(12) United States Patent
`Bouloumie et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,284,277 B1
`Sep. 4, 2001
`
`US006284277B1
`
`(54) STABLE FREEZE-DRIED
`PHARMACEUTICAL FORMULATION
`
`9/1996 0016 et al. .
`5,558,880
`5,885,486 * 3/1999 Westesen et al. .................. .. 252/311
`
`(75) Inventors: Colette Bouloumie; Thierry Breul,
`both of Montpellier; Laurence Colliere,
`Montbartier; Philippe Faure, Maurin,
`all of (FR)
`
`(73) Assignee: Sano?-Synthelabo, Paris (FR)
`
`* N'
`ot1ce:
`
`(21) Appl. No.:
`(22) PCT Filed:
`
`Sbj
`yd'l'
`h
`fh'
`u ect to an 1sc a1mer, t e term 0 t is
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`09/066,387
`Oct. 30, 1996
`
`(86) PCT No.:
`
`PCT/FR96/01706
`
`§ 371 Date:
`
`Dec. 9, 1998
`
`§ 102(e) Date: Dec. 9, 1998
`
`(87) PCT Pub. No.: WO97/17064
`
`PCT Pub. Date: May 15, 1997
`Foreign Application Priority Data
`
`(30)
`
`Nov. 3, 1995
`
`(FR) ................................................ .. 95/13022
`
`(51) Int. Cl.7 ..................................................... .. A61K 9/14
`(52) US. Cl. ........................................... .. 424/489; 424/450
`(58) Field of Search .................................... .. 424/489, 450
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`FOREIGN PATENT DOCUMENTS
`
`394045
`682944
`2021581
`WO 93/23017
`
`10/1990 (EP).
`11/1995 (EP).
`12/1979 (GB).
`11/1993 (WO).
`
`OTHER PUBLICATIONS
`
`Chemical Abstract, 83:183393 (1975).
`DerWent Abstract, 75—85480W (1975).
`DerWent Abstract, 90—151822 (1990).
`Patent Abstracts of Japan, vol. 14, No. 294 (C—732) (1990).
`DerWent Abstracts of EP682944.
`
`* cited by examiner
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—R. Joynes
`(74) Attorney, Agent, or Firm—Paul E. Dupont; Michael D.
`Alexander
`
`(57)
`
`ABSTRACT
`
`The subject of the invention is a freeze-dried formulation
`consisting of an amorphous phase and a crystalline phase,
`Which is pharmaceutically acceptable, comprising at least
`one nonprotein active ingredient, characterized in that it
`contains mannitol and alanine in a ratio R of betWeen 0.1 and
`1, R representing the mass of mannitol to the mass of
`alanine.
`
`4,537,883
`
`8/1995 Alexander et a1. .
`
`13 Claims, 2 Drawing Sheets
`
`2000.00
`
`2_Tlheta-Slca‘e l
`
`l
`
`l
`
`|
`|
`l
`l
`AGH9549/02.03.1995
`
`1
`
`Counts
`
`\
`
`_
`
`Mannitol
`
`Alanine
`
`4
`
`3
`
`2 _
`
`0.00
`
`llIllllllllllllllllllllllllIllll'llllllllllllllllllllllll‘lllllllll
`50 55
`60 65
`30 35 40 45
`5
`l0 15 20 25
`
`LYOPHILIZED PRODUCTS 8R27897B l
`
`Mylan Ex 1052, Page 1
`
`

`

`U.S. Patent
`
`US 6,284,277 B1
`
`
`
`m w HOQHQQME 5:300 . V
`
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`Mylan Ex 1052, Page 2
`
`

`

`U.S. Patent
`
`Sep. 4, 2001
`
`Sheet 2 0f 2
`
`US 6,284,277 B1
`
`FIG. 2
`
`50
`
`40
`
`30*
`
`TC °C
`
`20
`
`10"
`
`1/R = alanine/mannitol
`
`Mylan Ex 1052, Page 3
`
`

`

`US 6,284,277 B1
`
`1
`STABLE FREEZE-DRIED
`PHARMACEUTICAL FORMULATION
`
`This application is a 371 of PCT/FR 96/01706 ?led Oct.
`30, 1996.
`The present invention relates to a pharmaceutical formu
`lation provided in the form of a freeZe-dried product and
`containing at least one active ingredient of nonprotein
`nature. More particularly, the invention relates to such a
`formulation, stable at temperatures Which may be as high as
`25° C. to 40° C., Which may be either reconstituted in liquid
`form by addition of a solvent for its administration via the
`parenteral or oral route, or directly administered via the oral
`route, to man or to animals.
`The active ingredient contained in the formulation
`according to the invention may be alone or else combined
`With another active ingredient of protein or nonprotein
`nature.
`It is knoWn that freeZe-drying may have a considerable
`effect on the degradation of the pharmaceutical active ingre
`dients in a formulation, as Well as a strong impact on their
`stability in freeZe-dried form. The various variables Which
`affect these parameters are mainly the pH, the quantity of
`salts present, the type and quantity of eXcipients in the
`formulation, the type of cryoprotection chosen, as Well as
`the temperatures, pressure and time chosen for the freeZing,
`sublimation and drying operations. These different variables
`in?uence the physical state of the freeZe-dried product
`obtained, namely: vitreous amorphous, soft amorphous,
`crystalline or a combination of these states.
`For the preservation of the freeZe-dried products, amino
`acids, preferably glycine, and polyols, preferably mannitol,
`are often used; but the literature, Which is highly abundant
`on the subject, gives no information on the solution to the
`general problem of obtaining a stable pharmaceutical for
`mulation Which takes into account the different parameters
`involved in the operations for formulating and freeZe-drying
`a nonprotein active ingredient in combination With an amino
`acid and a polyol.
`More particularly, the literature teaches that the presence
`of an amino acid, of a polyol, for eXample mannitol, of a
`crystalline phase or of an amorphous phase may have,
`besides certain advantages, disadvantages Which lead, in the
`case of freeZe-dried products containing particularly sensi
`tive active ingredients, to relatively short shelf lives and/or
`storage temperatures for these freeZe-dried products Which
`are less than 8° C. It Would, hoWever, be particularly
`advantageous, especially for an ambulatory treatment, to be
`able to obtain a formulation Which is stable at room tem
`perature until it is reconstituted and to thereby avoid its
`storage in a refrigerator before or during treatment.
`The role of the polyol and of amino acid has been studied
`separately in the case of the human groWth hormone (hGH),
`but their synergistic effect is still poorly elucidated (Pikal M.
`J., Dellermann K. M., Roy M. L., Riggin M. N., The effects
`of formulation variables on the stability of freeZe-dried
`Human GroWth Hormone, Pharm. research., 1991, 8, No. 4,
`427—436).
`The advantages and disadvantages linked to the presence
`of amino acids, of mannitol, of a crystalline phase or of an
`amorphous phase are listed beloW.
`Advantages linked to the presence of amino acids.
`It has been demonstrated that the presence of glycine in
`a freeZe-dried product induced crystalliZation of the mol
`ecules present in solution during the freeZing stage of the
`freeZe-drying (Korey D. J ., SchWartZ J. B., Effects of eXcipi
`ents on the cristalliZation of pharmaceutical compounds
`
`10
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`2
`during lyophyliZation, J. Parenteral Sci. Tech., 1989, 43, 2,
`80—83). This crystalliZation of the active ingredient makes it
`possible to enhance its stability.
`Alanine, in crystalliZed form, has the advantage of pre
`venting the collapse of the freeZe-dried product during
`sublimation and drying and or alloWing the production of a
`freeZe-dried product With a greater speci?c surface area and
`therefore alloWs a more rapid drying (Pikal M. J ., FreeZe
`drying of proteins, Biopharm., 26—30 October 1990).
`Disadvantages linked to the presence of amino acids.
`The addition of an amino acid to a sugar or to a polyol
`in a solution to be freeZe-dried generally has the effect of
`decreasing the glass transition temperature of the sugar (te
`Booy M. P. W. M., de Ruiter R. A., de Meere A. L. 1.,
`Evaluation of the physical stability of freeZe-dried sucrose
`containing formulations by differential scanning
`calorimetry, Pharm. Research., 1992, 9, 109—114). NoW, a
`decrease in the glass transition temperature is generally
`synonymous With a loWer stability of a freeZe-dried product
`(Franks F., Freeze-drying; from empiricism to predictability,
`Cryo-letters, 1990, 11, 93—110).
`Advantages linked to the presence of mannitol.
`The presence of mannitol in the composition of a freeZe
`dried product is generally justi?ed as freeZe-drying ballast,
`that is to say that it makes it possible both to maintain the
`solid and rigid structure of the volume of the freeZe-dried
`product corresponding to the volume of solution to be
`freeZe-dried, but its presence also makes it possible to adjust
`the isotonicity of the reconstituted solution to be injected.
`When mannitol is the predominant eXcipient in the compo
`sition of a freeZe-dried product, it is most often in crystalline
`form (LyophiliZed formulations recombinant tumor necrosis
`factor, Hora M. S., Rana R. K., Smith F. W., Pharm. Res.,
`1992, 9 (1), 33—36).
`Disadvantages linked to the presence of mannitol.
`It has been reported that the degree of hydrolysis of
`methylprednisolone sodium succinate, in freeZe-dried form,
`Was greater in the presence of mannitol than in the presence
`of lactose, and that this level increased With the quantity of
`mannitol present in the freeZe-dried product. This has been
`eXplained by the fact that the crystalliZation of mannitol
`during freeZe-drying changes the distribution of Water in the
`matriX of the freeZe-dried product. The increase in the
`quantity of Water present in the microenvironment of the
`active ingredient resulting therefrom enhances the hydroly
`sis of the active ingredient and reduces its stability (The
`effect of bulking agent on the solid state stability of freeZe
`dried methylprednisolone sodium succinate, Herman B. D.,
`Sinclair B. D., Milton N., Nail S. L., Pharma. Res., 1994, 11
`(10), 1467—1473).
`Advantages linked to the presence of a crystalline phase.
`The presence of a crystalliZed solute in a froZen solution
`is a means of stabiliZing the proteins during drying
`(Carpenter J. F. & CroWe J. H., Modes of stabiliZation of a
`protein by organic solutes during dessiccation, Cryobiology,
`1988, 25, 459—470). Furthermore, the crystalliZation, during
`freeZing, of the predominant eXcipients present in a solution
`to be freeZe-dried makes the secondary sublimation and
`drying operations more effective by increasing the speci?c
`surface area for exchange betWeen the atmosphere in the
`freeZe-drying vessel and the solid to be sublimed. This
`increase in the speci?c surface area of the crystalline forms
`compared With the amorphous forms facilitates heat
`exchanges during freeZe-drying. The consequence of this
`increased ef?ciency in the freeZe-drying is the production of
`freeZe-dried forms Whose residual Water content is loWer,
`Which means an increased stability of the freeZe-dried
`
`Mylan Ex 1052, Page 4
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`

`

`US 6,284,277 B1
`
`3
`product at higher temperatures (Korey D. J ., Schwartz. J. B.,
`Effects of excipients on the cristalliZation of pharmaceutical
`compounds during lyophyliZation, J. Parenteral Sci. Tech.,
`1989, 43, 2, 80—83).
`Disadvantages linked to the presence of a crystalline
`phase.
`In general, the crystalliZed substances have less rapid
`dissolution rates than the amorphous substances. Indeed,
`more energy is required to detach a molecule from an
`organiZed lattice of a crystalline arrangement than to detach
`it from a disorganiZed assembly of an amorphous state.
`Sometimes, the dissolution rate becomes insuf?cient to
`alloW a suf?ciently rapid absorption of these substances,
`Which may lead to a decrease in their activity, especially in
`the case of molecules Which are not very stable in solution.
`Likewise, the perfect regularity of crystals being an ideal
`case, the heterogeneity of the crystalline phase and the
`polymorphism Which are obtained for the same substance
`and betWeen associated substances induce different rates of
`dissolution for the same substance and betWeen each of the
`substances, Which may result in unreproducible therapeutic
`effects (Galénica 2, Biopharmacie 2nd edition, 1982, tech
`nique and documentation).
`In addition, it has been demonstrated that the loss of
`activity of a freeZe-dried protein Was directly linked to the
`degree of crystallinity of the cryoprotective molecule (IZutsu
`K. L., Yoshioka S., Terao T., Decreased protein-stabilizing
`effects of cryoprotectants due to crystalliZation, Pharm.
`Research. 1993, 10, No. 8, 1232—1237; IZutsu K. I.,
`Yoshioka S., Kojima S., Increased stabiliZing effects of
`amphiphilic excipients on freeZe drying of lactate dehydro
`genase (LDH) by dispersion into sugar matrixes, Pharm.
`Res., 1995, 12 (6), 838—843). In the formulation of medi
`cines containing proteins, the crystallization of the excipi
`ents should be avoided according to: (Hermansky M., Pesak
`M., LyophiliZation of drugs, VI Amorphous and Cristalline
`forms Cesk. Farm., 1993, 42, (2), 95—98).
`Advantages linked to the presence of an amorphous
`phase.
`Based on the same line of thinking, the amorphous form
`dissolves more rapidly than the crystalliZed form and does
`not exhibit the disadvantages linked to the heterogeneity and
`to the polymorphism of the crystalliZed substances.
`Moreover, the presence of additives in the amorphous
`state stabiliZes the activity of certain enZymes proportionally
`to the concentration of the additive according to IZutsu K. L.,
`Yoshioka S., Terao T., Decreased protein-stabiliZing effects
`of cryoprotectants due to crystalliZation, Pharm. Research.,
`1993, 10, No. 8, 1232—1237.
`The cryoprotective effect of the excipients is attributed to
`the amorphous state of the glycine in the freeZe-dried
`product obtained (Pikal M. J ., Dellermann K. M., Roy M. L.
`Riggin M. N., The effects of formulation variables on the
`stability of freeZe-dried Human GroWth Hormone, Pharm.
`Research., 1991, 8, No. 4, 427—436).
`Disadvantages linked to the presence of an amorphous
`phase.
`In the presence of a solid amorphous phase alone, the
`freeZe-dried product collapses at temperatures greater than
`the glass transition temperature during freeZing. Within a
`soft amorphous phase, the chemical degradation reactions
`have much more rapid kinetics than Within a crystalline
`phase (Solid state stability and preformulation study of a
`neW parenteral cephalosporin antibiotics (E1040), AshiZaWa
`K., UchikaWa K., Hattori T., Ishibashi Y., Miyake Y., Sato T.,
`Yakugaku Zasshi, 1990, 110 (3), 191—201).
`Furthermore, the higher rate of dissolution of the amor
`phous substances is sometimes accompanied by a greater
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`4
`instability, the conversion of a form generally occurring
`from the amorphous state to the crystalliZed state (Galénica
`2, Biopharmacie 2nd edition, 1982, technique et
`documentation).
`In conclusion, the scienti?c literature on the subject of
`the effect of excipients on the stabiliZation of pharmaceutical
`active ingredients gives contradictory information on their
`properties and furthermore does not make it possible to
`obtain some information on the subject of the relationships
`betWeen the structure of a freeZe-dried product and its
`stability. LikeWise, the role of the polyols and of the amino
`acids, alone or in combination, is not described according to
`a set of generaliZable properties, but has been observed With
`contradictory results according to the active principles stud
`ied and the quantities of excipients used.
`It has noW been found that a synergistic effect exists
`betWeen mannitol and alanine on the stabiliZation of freeZe
`dried pharmaceutical active ingredients. It has in particular
`been demonstrated that this synergistic effect exists only in
`a narroW range of relative concentrations of each of these
`tWo excipients.
`The discovery of a surprising synergistic effect resulting
`from the coexistence of an amorphous phase and a crystal
`line phase Which has the consequence of stabiliZing the
`freeZe-dried pharmaceutical active ingredient forms the
`basis of the present invention. The present invention there
`fore describes the production of this effect for speci?c
`mannitol/alanine ratios.
`Thus, the present invention relates to a freeZe-dried
`pharmaceutical formulation consisting of an amorphous
`phase and a crystalline phase, comprising an effective quan
`tity of at least one nonprotein pharmaceutical active
`ingredient, mannitol and alanine, the latter tWo excipients
`being in a mass ratio R of betWeen 0.1 and 1, R being the
`ratio of the mass of the mannitol to the mass of the alanine.
`The active ingredient included in the said formulation
`remains stable at temperatures Which may range from 25° C.
`to 40° C. in freeZe-dried form. Where appropriate, the
`dissolution of the freeZe-dried product obtained is rapid and
`complete. The freeZe-dried product does not have a col
`lapsed appearance and its Water content is compatible With
`maintaining the stability of the active ingredient.
`It has been demonstrated that, for R of betWeen 0.1 and
`
`1:
`
`the freeZe-dried product consists of an amorphous phase
`and a crystalline phase,
`the amorphous phase predominantly consists of mannitol
`and active ingredient,
`the crystalline phase predominantly consists of alanine
`Although the invention is not limited to a speci?c theory
`Which explains the stabiliZation obtained by combining one
`or more nonprotein active ingredients, mannitol and alanine
`in the indicated ratios, the folloWing hypothesis can be
`made:
`the amorphous phase, demonstrated by differential scan
`ning calorimetry, cryoprotects the pharmaceutical
`active ingredient during freeZing, the active ingredient
`itself being dispersed in this amorphous form, and the
`crystalline phase, demonstrated by X-ray
`diffractometry, ?xes the structure of the freeZe-dried
`product and avoids its collapse.
`According to another of these features, the subject of the
`present invention is the production of stable freeZe-dried
`products containing a pharmaceutical active ingredient cryo
`protected by an amorphous solid phase consisting com
`pletely or partially of mannitol, this amorphous phase coex
`isting Within the freeZe-dried product obtained after
`
`Mylan Ex 1052, Page 5
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`

`

`US 6,284,277 B1
`
`5
`sublimation and drying of the frozen solution, With a crys
`talline phase consisting essentially of alanine.
`Thus, the subject of the present invention is also a process
`for the preparation of freeZe-dried pharmaceutical formula
`tions comprising at least one nonprotein active ingredient
`characterized in that a mixture of the said active ingredient,
`mannitol and alanine in Which the mannitol and alanine are
`present in the ratio of betWeen 0.1 and 1, R being the ratio
`of the mannitol mass to the alanine mass,is freeZe-dried.
`Other pharmaceutically acceptable excipients normally
`used in freeZe-dried forms may be introduced into the
`formulation according to the present invention, such as for
`example buffers or acid-bases Which make it possible to
`adjust the pH, surfactants, salts, preservatives, especially
`antibacterial preservatives, antioxidants or chelating agents,
`excluding excipients Which, in the freeZe-dried product
`containing the active ingredient, Would prevent the coexist
`ence of the crystalline phase consisting predominantly of
`mannitol and of the crystalline phase consisting predomi
`nantly of alanine, such as for example certain protein
`derivatives of animal or plant origin such as gelatines,
`dextrins or proteins extracted from Wheat grain or soya bean,
`gums such as agar or xanthan, polysaccharides, alginates,
`carboxymethylcelluloses, pectins, synthetic polymers such
`as polyvinylpyrrolidone or complexes of a polysaccharide
`nature such as acacia gelatine. Among the buffers Which may
`be introduced into the formulation according to the present
`invention, there may be mentioned in particular carbonate,
`borate, phosphate, citrate, tri(hydroxy-methyl)
`aminomethane, maleate and tartrate buffers, it being under
`stood that the acids and bases composing said buffers may
`also be introduced alone. Among the surfactants Which may
`be introduced into the formulation according to the present
`invention, there may be mentioned in particular
`polysorbates, poloxamers, tyloxapol, lecithins. Among the
`salts Which may be introduced into the formulation accord
`ing to the present invention, there may be mentioned in
`particular the sodium salts such as ededate (tetrasodium
`EDTA), chloride, docusate (sodium 1,4-bis(2-ethylhexyl)
`sulphosuccinate), bicarbonate, glutamate; potassium
`acetate; dipotassium carbonate and magnesium stearate.
`Among the preservatives Which may be introduced into
`the formulation according to the present invention, there
`may be mentioned in particular methyl and propyl para
`hydroxybenZoate, benZethonium chloride, sodium
`mercurothiolate, phenylmercuric nitrate, benZyl alcohol,
`phenol and metacresol.
`The coexistence of the amorphous mannitol phase and the
`crystalline alanine phase is independent of the presence and
`of the concentration of the buffer used to adjust the pH of the
`solution, but it depends on the ratio R de?ned above.
`Examples of formulation of the solutions to be freeZe
`dried leading to the formulations of the invention are the
`folloWing:
`One or a combination of pharmaceutical active
`ingredients, a pharmaceutically acceptable buffer for adjust
`ing the pH, mannitol and alanine With a mass ratio R=mass
`of mannitol/mass of alanine of betWeen 0.1 and 1, Water for
`inj ectable preparations, as Well as, if necessary, antibacterial
`preservatives and excipients Which alloW solubiliZation of
`the active ingredient or ingredients. According to a preferred
`embodiment of the invention, the alanine/mannitol mixture
`is predominant.
`The quantity of active ingredient present is limited by its
`solubility in Water. The formulations of the invention indeed
`result from the freeZe-drying of aqueous solutions in Which
`the active ingredient is perfectly dissolved.
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`6
`Likewise, any excipient is present in the formulation in a
`quantity beloW the quantity of the alanine/mannitol mixture.
`The solutions to be freeZe-dried are prepared in the
`folloWing manner:
`The desired quantities of buffer, alanine, mannitol, pre
`servatives and active ingredient are added, at the appropriate
`dissolution temperature, to the quantity of Water for inject
`able preparations or of solubiliZing agent necessary for their
`solubiliZation until complete dissolution is obtained. The
`solutions obtained are ?ltered in a sterile medium and
`distributed into containers, preferably vials or capsules.
`The freeZe-drying of the solutions is carried out as fol
`loWs:
`The solution folloWs a cycle comprising freeZing, then
`sublimation and drying adapted to the volume to be freeZe
`dried and to the container containing the solution.
`Preferably, a freeZing rate close to —2° C./min is chosen
`in an Usifroid (France) freeZe-drier type SMH15, SM] 100 or
`SMH2000.
`The sublimation and drying times, temperatures and pres
`sures are adjusted according to the volumes of solution to be
`freeZe-dried and the residual Water content desired in the
`freeZe-dried product.
`A freeZe-dried product is then obtained in Which the
`alanine exists in crystalliZed form, and the mannitol in a
`completely or partially amorphous form. The freeZe-dried
`product may be stored at 25° C. and even up to 40° C.
`Without adversely affecting the chemical and biological
`stability of the active ingredient Which it contains.
`Full information on the techniques of preparation of
`injectable formulations by dissolution of the compositions
`of the invention is available to a person skilled in the art in
`Remington’s Pharmaceutical Sciences, 1985, 17th Edition
`or in William N. A. & Polli G. P., The lyophiliZation of
`pharmaceuticals: a literature revieW, J. Parenteral Sci. Tech.,
`1984, 38, (2), 48—59 or in Franks F., Freeze-drying: from
`empiricism to predictability, Cryo-letters, 1990, 11, 93—110.
`The active ingredient or the combined active ingredients,
`of the nonprotein type, formulated according to the present
`invention may be analgesics, anti-in?ammatory agents, anti
`spasmodic agents, anticancer agents or active ingredients
`Which can be used in cardiology, angiology, gastro
`enterology, haematology and haemostasis, hepatology,
`infectiology, neurology-psychiatry, rhinology,
`rheumatology, toxicology, urology, or in the diagnostic ?eld
`or as metabolism and nutrition regulators.
`In the therapeutic families and the ?eld of biological
`activity Which are mentioned above by Way of example, any
`product can constitute the active ingredient of the formula
`tions of the present invention Which represent a considerable
`technical advance in the pharmaceutical technique.
`Preferably, the active ingredients Which are most adapted to
`the formulations of the present invention are those Whose
`stability in aqueous solution is problematical. It is hoWever
`conceivable to apply the present invention to active ingre
`dients Which have no speci?c problem of stability.
`In the text Which folloWs, the international nonproprietary
`names have been adopted to designate the active ingredients.
`The active ingredient of the freeZe-dried pharmaceutical
`formulations of the present invention may be chosen espe
`cially from the group consisting of:
`phenylalkanoic acids, for example ketoprofen;
`nonsteroid anti-in?ammatory agents of the “oxicam”
`type, for example piroxicam, isoxicam, tenoxicam;
`paracetamol;
`lysine or arginine acetylsalicylate;
`corticosteroids, for example methylprednisolone;
`
`Mylan Ex 1052, Page 6
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`

`US 6,284,277 B1
`
`7
`
`phloroglucinol;
`bile acids, for example ursodeoxycholic acid or one of its
`pharmaceutically acceptable salts With inorganic or
`organic bases, preferably its sodium salt;
`anthracyclines, for example doxorubicin, epirubicin,
`idarubicin, daunorubicin, pirarubicin;
`platinum derivatives, for example cisplatin, oxaliplatin,
`carboplatin;
`derivatives of alkaloids from Vinca minor, for example
`vinblastine, vincristine;
`derivatives of alkaloids from rye ergot, for example
`dihydroergotamine, dihydroergotoxine, nicergoline;
`derivatives of purine or pyrimidine bases, for example
`acyclovir, gancyclovir, cytarabine;
`prostaglandins, for example sulprostone, alprostadil;
`benZodiaZepines, for example dipotassium cloraZepate,
`devaZepide;
`beta-lactam antibiotics, for example piperacillin, taZobac
`tam;
`macrolide antibiotics, for example erythromycin or one of
`its derivatives, in general a leukomycin;
`antibiotics of the tetracycline family, for example minocy
`cline;
`antibiotics of the chloramphenicol type, for example
`thiamphenicol;
`antibiotics of the spiramycin type;
`nitrogenous mustards, for example chlorambucin and
`nitrosoureas, for example carmustine and streptoZocin.
`The nitrogenous mustards and the nitrosoureas are
`described in greater detail in Pharmacologie by M.
`Schorderet et al., 1992, 2nd edition, chapter 69, Ed.,
`Frison, Roche, Paris;
`H2 antagonists, for example ranitidine, famotidine or one
`of their pharmaceutically acceptable salts;
`omepraZole and its analogues;
`vitamins, for example thiamine, ribo?avin, nicotinamide,
`pyridoxine, sodium panthotenate, biotin, ascorbic acid,
`folic acid, cyanocobalamin, retinol, cholecalciferol,
`alphatocopherol, cobalamide, hydroxycobalamide;
`antitumour agents chosen from taxol, taxotere and their
`analogues, dacarbaZine, methotrexate, plicamycin,
`thiotepa, streptoZocin;
`cardiovascular medicines chosen from molsidomine or
`one of its pharmaceutically acceptable salts, especially
`its hydrochloride, linsidomine, acetaZolamide,
`meclofenoxate, diltiaZem, sodium nitroprussiate;
`haematological medicines chosen from ticlopidine or one
`of its pharmaceutically acceptable salts, especially its
`hydrochloride, molgramostim, folinic acid;
`anticoagulant and antithrombotic medicines chosen from
`heparin, loW-molecular Weight heparin in the form of
`nadroparin calcium, parnaparin sodium, dalteparin
`sodium, enoxaparin sodium, ardeparin sodium, certo
`parin sodium, reviparin sodium, minolteparin sodium,
`natural or synthetic antithrombotic pentasaccharides;
`heparinoids, for example lomoparan;
`diarginine oxoglutarate and the pharmaceutically accept
`able salts of oxoglutaric acid;
`plant extracts, for example based on WilloW,
`harpagophytum, ginseng, fucus;
`a gene, a DNA or RNA fragment intended for gene
`therapy, an oligonucleotide, an antisense
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`8
`oligonucleotide, nucleotides associated With protein
`compounds such as for example extracts of ribosome
`fractions, attenuated or inactivated live viruses;
`valproic acid and its analogues;
`metopimaZine;
`moxisylite;
`pralidoxime;
`deferoxamine;
`phenobarbital or other barbiturates;
`clomethiaZole;
`sodium pamidronate, sodium alandronate, sodium risen
`dronate and other diphosphonates active as antios
`teoporotic agent, especially {[(4-chlorophenyl)thio]
`methylene}bis(phosphonate) tiludronate or disodium
`salt (SR 41319) in hemihydrate or monohydrate form;
`5-HT2 antagonists, especially ketanserine, ritanserine,
`(1Z,2E))-1-(2-?uorophenyl)-3-(4-hydroxyphenyl)
`prop-2-en-1-one-O-(2-dimethylaminoethyl)oxime (SR
`46349) or one of its pharmaceutically acceptable salts;
`antagonists of angiotensin II, especially tasosartan,
`telmisartan, losartan potassium, losartan combined
`With hydrochlorothiaZide (HCTZ), eprosartan, cande
`sartan cilexetil, valsartan, irbesartan or 2-n-butyl-3
`{[2‘-(1H-tetraZol-5-yl)biphenyl-4-yl]methyl}-1,3
`diaZaspiro[4.4]non-1-en-4-one (SR 47436) and its
`pharmaceutically acceptable salts;
`fantofarone or 1-[(p-{3-[(3,4-dimethoxyphenethyl)
`methylamino]propoxy}phenyl) sulphonyl]-2
`isopropylindoliZine and its pharmaceutically accept
`able salts;
`tirapaZamine or 3-amino-1,2,4-benZotriaZine-1,4-dioxide
`and its pharmaceutically acceptable salts;
`(2S)-1-[(2R,3S)-5-chloro-3-(2-chlorophenyl)-1-(3,4
`dimethoxybenZenesulphonyl)-3-hydroxy-2,3-dihydro
`1H-indole-2-carbonyl]pyrrolidine-2-carboxamide (SR
`49059) and its pharmaceutically acceptable salts;
`N,N-dibutyl-3-{4-[(2-butyl-5-methylsulphonamido)
`benZofuran-3-ylcarbonyl]phenoxyl}propylamine and
`its pharmaceutically acceptable salts, especially the
`hydrochloride (SR 33589);
`6-(2-diethylamino-2-methyl)propylamino-3-phenyl-4
`propylpyridaZine (SR 46559) and its pharmaceutically
`acceptable salts;
`ethyl {(7S)-7-[(2R)-2-(3-chlorophenyl)-2-hydroxy
`ethylamino]-5,6,7,8-tetrahydronaphthalen-2-yloxy}
`acetate and its pharmaceutically acceptable salts, espe
`cially the hydrochloride (SR 58611A);
`1-(2,4-dichlorophenyl)-3-(N-piperidin-1-yl
`carboxamido)-4-methyl-5-(4-chlorophenyl)-1H
`pyraZole and its pharmaceutically acceptable salts,
`especially the hydrochloride (SR 141716A);
`4-{[N-(3,4-dimethoxyphenethyl)]-N-methylamino
`propoxyl}-2-benZenesulphonyl-3-isopropyl-1
`methylindole (SR 33805) and its pharmaceutically
`acceptable salts;
`2-{[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)
`1H-pyraZole-3-carbonyl]amino}adamantane-2
`carboxylic acid (SR 48692) and its pharmaceutically
`acceptable salts;
`N-cyclohexyl-N-ethyl-3-(3-chloro-4-cyclohexylphenyl)
`prop-2-enylamine (SR 31747);
`(—)-N-methyl-N-[4-(4-acetylamino-4-phenylpiperidino)
`2-(3,4-dichlorophenyl)butyl]benZamide (SR 48968)
`and its pharmaceutically acceptable salts;
`
`Mylan Ex 1052, Page 7
`
`

`

`US 6,284,277 B1
`
`9
`(S)- 1 -{2-[3-(3,4-dichlorophenyl)-1 -(3-isopropoxy
`phenylacetyl)piperidin-3-yl]ethyl}-4-phenyl-1 -
`aZoniabicyclo[2.2.2]octane chloride (SR 140333A) and
`its pharmaceutically acceptable quaternary salts, for
`example the benZenesulphonate;
`4-amino-1-(6-chloropyrid-2-yl)piperidine and its pharma
`ceutically acceptable salts, especially the hydrochloride
`(SR 57227A);
`(S)-N-(1-{3-[1-benZoyl-3-(3,4-dichlorophenyl)piperidin
`3-yl]propyl}-4-phenylpiperidin-4-yl)N
`methylacetamide (SR 142801) and its pharmaceutically
`acceptable salts;
`2-{[4-(2-chlorophenyl) thiaZol-2-yl]aminocarbonyl}
`indole-1-acetic acid (SR 27897) and its pharmaceuti
`cally acceptable salts;
`clopidogrel or methyl (+)-(S)-ot-(2-chlorophenyl)- 4,5,6,
`7-tetrahydrothieno-[3,2-c]pyridine-5(4H)-acetate and
`its pharmaceutically acceptable salts, especially its
`hydrogen sulphate;
`1-(2-naphthalen-2-ylethyl)-4-(3-tri?uoromethylphenyl)
`1 ,2,3, 6-tetrahydropyridine hydrochloride (SR
`57746A) and its pharmaceutically acceptable salts,
`especially its hydrochloride;
`N,N-dimethyl-N‘-(pyridin-3-yl)methyl-N‘-[4-(2,4,6
`triisopropylphenyl)thiaZol-2-yl]ethane-1,2-diamine
`and its pharmaceutically acceptable salts, especially the
`fumarate (SR 27417);
`2-[(5-(2,6-dimethoxyphenyl)-1 -{4-[(3-dimethyl
`aminopropyl)methylcarbamoyl]-2-isopropylphenyl}
`1H-pyraZole-3-carbonyl)amino]adamantane-2
`carboxylic acid and its pharmaceutically acceptable
`salts (SR 142948A);
`3-(1-{2-[4-benZoyl-2-(3,4-di?uorophenyl)morpholino-2
`yl]ethyl}-4-phe