabbits
`from which the hair had been carefully clipped, after 23
`hours, the patches were removed and the in vivo skin
`?uxes determined and summarized in Table II.
`TABLE II
`Rabbit Test Results
`Drug
`Calculated Remaining Drug Delivered
`Film
`Patch
`Weight Weight Drug Load in Patch‘ AMass AMass
`(mg)
`(mg)
`(mg)
`(mg)
`(mg)
`(%)
`Patch
`408
`229
`22.0
`6.8
`15.2
`69
`l
`412
`233
`22.4
`7.4
`15.0
`67
`2
`396
`217
`20.8
`6.8
`14.0
`67
`3
`417
`238
`22.8
`7.1
`15.7
`69
`4
`359
`180
`17.2
`5.2
`12.0
`70
`5
`415
`236
`22.7
`6.7
`16.0
`70
`6
`367
`188
`18.0
`5.2
`12.8
`71
`7
`393
`214
`20.5
`6.2
`14.3
`70
`8
`390
`211
`20.2
`6.5
`13.7
`68
`9
`411
`232
`22.3
`7.1
`15.2
`68
`10
`371
`192
`18.4
`5.7
`12.7
`69
`11
`353
`174
`16.7
`4.9
`11.8
`71
`12
`Average 391
`212
`20.3
`6.3
`14.0
`69
`Std. Dev. 22
`22
`2.1
`0.8
`1.4
`1
`% CV
`5.6
`10.4
`10.5
`12.9
`9.8
`1.9
`‘Measured by HPLC?
`Average weight of backing, adhesive, and liner = 0.179 g
`Patch area = 7.9 cm2
`
`5,338,548
`10
`70% of the drug delivered. Average Physostigmine free
`base ?ux was 160 pg/cmZ-h.
`We claim:
`1. A process for increasing the storage stability of
`physostigmine comprised of:
`a. dissolving a polymer having a water absorption of
`less than 5 wt % at 100% relative humidity at 20°
`C. and Physostigmine in a solvent to form a drug
`and polymer solution;
`b. casting said drug and polymer solution to form a
`cast solution;
`0. removing the solvent from said cast solution t