`Ulmius
`
`tlllllllllllllllllllllll'lllllllillll|||||llllllllllIIII‘IIIIIIIIIIIIIIII'I
`5,643,602
`Jul. 1, 1997
`
`I
`
`|
`
`l
`
`US005643 602A
`[11] Patent Number:
`[45] Date of Patent:
`
`[54] ORAL COMPOSITION FOR THE
`TREATMENT OF INFLAMMATORY BOWEL
`DISEASE
`
`[75] Inventor: Jan Ulmius, Lund, Sweden
`
`[73] Assignee: Astra Aktiebolag, Sodertalje, Sweden
`
`[21] Appl. No.: 240,078
`[22] Filed:
`May 9, 1994
`
`Related US. Application Data
`
`[63] Continuation of Ser. N 0. 855,623, ?led as PCT/SE90/00738,
`Nov. 15, 1990, abandoned.
`Foreign Application Priority Data
`
`[30]
`
`Nov. 22, 1989 [SE]
`
`Sweden ................................ .. 8903914
`
`[51] Int. Cl.6 ............................. .. A61K 9/58; A61K 9/62;
`A61K 9/ 14; A61K 47/32
`[52] US. Cl. ........................ .. 424/462; 424/461; 424/494;
`424/495; 424/497; 514/951; 514/925
`[58] Field of Search ............................ .. 424/451, 461-62,
`424/494-95, 497, 471-72; 514/915, 925-26
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`9/1976 Brattsand et al. .................... .. 424/241
`3,983,233
`3,996,356 12/1976 Brattsand et al. .
`424/241
`4,606,940
`8/1986 Frank et al.
`424/494
`
`4,708,867 11/1987 Hsiao . . . . . . . . . . . .
`. . . .. 424/462
`4,966,770 10/1990
`et al. ...................... .. 424/470
`
`FOREIGN PATENT DOCUMENTS
`
`0040590 5/1981 European Pat. 01f. .
`1480811
`1/1985 European Pat. 01f. .
`0054010 2/1985 European Pat. 01f. .
`0143764 6/1985 European Pat. O?’. .
`M78174 8/1986 European Pat. 01f. .
`0232690 8/1987 European Pat. 01f. .
`0218174 12/1987 European Pat. Off. .
`WO8300435 2/1983 WIPO .
`8603676 12/1985 WLPO .
`
`OTHER PUBLICATIONS
`
`Wolman et al., Scand. J. Gastroenterology, vol. 24, Suppl.
`15, pp. 146-147 (1989).
`Manufacturer’s Info. (FMC Corporation) re: “Aquacoat”
`(ethyl-cellulose), 1987: Altering Drug Release Rates-Coat
`ing Methods.
`Manufacturer’s Info. re: “Eudragit” (Apr. 1989), Lehmann,
`et al., Practical Course in Lacquer Coating and Survey of
`Course (Apr. 1989) relating to the use of Eudragit, pp.
`l-l67.
`
`Johansson et al., Eur. J. Respir: Dis., vol. 63, Suppl. 122, pp.
`74-84, 1982.
`Manufacturer’s Info. re: “Aquacoat” (ethylcellulose), pp.
`17-36, 1985.
`H. Bechgaard “Critical factors in?uencing gastrointestinal
`absorption-what is the role of pellets?” Acta Pharmaceutic
`Tech 28 (1982) 149.
`Wolman “Use of Oral Budesonide in a Patient with Small
`Bowel Crohn’s Diseae .
`.
`. ” Scand. J. Gastroenterol. 24
`(1989) pp. 146-147.
`Danielsson et al. “A controlled randomized trial of Budes
`onide 20. Prednisolone Retention Enemas .' . . ” Scand. J.
`Gastroenterol. 22 (1987) pp. 987-992.
`Levine et al. “Coating of Oral Beclomethasone Dipropionate
`Capsules with Cellulose Acetate Phthalate ._ . . ” Gastroen
`terology 92 (1987) pp. 1037-1044.
`Richards et al. “Absorption of Delayed Release A Predniso
`lone in Ulcrative Colitis and Crohn’s Disease”, J. Pharm.
`Pharmacol. 37 (1985), pp. 757-758.
`Jewell “Corticosteroids for the Management of Ulcerative
`Colitis and Crohn’s Disease” 18 (1989) pp. 21-34.
`Jamstedt et al. “Etfect of Bethmethasone Treatment on
`Iodothyronimes and Thyroid Hormone-binding Proteins
`During Controlled Nutrition”, Acta Endocrinologica 103
`(1983) pp. 188-191.
`Malchow et al., “Therapie des Morbus Crohn” Deutsche
`Medizinische Wochenschrift 1090 (1984) pp. 1811-1816.
`Andersson et al., “In Vitro Biotransformation of Glucocor
`ticoids in Liver and Skin Hornogenate Fraction from Man,
`Rat and Hairless Mouse”. J. Steroid Biochem. 16 (1982) pp.
`787-795.
`Anders Gamstedt et a1 1983 “Etfect of betarnethasone treat
`ment .
`. . ” Acta Endocrinology 103: 188-191.
`A. Kresznai et al. 1986 “Decreased number of steroid
`receptors . . . ” Haematologia 19: 299-301.
`
`P. Thomas et al. 1985 “Absorption of delayed-release . . .
`” J. Pharmaceutical Pharmocology 37: 757.
`Kumana et al. 1982 “Beclomethasone dipropionate
`enemas .
`. . ” Lancet 1 pp. 579-583 (Dialog).
`
`Primary Examiner-Edward J. Webman
`Attorney, Agent, or Firm-White & Case
`
`[57]
`
`ABSTRACT
`
`An oral pharmaceutical composition is described for tar
`geted slow release in the treatment of in?ammatory bowel
`diseases. Also described are pharmaceutical compositions
`for peroral treatment targeted to different areas of the
`intestinal tract afflicted by ulcerative colitis and certain
`aspects of Crohn’s disease.
`
`26 Claims, No Drawings
`
`Exhibit 1041
`ARGENTUM
`IPR2018-00080
`
`000001
`
`
`
`5,643,602
`
`1
`ORAL COMPOSITION FOR THE
`TREATMENT OF INFLAMMATORY BOWEL
`DISEASE
`
`This application is a continuation of application Ser. No.
`07/855,623, ?led as PCI‘lSE90/00738 Nov. 15, 1990 now
`abandoned.
`
`FIELD OF THE lNVENTION
`The present invention relates to oral pharmaceutical com
`positions for use in the treatment of in?ammatory bowel
`diseases and the use of certain glucocorticosteroids in the
`preparation of pharmaceutical compositions for the treat
`ment by the oral route of certain in?ammatory bowel
`diseases.
`
`1O
`
`20
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`25
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`2
`Very often in Crohn’s disease, however, primary medical
`treatment of the disease process is ine?’ective, and only
`symptomatic treatment is of value i.e. analgesics for pain
`and opiates for diarrhoea. Most patients eventually require
`surgery.
`
`DISCLOSURE OF THE INVENTION
`Our studies indicate that the compositions according to
`the present invention may advantageously be used in the
`treatment of ulcerative colitis including idiopathic proctitis
`and certain aspects of Crohn’s disease by the oral route.
`In ulcerative colitis the compositions can be used for the
`treatment of both active and chronic continuous disease and
`as a relapse preventing treatment (i.e. maintenance therapy
`once remission has been achieved).
`In Crohn’s disease the compositions can be used for the
`treatment of Crohn’s colitis in its active phase and as a
`relapse preventing therapy (i.e. maintenance therapy once
`remission has been achieved), and for the treatment of the
`small intestine as a relapse preventing treatment (i.e. main
`tenance therapy).
`It has been found that the diseases de?ned above can be
`treated using the anti-in?ammatory steroids
`(22RS)-160c,17ot-butylidenedioxy-l 1 [5,2l-dihydroxy
`pregna-l,4-diene-3,20-dione [I],
`the 22R-epimer of [I],
`(22RS)- 160i,170t-butylidenedioxy-9ot-?uoro- 1 15,2 1
`dihydroxy-pregna-l,4-diene-3,20-dione [II],
`the 22R-epimer of [II],
`(22RS)-160L170t-butylidenedioxy-6ot,9ot-di?uoro-11B,
`2l-dihydroxy-pregna-1,4~diene-3,20-dione [III],
`the 22R-epimer of [III],
`(22RS)-2 l-acetoxy- l6ot l7tx-butylidenedioxy-11B
`hydroxy-pregna-l,4-diene-3,20-dione [IA],
`the 22R-epimer of [IA],
`(22RS)-21-acetoxy-160i,17ot-butylidenedioxy-9ot-?uoro
`1IB-hydroxy-pregna-l,4-diene-3,20-dione [IIA],
`the 22R-epirner of [11A],
`
`BACKGROUND OF THE INVENTION
`In?ammatory bowel disease is the term generally applied
`to two diseases, namely ulcerative colitis and Crohn’s dis
`ease.
`Ulcerative colitis is a chronic in?ammatory disease of
`unknown aetiology afflicting only the large bowel and,
`except when very severe, limited to the bowel mucosa. The
`course of the disease may be continuous or relapsing, mild
`or severe. It is curable by total colectomy which may be
`needed for acute severe disease or chronic unremitting
`disease. Most patients with ulcerative colitis are managed
`medically rather than surgically.
`Crohn’s disease is also a chronic in?ammatory disease of
`unknown aetiology but, unlike ulcerative colitis, it can atfect
`any part of the bowel. Although lesions may start
`super?cially, the in?ammatory process extends through the
`bowel wall to the draining lymph nodes. As with ulcerative
`colitis, the course of the disease may be continuous or
`relapsing, mild or severe but, unlike ulcerative colitis it is
`not curable by resection of the involved segment of bowel.
`Most patients with Crohn’s disease come to surgery at some
`time, but subsequent relapse is common and continuous
`medical treatment is usual.
`For treatment of acute attacks of ulcerative colitis, glu
`cocorticosteroids such as prednisone or prednisolone acetate
`are almost invariably used and given by mouth for the
`average acute attack or relapse, or locally, by enema.
`After remission has been achieved, sulphasalazine is the
`maintenance treatment of choice in treating ulcerative coli
`tis. This drug, however, has a signi?cant number of side
`effects chie?y due to absorption of the sulphapyridine moi
`ety from the colon. Recently compounds which contain only
`S-aminosalicylic acid have been developed; these are as
`effective as sulphasalazine and do not have the sulphapyri
`dine side effects but do have side effects of their own,
`notably diarrhoea.
`Glucocorticosteroids are, however, not used for mainte
`nance of remission in ulcerative colitis; doses that do not
`produce unacceptable side effects are ineffective, and
`patients who need chronic high dose glucocorticosteroids for
`control of their disease almost invariably are treated by
`colectomy.
`As with ulcerative colitis, glucocorticosteroids are the
`treatment of choice for severe active Crohn’s disease, but
`ideally only to achieve remission, after which they should be
`stopped. However, all too frequently the disease does not
`satisfactorily remit, and glucocorticosteroids may be neces
`sary to maintain control of symptoms. Sulphasalazine is also
`useful in less severe cases, particularly for disease involving
`the colon.
`
`35
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`45
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`55
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`65
`
`di?uoro-l1B-hydroxy-1,4-diene-3,20-dione [IIIA],
`the 22R-epimer of [IIIA],
`(22RS)-160t, 17ot-butylidenedioxy-l 15,2 l-dihydroxy
`pregna-4-ene-3,20-dione [IV], _
`the 22R-epirner of [IV],
`(22RS)- l6ot,l7ot-pentylidenedioxy-l1B,21-dihydroxy
`pregna-4-ene-3,20-dione [V],
`the 22R-epirner of [V],
`(22RS)-21-acetoxy- 160t,17ot-butylidenedioxy- 1 1 [5,
`hydroxypregn-4-ene-3,20-dione [IVA],
`the 22R-epimer of [IVA],
`(22RS)-2 l-acetoxy- 1 60., 17 ot-pentylidenedioxy- l 1 B,
`hydroxypregn-4-ene-3,20-dione [VA],
`the 22R-epimer of [VA],
`methyl (20RS)-l6ot,l7a-butylidenedioxy-llB-hydroxy
`androsta-1,4-diene-3-one-17[5-carboxylate [VI],
`the 20R-epirner of [VI],
`methyl (2ORS)-l60t,17ot-butylidenedioxy-9oL-?uoro- 11B
`hydroxy-androsta-l,4-diene-3-one-l7B-carboxylate
`[VII],
`the 20R-epimer of [V11],
`methyl (20RS)-160i,17ot-butylidenedioXy-60t,9ot
`di?uoro-ll[i-hydroxy-androsta-l,4-diene-3-one-l7[5
`carboxylate [VIII],
`
`000002
`
`
`
`5,643,602
`
`10
`
`15
`
`25
`
`35
`
`3
`the 20R-epimer of [VIII],
`methyl (22RS)-16oz.l7ot-butylidenedioxy-6ot,9ot
`di?uoro-llB-hydroxy-3,20-dioxopregna-1,4-diene-2l
`oate [IX] and
`the 22R-epimer of [IX].
`Compound [I] has the approved name “budesonide”.
`Compound [I] and its 22R-epimer are particular preferred
`compounds.
`Budesonide and compounds [II], [III]. [IA], [HA] and
`[IIIA] are described and claimed in Swedish Patent Speci
`?cation 378 109. Budesonide is known to have an anti
`in?ammatory activity and, compared to preduisone, pred
`nisolone and other glucocorticosteroids, an advantageous
`ratio between local and systemic elfect when administered
`topically to the skin or to the lungs by inhalation.
`Budesonide is a potent steroid, which is successfully used
`when locally treating (via aerosol) asthma and rhinitis. Also
`controlled trials of budesonide enema for locally treating
`proctitis and distal ulcerative colitis are in progress
`(Danielsson A et al: A controlled randomized trial of budes
`onide versus prednisolone retention enemas in active distal
`ulcerative colitis, Scand. J. Gastroenterol. 22:987-992, 1987
`and Danielsson A et a1: Controlled trial of budesonide
`enema and placebo in proctitis and distal ulcerative colitis.
`Scand. J. Gastroenterol. 24. supplement 159:88). The use of
`oral budesonide in the treatment of small bowel Crohn’s
`disease in its active phase has been described (Wolman SL:
`Use of oral budesonide in a patient with small bowel
`Crohn’s disease and previous pseudotumor cerebri second
`ary to steroids. Scand J. Gastroenterol. 24, Supplement
`158:146-147).
`The characteristic pro?le of budesonide when used for the
`treatment of these diseases is a high anti-in?ammatory effect
`at the place of application but a low degree of unwanted
`systemic glucocorticoid side etfects. The low degree of
`systemic side effects of budesonide is a result of a high ?rst
`pass liver metabolism transferring budesonide into substan
`tially less active metabolites.
`Especially the 22R-epimer of budesonide seems to be
`very promising in the treatment of in?ammatory bowel
`diseases as hereinbefore de?ned when orally administered
`because, compared to budesonide it is more potent, is more
`rapidly metabolised by the liver and thus less available in the
`systemic circulation and thereby causing less unwanted
`systemic effects.
`The 22R-epimers of compounds [I], [H], [HI], [IA], [11A]
`and [IIIA] are described and claimed in Swedish Patent
`Speci?cation 378 110.
`Compounds [IV], [V], [IVA], [VA] and the 22R-epimers
`thereof are described and claimed in European Patent Speci
`?cation 54010.
`Compounds [VI], [VII], [VIII] and the 20R-epimers
`thereof are described and claimed in European Patent Appli
`cation 143 764.
`Compound [IX] and the 22R-epimer thereof are described
`add claimed in European Patent Application 232 690.
`We have surprisingly found that the above identi?ed
`glucocorticosteroids administered by the convenient oral
`route are of great potential bene?t in the treatment of
`in?ammatory bowel diseases as hereinbefore de?ned.
`The above mentioned compounds thus potentially repre
`sents a very signi?cant advance over other glucocorticos
`teroids which exert their elfects systemically and other drugs
`previously used for the management of Crohn’s disease,
`particularly in avoiding the systemic side effects normally
`associated with glucocorticosteroid therapy. The high ?rst
`pass liver metabolism of the drug renders possible its safe
`
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`4
`use in the maintenance therapy of the disease as well as
`achieving remission in the acute phase. Although Crohn’s
`disease is not a very common condition, it is a chronic and
`often debilitating disorder that can bene?t from a safer and
`more effective treatment.
`In ulcerative colitis, the drug may help to reduce the
`number of patients having to undergo surgery and in
`addition, its lack of systemic e?’ects makes it possible to use
`the drug for maintenance therapy once remission has been
`achieved.
`The invention therefore provides pharmaceutical compo
`sitions comprising the glucocorticosteroids hereinbefore
`de?ned for use in the treatment by the oral route of bowel
`diseases as hereinbefore de?ned.
`The invention also provides the use of the glucocorticos
`teroids as hereinbefore de?ned in the preparation of phar
`maceutical compositions for the treatment by the oral route
`of bowel diseases as hereinbefore de?ned
`The invention further provides a method of treatment of
`bowel diseases as hereinbefore de?ned wherein an effective
`dose of a glucocorticosteroid as hereinbefore de?ned is
`administered by the oral route to a human or animal subject
`su?ering from said bowel disease.
`In order for the oral composition containing the gluco
`corticosteroids as hereinbefore de?ned to be applicable for
`the treatment of the bowel diseases as hereinbefore de?ned
`the composition must be adjusted to this particular purpose.
`The adjusted composition is a further aspect of the present
`invention, and it can be used generally when treating ulcer
`ative colitis and Crohn’s disease.
`The transit time through the gastro-intestinal canal for
`different dosage forms are rather well known. When the
`dosage form has been emptied from the stomach the transit
`through the small intestine takes 3 to 5 hours. The residence
`time in the large intestine is considerably longer, 25 to 50
`hours. Ideally, as long as the dosage form remains in the
`stomach no release should occur. If Crohn’s disease in small
`intestine is going to be treated the release should continue
`during about 5 hours after the dosage form has left the
`stomach. If the large intestine is going to be treated the
`release should ideally start at caecum, and continue for up to
`50 hours.
`The present invention utilizes pharmaceutical formulation
`techniques to provide compositions of a glucocorticosteroid
`for treating the in?ammatory diseases of the bowel as
`hereinbefore de?ned. The glucocorticosteroid must have a
`chance to reach the in?amed part of the bowel in su?icient
`concentration and for a su?icient long time to exert it’s local
`action, in the case of Crohn’s disease the whole bowel or
`only the small intestine and in the case of ulcerative colitis
`the caecum (cecum), colon and the rectum.
`A multiple unit composition in a capsule has been found
`suitable for ful?lling the above-mentioned demands. In
`ulcerative colitis, the composition should be formulated so
`that the glucocorticosteroid is released preferentially during
`the passage of the colon. In Crohn’s disease in the ileum the
`composition should be formulated so that the glucocorticos
`teroid is released preferentially during the passage of the
`small intestine. This can be accomplished by enteric and/or
`slow release coating of the units containing the glucocorti
`costeroid. Such formulations of glucocorticosteroids are
`novel.
`The dosage range for treatment of the bowel diseases as
`hereinbefore de?ned is suitably 2-20 mg divided into 1 to 4
`doses during a 24-hour period.
`DETAILED DESCRIPTION
`The units will have a size between 0.3 and 5 mm,
`preferably a size between 0.5 and 2 mm. The units will be
`
`000003
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`administered in hard gelatine capsules, the size of which will
`depend on the dose administered.
`Each unit comprises a core, a ?rst layer on the core and
`a second layer on the ?rst layer.
`"
`The core consists of a non-pareil seed, preferably having
`a diameter between 0.2 and 1.0 mm, to which the glucocor
`ticosteroid is applied or a seed in which the glucocorticos
`teroid is homogeneously distributed. The excipients used to
`prepare the seeds comprise one or more of pharmaceutically
`acceptable materials, eg sugar, starch, microcrystalline
`cellulose, waxes and polymeric binding agents.
`The ?rst layer on the non-pareil seeds comprises the
`glucocorticosteroid and a water-soluble or water-insoluble
`polymer which acts both as binder for the glucocorticoster
`oid and as a rate-limiting layer for release of the glucocor
`ticosteroid. Such polymers may be selected from cellulose
`derivatives, acrylic polymers and copolymers, vinyl poly
`mers and other high molecular polymer derivatives or syn
`thetic polymers such as methylcellulose,
`hydroxypropylcellulose, hydroxypropyhnethylcellulose,
`ethylcellulose, cellulose acetate, polyvinyl pyrrolidone,
`polyvidone acetate, polyvinyl acetate, polymethacrylates
`and ethylene-vinyl acetate copolymer or a combination
`thereof. Preferred ?lm-forming polymers are ethylcellulqse
`or copolymers of acrylic and methacrylic acid esters
`(Eudragit NE, Eudragit RL, Eudragit RS) in aqueous dis
`persion form.
`The ?rst, optionally rate-limiting layer on the seeds with
`homogeneously distributed glucocorticosteroid comprises a
`water insoluble polymer or a mixture of water insoluble
`polymers or a mixture of water soluble and water insoluble
`polymers mentioned above.
`The polymers in the second layer may be selected from
`the group of anionic carboxylic polymers suitable for phar
`maceutical purposes and being soluble with di?iculty at a
`low pH but being soluble at a higher pH, the pH limit for
`solubility being in the interval of pH 4 to pH 7.5, said group
`comprising cellulose acetate phthalate, ceHulose acetate
`trimellitate, hydroxypropylrnethylcellulose phthalate, poly
`vinyl acetate phthalate and acrylic acid polymers e.g. partly
`esteri?ed methacrylic acid polymers such as Eudragit L,
`Eudragit L100-55 and Eudragit S. These polymers may be
`used alone or in combination with each other or in combi
`nation with water insoluble polymers mentioned before.
`Preferred polymers are the Eudragits in aqueous dispersion
`form. The anionic carboxylic polymer comprises 25 to 100
`% of the total polymer content.
`The coatings may optionally comprise other pharmaceu
`tically acceptable materials which improve the properties of
`the ?lm-forming polymers such as plasticizers, anti
`adhesives, surfactants, and diiTusion-accelerating or
`diifusion-retarding substances.
`Suitable plasticizers comprise phthalic acid esters,
`triacetin, dibutylsebacate, monoglycerides, citric acid esters
`and polyethylene glycols. Preferred plasticizers are acetyl
`nibutyl citrate and triethyl citrate.
`Suitable antiadhesives comprise talc and metal stearates.
`The amount of the ?rst coating applied on the units is
`normally in the range between 0.5% and 30% by weight,
`preferably between 1% and 15%. This amount includes in
`the relevant case the weight of the steroid as well. The
`amount of the second coating applied on the units is nor
`mally in the range between 1% and 50% by weight, pref
`erably between 2% and 25%, calculated on the weight of the
`coated units. The remainder constitutes the weight of the
`seed.
`
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`5,643,602
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`6
`The preparation of the controlled release pellet fonnula
`tion according to the present invention is characterized in
`that a non-pareil seed is enclosed in a layer of a glucocor
`ticosteroid as hereinbefore de?ned and a water soluble or
`water insoluble polymer or a seed with homogeneously
`distributed glucocorticosteroid as hereinbefore de?ned is
`optionally enclosed in a layer of a water insoluble polymer
`or a mixture of water insoluble polymers or a mixture of
`water soluble or water insoluble polymers which in turn is
`enclosed in a membrane of a ?lm-forming anionic carboxy
`lic polymer or a mixture of a ?lm-forming anionic carboxy
`lic polymer and a water insoluble polymer which permits
`release of the glucocorticosteroid as hereinbefore de?ned in
`a manner set out below.
`The controlled release pellet formulation according to this
`invention is thus characterized in that the pellet comprises
`i) a core consisting of a non-pareil seed or a seed in which
`a glucocorticosteroid as de?ned below is homoge
`neously distributed and
`ii) in case of a core consisting of a non-pareil seed, a layer
`of
`a) a glucocorticosteroid selected from the group con
`sisting of (22RS)-l6ot,l70t-butylidenedioxy-1115,21
`dihydroxypregna-l,4-diene-3,20-dione [I],
`the 22R-epimer of [I],
`(22RS)-160t, 17 ot-butylidenedioxy- 9ot-?uoro- 1 1B,
`2l-dihydroxy-pregna-1,4-diene-3 ,20-dione [II],
`the 22R-epimer of [II],
`(22RS)-l60t,170t-butylidenedioxy-60t,9ot-di?uoro
`11[5,2l-dihydroxy-pregna-1,4-diene-3,20-dione
`[III],
`the 22R-epimer of [III],
`(22RS)-21-acetoxy-160a170t-butylidene-dioxy-11B
`hydroxypregna-1,4-diene-3,20-dione [IA],
`the 22R-epi11er of [IA],
`(22RS)-2l-acetoxy-16ot, 17ot-butylidene-dioxy-90t
`?uoro-llB-hydroxy-pregna-1,4-diene-3 ,20-dione
`[11A],
`the 22R-epimer of [HA],
`(22RS)-2l-acetoxy-160t,17u-butylidenedioxy-60t,
`9ot-di?uoro-11[S-hydroxy-1,4-diene-3,20-dione
`[111A],
`the 22R-epimer of [IIIA],
`(22RS)- 16a,l7ot-butylidenedioxy-1 1[5,2l
`dihydroxypregn-4-ene-3,20-dione [IV],
`the 22R-epimer of [IV],
`(22RS)-160L, l7ot-pentylidenedioxy-1l [5,21
`dihydroxypregn-4-ene-3,20-dione [V],
`the 22R-epimer of [V],
`(22RS)-21-acetoxy-l6ot,l7ot-butylidene-dioxy-11B,
`hydroxypregn-4-ene-3,20-dione [IVA],
`the 22R-epimer of [IVA],
`(22RS)-2 l-acetoxy- l6a,17ot-pentylidene-dioxy
`l1[5,hydroxypregn-4-ene-3,20-dione [VA],
`the 22R-epimer of [VA],
`methyl (20RS)- 16oz, l70t-butylidenedioxy- 1 1B
`hydroxy-androsta- 1,4-diene-3-one-17B
`carboxylate [V1],
`the 20R-epimer of [VI],
`methyl (20RS)-160t,17ot-buty1idenedioxy-90t
`?uoro-llB-hydroxy-androsta-1,4-diene-3-one
`l7?-carboxylate [V11],
`the 20R-epimer of [VII],
`methyl (20RS)-l60L,170t-butylidenedioxy-6ot,9ot
`di?uoro-llB-hydroxy-androsta-1,4-diene-3-one
`17B-carboxylate [VIII],
`the 22R-epimer of [V111],
`
`000004
`
`
`
`7
`methyl (22RS)-160L,17a-butylidenedioxy-60t,90t
`di?uoro-11B-hydroxy-3,20-dioxo-pregna-1,4
`diene-21-oate [IX] and the 22R-epimer of [IX]
`and
`b) a pharmaceutical acceptable ?lm forming water
`insoluble or water soluble polymer, or
`in case of a core consisting of a seed in which a
`glucocorticosteroid as de?ned above is homogeneously
`distributed. an optionally layer of a pharrnaceutically
`acceptable ?lm forming water insoluble polymer or a
`mixture of water insoluble polymers or a mixture of
`water soluble and water insoluble polymers and
`iii) a membrane surrounding said core and layer and
`containing a pharrnaceutically acceptable ?lm-forming
`anionic carboxylic polymer being soluble with di?i
`culty at low pH but being soluble at a higher pH, either
`alone or in combination with a phannaceutically
`acceptable ?lm-forming water insoluble polymer,
`the thickness of said layer or said membrane and/or the ratio
`of said anionic carboxylic polymer to said insoluble polymer
`being e?ective to prevent release of said glucocorticosteroid
`from said pellet in gastric ?uids, but to permit release of said
`glucocorticosteroid from said pellet in intestinal ?uids at a
`rate allowing treatment of the part of the intestinal tract
`where the disease resides, i.e. at a rate corresponding to a
`release time of 1 to 50 hours, preferably 5 to 10 hours when
`treating the small intestine and 25 to 50 hours when treating
`the large intestine, said rate being measured in vitro as a
`dissolution rate of said unit in simulated gastric and intes
`tinal ?uids, when measured in a ?ow through cell at 8
`mL/min and 37° C. substantially corresponds to the follow
`ing for units intended for treating the small intestine:
`a) not more than 10%, preferably not more than 5%, of the
`total glucocorticosteroid is released after two hours in
`simulated gastric ?uid in said assembly,
`b) from 15 to 55%, preferably from 20 to 50%, of the total
`glucocorticosteroid is released after two hours in simu
`lated intestinal ?uid in said assembly,
`c) from 35 to 80%, preferably from 40 to 70%, of the total
`glucocorticosteroid is released after four hours in simu
`lated intestinal ?uid in said assembly,
`d)~not less than 60, preferably 60 to 90%. of the total
`glucocorticosteroid is released after eight hours in
`simulated intestinal ?uid in said assembly,.
`e) not less than 80% of the total glucocorticoid steroid is
`released after twelve hours in simulated intestinal ?uid
`in said assembly,
`and for units intended for treating the large intestine:
`a) not more than 10%, preferably not more than 5%, of the
`total glucocorticosteroid is released after two hours in
`simulated gastric ?uid in said assembly,
`b) from 5 to 30%, preferably from 10 to 30%, of the total
`glucocorticosteroid is released after four hours in simu
`lated intestinal ?uid in said assembly,
`0) from 20 to 65%, preferably from 35 to 55%, of the total
`glucocorticosteroid is released after twelve hours in
`simulated intestinal ?uid in said assembly,
`d) from 40 to 95%, preferably from 55 to 85%, of the total
`glucocorticosteroid is released after twenty-four hours
`in simulated intestinal ?uid in said assembly,
`e) not less than 70%, preferably not less than 80%, of the
`total glucocorticosteroid is released after forty-eight
`hours in simulated intestinal ?uid in said assembly.
`In one embodiment of the composition there is a layer
`which comprises budesonide or the 22R epimer thereof and
`
`8
`a water soluble or Water insoluble polymer beneath the
`membrane surrounding the pellet
`In another embodiment of the composition the polymeric
`material of the layer in which budesonide or its 22R epimer
`is embedded is selected from polyvinylpyrrolidone and
`hydroxypropylmethylcellulose or alternatively from
`ethylcellulose, cellulose acetate and copolymers of acrylic
`and methacrylic acid esters.
`In still another embodiment of the composition the layer
`which comprises budesonide or its 22R epimer and a water
`soluble or water insoluble polymer includes one or more
`additional components selected from plasticizers, anti
`adhesives adhesives and surfactants.
`
`WORIGNG EXAMPLES
`
`The following pharmaceutical compositions can be used
`in the treatment of bowel diseases according to the inven
`tion.
`
`Example 1
`
`Budesonide micronized
`Sugar spheres
`Aquacoat ECD 30
`Acetyltributyl citrate
`Polysorbate 80
`Eudragit L100-55
`Triethylcitrate
`Talc
`Antifoam MNIS
`
`mg/capsule
`
`1.0
`321
`6.6
`0.5
`0.1
`17.5
`1.8
`8.8
`0.01
`
`Budesonide (32.2 g) was suspended in the Aquacoat ECD
`30 dispersion (0.70 kg) with the aid of the Polysorbate 80
`(0.42 g) together with acetyltributyl citrate (15.8 g). The
`mixture was sprayed on to sugar spheres (10.2 kg) in a ?uid
`bed apparatus. The enteric coating consisting of the Eudragit
`L100-55 dispersion, ( Eudragit L100-55 (0.558 kg), trieth
`ylcitrate (55.8 g), talc (0.279 kg), Antifoam NEVIS (0.44 g)
`and Polysorbate 80 (2.79 g)) was then sprayed on the
`spheres. The pellets were dried in the ?uid bed apparatus,
`sieved and filled in hard gelatine capsules.
`
`The ?nished pellets were then subjected to a dissolution
`test as follows:
`
`Apparatus: Flow-through cells (Sotax Dissotest CH6,
`equipped with 12 mm cells) at a ?ow rate of 8 mL/min
`and at 37° C.
`Medium: Simulated gastric ?uid (SGF), pH 1.2 and
`simulated intestinal ?uid (SIF), pH 7.5 according to
`USP without enzymes.
`Method: For the dissolution test in simulated gastric ?uid,
`2.8 g of pellets, and for the test in simulated intestinal
`?uid, 1.4 g of pellets were placed in the cells and the
`test commenced. For speci?ed time periods fractions
`were collected and analyzed for budesonide by a liquid
`chromatographic method. The percentage dis solution at
`each time point was calculated. The results are shown
`in Table l.
`
`5,643,602
`
`10
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`60
`
`65
`
`000005
`
`
`
`5,643,602
`
`10
`Example 3
`
`TABLE 1
`
`Dissolution of budesonide of Example 1
`
`'
`
`Percentage dissolution after
`
`Medium
`
`1 hour
`
`2 hours
`
`4 hours
`
`8 hours
`
`12 hours
`
`SGF
`81F
`
`l
`34
`
`2
`53
`
`3
`75
`
`—
`92
`
`—
`97
`
`Example 2
`
`Budesonide micronized
`Sugar spheres
`Auquacoat ECD 30
`Acetyltributyl citrate
`Polysorbate 80
`Eudragit NE3OD
`Eudragit S100
`Talc
`
`rug/capsule
`
`2.0
`292
`4.8
`0.4
`0.01
`17.5
`17.5
`17.5
`
`5
`
`10
`
`20
`
`25
`
`Budesonide (3.5 g) was suspended in the Aquacoat ECD
`30 dispersion (28.0 g) with the aid of the Polysorbate 80
`(0.02 g) together with acetyltributyl citrate (0.63 g). The
`mixture was sprayed on to sugar spheres (510 g) in a ?uid
`bed apparatus. The rate-limiting and enteric coating consist
`ing of Eudragit S100 (30.0 g) and talc (30.0 g) suspended in
`the Eudragit NE30D dispersion (100 g) with the aid of
`Polysorbate 80 (0.3 g) was then sprayed on the spheres. The
`pellets were dried, sieved and ?lled in hard gelatine cap~
`sules.
`
`30
`
`35
`
`Budesonide micronized
`Sugar spheres
`Auquacoat ECD 30
`Acetyltributyl citrate
`Polysorbate 80
`Eudragit NE30D
`Eudragit S100
`Talc
`
`mg/capsule
`
`2.0
`305
`5.0
`0.4
`0.14
`12.6
`12.6
`12.6
`
`Budesonide (6.69 g) was suspended in the Aquacoat ECD
`30 dispersion (56.0 g) with the aid of the Polysorbate 80
`(0.04 g) together with acetyltributyl citrate (1.26 g). The
`mixture was sprayed on to sugar spheres (1020 g) in a ?uid
`bed apparatus. The rate-limiting and enteric coating consist
`ing of Eudragit S100 (42.0 g) and talc (42.0 g) suspended in
`the Eudragit NFJOD dispersion (140 g) with the aid of
`Polysorbate 80 (0.42 g) was then sprayed on the spheres.
`The pellets were dried, sieved and ?lled in hard gelatine
`capsules.
`The ?nished pellets were then subjected to a dissolution
`test as follows:
`Apparatus: Flow-through cells (Sotax Dissotest CE6,
`equipped with 12 mm cells) at a ?ow rate of 8 mIJmin
`and at 37° C.
`Medium: Simulated gastric ?uid (SGF), pH 1.2 and
`simulated intestinal ?uid (SIF), pH 7.5 according to
`USP Without enzymes.
`Method: For the dissolution test in simulated gastric ?uid,
`2.8 g of pellets, and for the test in simulated intestinal
`?uid, 2.1 g of pellets were placed in the cells and the
`test commenced. For speci?ed time periods fractions
`were collected and analyzed for budesonide by a liquid
`chromatographic method. The percentage dissolution at
`each time point was calculated. The results are shown
`in Table 3.
`
`The ?nished pellets were then subjected to a dissolution
`test as follows:
`
`Apparatus: Flow-through cells (Sotax Dissotest CE6,
`equipped with 12 mm cells) at a ?ow rate of 8 mL/min
`and at 37° C.
`Medium: Simulated gastric ?uid (SGF), pH 1.2 and
`simulated intestinal ?ui