US 7,704,977 B2
`(10) Patent No.:
`(12) Unlted States Patent
`Leonard
`(45) Date of Patent:
`Apr. 27, 2010
`
`
`USOO7704977B2
`
`(54) SOLID ORAL DOSAGE FORM CONTAINING
`AN ENHANCER
`
`(75)
`
`Inventor: Thomas W. I. Leonard, Wilmington,
`NC (US)
`.
`.
`.
`.
`.
`(73) A551gnee: Merrlon Research III lelted, Dublin
`(IE)
`J
`y
`Sub'ect to an disclaimer, the term of this
`patent is extended or adjusted under 35
`U‘S‘C‘ 154(1)) by 112 days‘
`
`*
`
`Notice:
`
`(21) APP1~ N0: 11/733,007
`
`(22)
`
`Filed:
`
`Apr. 9, 2007
`
`(65)
`
`Prior Publication Data
`
`US 2007/0238707 A1
`
`Oct. 11: 2007
`
`4,789,547 A
`5,169,933 A
`5,190,748 A
`
`5,221,734 A
`5,229,130 A
`5,288,497 A
`5,346,701 A
`5,541,155 A
`5,631,347 A
`5,650,386 A
`
`12/1988 Song et a1.
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`
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`t
`l.
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`(Continued)
`FOREIGN PATENT DOCUMENTS
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`
`(Continued)
`
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`
`Related US. Application Data
`
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`
`(60) Provisional application No. 60/791,231, filed on Apr.
`7: 2006'
`
`(51)
`
`Int- Cl-
`(2006.01)
`A61K 31/675
`(2006.01)
`A61K 31/663
`(2006.01)
`A61K 31/20
`(2006.01)
`A61K 9/48
`(52) US. Cl.
`......................... 514/89; 514/102; 514/558;
`424/451
`(58) Field of Classification Search ................. 424/451;
`514/89, 102, 558
`See application file for complete search history.
`R f
`C't d
`e erences
`l e
`U.S. PATENT DOCUMENTS
`4,525,339 A
`6/1985 Behl et a1.
`4,656,161 A
`4/1987 Herr
`
`56
`
`)
`
`(
`
`(Continued)
`Primary ExamineriHumera N Sheikh
`Assistant ExamineriAradhana Sasan
`74 An
`A
`t
`F' 7M B'
`(Sajgvec grAney’
`gen ’ or
`”m
`ye“
`lge
`.
`.
`
`(57)
`
`ABSTRACT
`
`1 Sb]
`1 ey
`
`&
`
`The invention relates to a phannaceutical composition and
`oral dosage forms comprising a bisphosphonate in combina-
`tion with an enhancer to enhance intestinal delivery of the
`bisphosphonate to the underlying circulation. Preferably, the
`enhancer is a medium chain fatty acid or a medium chain fatty
`acid derivative having a carbon chain length of from 6 to 20
`carbon atoms, and the solid oral dosage form is a controlled
`release dosage form such as a delayed release dosage form.
`
`34 Claims, 17 Drawing Sheets
`
`Mean Plot
`
`0.30 -—
`
`Bloswdy 0601001
`Human Alendronate Study
`MEAN PLOT
`
`A 025
`
`E2
`
`‘ 020
`
`8 g
`
`] 0.15
`0.10
`0.05
`
`EE
`
`n <
`
`
`
`0.00 -
`
`-9- Trt A - 55mg Fosamax Fasted (P0)
`~H- Tn B - 17.51119 Alendronale + 0.59 010 as 2 tablets Fasten (PO)
`'9' Trt C - 17.5mg Alendronate 4» 0.59 010 as 21ab1615 Fed (PO)
`
`4! Trl D . 175mg Alsndronate + 0259 C10 as 21110191: Famed (PO)
`‘9“ Tr! E . 175mg Alendronaie + 0.259 C10 as 1 table! Famed (F0)
`
`Grun. Exh. 1009
`
`PGR for US. Patent No. 9,539,268
`
`Grun. Exh. 1009
`PGR for U.S. Patent No. 9,539,268
`
`

`

`US 7,704,977 B2
`Page 2
`
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`
`

`

`U.S. Patent
`
`Apr. 279 2010
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`oE.3998528.0,33+:33:288v.0.<E59135...28mm0.
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`

`

`U.S. Patent
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`Apr. 27, 2010
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`Sheet 14 of 17
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`US 7,704,977 B2
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`U.S. Patent
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`Apr. 27, 2010
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`Sheet 15 of 17
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`US 7,704,977 132
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`U.S. Patent
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`Apr. 27, 2010
`
`Sheet 16 of 17
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`US 7,704,977 B2
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`

`

`US. Patent
`
`Apr. 27, 2010
`
`Sheet 17 0f 17
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`US 7,704,977 B2
`
`Figure 17
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`

`

`US 7,704,977 B2
`
`1
`SOLID ORAL DOSAGE FORM CONTAINING
`AN ENHANCER
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is based on and claims priority to US.
`Provisional Application No. 60/791,231, filed Apr. 7, 2006,
`the contents of which are fully incorporated herein by refer-
`ence.
`
`FIELD OF THE INVENTION
`
`The present invention relates to a compositions and solid
`oral dosage forms containing an enhancer. In particular the
`invention relates to compositions and solid oral dosage forms
`comprising a pharmaceutically active ingredient in combina-
`tion with an enhancer which enhances the bioavailability
`and/or the absorption of the active ingredient.
`
`BACKGROUND OF THE INVENTION
`
`The epithelial cells lining the lumenal side of the gas-
`trointestinal tract (GIT) canbe a majorbarrier to drug delivery
`via oral administration. However, there are four recognized
`transport pathways which can be exploited to facilitate drug
`delivery and transport: the transcellular, paracellular, carrier-
`mediated and transcytotic transport pathways. The ability of
`a drug, such as a conventional drug, a peptide, a protein, a
`macromolecule or a nano- or microparticulate system, to
`“interact” with one or more of these transport pathways may
`result in increased delivery of that drug from the GIT to the
`underlying circulation.
`Certain drugs utilize transport systems for nutrients which
`are located in the apical cell membranes (carrier mediated
`route). Macromolecules may also be transported across the
`cells in endocytosed vesicles (transcytosis route). However,
`many drugs are transported across the intestinal epithelium
`by passive diffusion either through cells (transcellular route)
`or between cells (paracellular). Most orally administered
`drugs are absorbed by passive transport. Drugs which are
`lipophilic permeate the epithelium by the transcellular route
`whereas drugs that are hydrophilic are restricted to the para-
`cellular route.
`
`Paracellular pathways occupy less than 0.1% of the total
`surface area of the intestinal epithelium. Further, tight junc-
`tions, which form a continuous belt around the apical part of
`the cells, restrict permeation between the cells by creating a
`seal between adjacent cells. Thus, oral absorption of hydro-
`philic drugs such as peptides can be severely restricted. Other
`barriers to absorption of drugs may include hydrolyzing
`enzymes in the lumen brush border or in the intestinal epithe-
`lial cells, the existence of the aqueous boundary layer on the
`surface of the epithelial membrane which may provide an
`additional diffusion barrier, the mucus layer associated with
`the aqueous boundary layer and the acid microclimate which
`creates a proton gradient across the apical membrane.
`Absorption, and ultimately bioavailability, of a drug may also
`be reduced by other processes such as P-glycoprotein regu-
`lated transport of the drug back into the gut lumen and cyto-
`chrome P450 metabolism. The presence of food and/or bev-
`erages can also interfere with absorption and bioavailability.
`Bispho sphonates are a family of drugs used to prevent and
`treat bone fractures, osteoporosis, Paget’s disease, metastatic
`bone cancer, and other bone diseases with high bone resorp-
`tion. Bisphosphonates bind to bone hydroxyapatite and slow
`
`10
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`25
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`30
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`35
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`2
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`down bone-eroding cells known as osteoclasts. This effect
`allows the bone-building cells known as osteoblasts to work
`more effectively.
`Some of the limitations with conventional bisphospho-
`nates include irritation of the upper GIT, such as esophageal
`ulcers, and low bioavailability. As a result, conventional bis-
`phosphonates require a specific dosing regimen so that the
`patient can absorb some of the drug properly and avoid side
`effects. Because foods, beverages, medications and calcium
`interfere with absorption, conventional bisphosphonates
`must be administered on an empty stomach and, depending
`on the particular bisphosphonate, must wait from 30 minutes
`to two hours before consuming any food, beverages (other
`than water), medications or calcium supplements. As esoph-
`ageal ulcers are a known side effect, dosing regimens for
`conventional bisphosphonates specify that patients consume
`an entire glass of water with the dosage form and avoid
`assuming a horizontal orientation, such as by lying down,
`within 30 to 60 minutes after administration.
`
`The specific characteristics of alendronate served to exem-
`plify the members of the class of bisphosphonates and the
`issues associated with them. Alendronate is a white, crystal-
`line, odorless, non-hygroscopic bisphosphonate prepared by
`chemical synthesis. Alendronate mono sodium trihydrate has
`a molecular weight of 325.1. Alendronate is approved in the
`US. for the prevention and treatment of osteoporosis in men
`and postmenopausal women, and for the treatment of Paget’ s
`disease of bone and glucocorticoid induced osteoporosis in
`both sexes. Like other bispho sphonates, alendronate binds to
`bone hydroxyapatite and specifically inhibits the activity of
`osteoclasts. Alendronate reduces bone turnover in human and
`
`animal models and decreases activation frequency, reducing
`bone resorption in both cortical and trabecular bone and ulti-
`mately increasing bone density and strength.
`The oral bioavailability of alendronate is very low and
`independent of the dose (5-80 mg), averaging 0.76% in
`women and 0.59% in men. Presystemic metabolism does not
`occur. Following oral administration ofconventional forms of
`alendronate, 40% ofthe dose absorbed is excreted in the urine
`within 8 hours and a further 5% is excreted over the next 64
`
`hours. Sixty to seventy percent of the absorption occurs
`within 1 hour of dosing. Bioavailability is markedly reduced
`by coincident consumption of food (85%-90%) and even
`consumption of coffee or orange juice will impair absorption
`by as much as 60% or more. Coincident medication will also
`reduce absorption, as any calcium-containing compounds
`and multivalent cations will bind to the bisphosphonate.
`Elevation of gastric pH above 6 is associated with a twofold
`increase in alendronate absorption. Alendronate is not
`metabolized and is excreted unchanged with renal clearance
`comparable to the glomerular filtration rate.
`Bisphosphonate compositions and oral dosage forms with
`improved systemic bioavailability which are not subject to
`the dosing restrictions of conventional bisphosphonates
`would represent a considerable benefit for patients. As a
`result, new strategies for delivering drugs across the GIT cell
`layers are needed, particularly for bisphosphonates.
`Numerous potential absorption enhancers have been iden-
`tified. For instance, medium chain glycerides have demon-
`strated the ability to enhance the absorption of hydrophilic
`drugs across the intestinal mucosa (Pharm. Res. (1994), 11,
`1148-54). However, the importance of chain length and/or
`composition is unclear and therefore their mechanism of
`action remains largely unknown. Sodium caprate has been
`reported to enhance intestinal and colonic drug absorption by
`the paracellular route (Pharm. Res.
`(1993) 10, 857-864;
`Pharm. Res. (1988), 5, 341-346). US. Pat. No. 4,656,161
`
`

`

`US 7,704,977 B2
`
`3
`(BASF AG) discloses a process for increasing the enteral
`absorbability ofheparin and heparinoids by adding non-ionic
`surfactants such as those that can be prepared by reacting
`ethylene oxide with a fatty acid, a fatty alcohol, an alkylphe-
`nol or a sorbitan or glycerol fatty acid ester.
`US. Pat. No. 5,229,130 (Cygnus Therapeutics Systems)
`discloses a composition which increases the permeability of
`skin to a transdermally administered pharmacologically
`active agent formulated with one or more vegetable oils as
`skin permeation enhancers. Dermal penetration is also known
`to be enhanced by a range of sodium carboxylates [Int. J. of
`Pharmaceutics (1994), 108, 141-148]. Additionally, the use
`of essential oils to enhance bioavailability is known (US. Pat.
`No. 5,66,386 AvMax Inc. and others). It is taught that the
`essential oils act to reduce either, or both, cytochrome P450
`metabolism and P-glycoprotein regulated transport of the
`drug out of the blood stream back into the gut.
`Often, however, the enhancement of drug absorption cor-
`relates with damage to the intestinal wall. Consequently, limi-
`tations to the widespread use of GIT enhancers are frequently
`determined by theirpotential toxicities and side effects.Addi-
`tionally and especially with respect to peptide, protein or
`macromolecular drugs, the “interaction” ofthe GIT enhancer
`with one of the transport pathways should be transient or
`reversible, such as a transient interaction with or opening of
`tight junctions so as to enhance transport via the paracellular
`route.
`
`As mentioned above, numerous potential enhancers are
`known. However, this has not led to a corresponding number
`of products incorporating enhancers. One such product cur-
`rently approved for use in Sweden and Japan is the Doktacil-
`linTM. suppository [Lindmark et al. Pharmaceutical Research
`(1997), 14, 930-935]. The suppository comprises ampicillin
`and the medium chain fatty acid, sodium caprate (C10).
`Provision of a solid oral dosage form which would facili-
`tate the administration of a drug together with an enhancer is
`desirable. The advantages of solid oral dosage forms over
`other dosage forms include ease ofmanufacture, the ability to
`formulate different controlled release and extended release
`formulations and ease of administration. Administration of
`
`drugs in solution form does not readily facilitate control ofthe
`profile of drug concentration in the bloodstream. Solid oral
`dosage forms, on the other hand, are versatile and may be
`modified, for example, to maximize the extent and duration of
`drug release and to release a drug according to a therapeuti-
`cally desirable release profile. There may also be advantages
`relating to convenience of administration increasing patient
`compliance and to cost of manufacture associated with solid
`oral dosage forms.
`
`SUMMARY OF THE INVENTION
`
`According to one aspect of the present invention, the com-
`positions and dosage forms made therefrom of the present
`invention comprise a drug and an enhancer to promote
`absorption of the bisphosphonate at the GIT cell
`lining
`wherein the enhancer is a medium chain fatty acid or a
`medium chain fatty acid derivative having a carbon chain
`length of from 6 to 20 carbon atoms; with the provisos that (i)
`where the enhancer is an ester of a medium chain fatty acid,
`said chain length of from 6 to 20 carbon atoms relates to the
`chain length of the carboxylate moiety, and (ii) where the
`enhancer is an ether of a medium chain fatty acid, at least one
`alkoxy group has a carbon chain length of from 6 to carbon
`atoms, and wherein the enhancer and the composition are
`solids at room temperature.
`
`10
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`4
`
`According to another aspect of the present invention, the
`compositions and dosage forms made therefrom comprise a
`drug and an enhancer to promote absorption of the bisphos-
`phonate at the GIT cell lining, wherein the only enhancer
`present in the composition is a medium chain fatty acid or a
`medium chain fatty acid derivative having a carbon chain
`length of from 6 to 20 carbon atoms.
`In embodiments in which the drug comprises a bisphos-
`phonate,
`the drug may be selected from the group that
`includes the free acids forms and biologically acceptable salts
`of alendronate, clodronate, etidronate, incadronate, ibandr-
`onate, minodronate, neridronate, olpadronate, pamidronate,
`risedronate, tiludronate, zoledronate and derivatives thereof.
`The bisphosphonate dosage form may be an enteric coated
`instant
`release solid oral dosage form which provides
`improved oral bioavailability and minimizes the risk of local
`irritation of the upper GIT. In one embodiment, the bisphos-
`phonate is zoledronic acid.
`The dosage forms can be a tablet, a multiparticulate or a
`capsule. The multiparticulate can be in the form of a tablet or
`contained in a capsule. The tablet can be a single or multilayer
`tablet having compressed multiparticulate in one, all or none
`of the layers. Preferably, the dosage form is a controlled
`release dosage form. More preferably, it is a delayed release
`dosage form. The dosage form can be coated with a polymer,
`preferably a rate-controlling or a delayed release polymer.
`The polymer can also be compressed with the enhancer and
`drug to form a matrix dosage form such as a controlled release
`matrix dosage form. A polymer coating can then be applied to
`the matrix dosage form.
`Other embodiments ofthe invention include the process of
`making the dosage forms, and methods for the treatment of a
`medical condition by administering the dosage forms to a
`patient and use of a drug and enhancer in the manufacture of
`a medicament.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`FIG. 1 shows the effect ofthe sodium salts ofC8, C10, C12,
`C14, C18 and C18:2 with 3H-TRH on TEER (Qcmz) in
`Caco-2 monolayers at time 0 and at 30 min. intervals up to 2
`hours as described in Example 1.
`FIG. 2 shows the effect ofthe sodium salts ofC8, C10, C12,
`C14, C18 and C18:2 on Pa” for 3H-TRH transport in Caco-2
`monolayers as described in Example 1.
`FIG. 3 shows the serum TRH concentration-time profiles
`following interduodenal bolus dose of 500 ug TRH with
`NaC8 or NaC10 (35 mg) enhancer present according to the
`closed loop rat model described in Example 1.
`FIG. 4 shows the serum TRH concentration-time profiles
`following interduodenal bolus dose of 1000 pg TRH with
`NaC8 or NaC10 (35 mg) enhancer present according to the
`closed loop rat model described in Example 1.
`FIG. 5 shows the APTT response over a period of 4 hours
`following administration of USP heparin (1000 IU) with dif-
`ferent sodium caprate (C10) levels (10 and 35 mg) according
`to the closed loop rat model described in Example 2.
`FIG. 6 shows the anti-factor Xa response over a period of 5
`hours following administration of USP heparin (1000 IU) in
`the presence of different sodium caprylate (C8) levels (10 mg
`and 35 mg) according to the closed loop rat model described
`in Example 2.
`FIG. 7 shows the anti-factor Xa response over a period of
`five hours following administration ofUSP heparin (10001U)
`in the presence of different sodium caprate (C10) levels (10
`mg and 35 mg) according to the closed loop rat model
`described in Example 2.
`
`

`

`US 7,704,977 B2
`
`5
`FIG. 8 shows the mean anti-factor Xa response in dogs over
`a period of time up to 8 hours following administration of: a)
`s.c. USP heparin solution (5000 IU); b) oral uncoated instant
`release tablet formulation containing USP heparin (90000
`IU) and NaC10; c) oral uncoated instant release tablet formu-
`lation containing USP heparin (90000 IU) and NaC8; and d)
`oral uncoated sustained release tablet formulation containing
`USP heparin (90000 IU) and sodium caprate prepared
`according to the invention as described in Example 2.
`FIG. 9 shows the anti-factor Xa response over a period of
`three hours following intraduodenal administration to rats of
`phosphate buffered saline solutions of parnaparin sodium
`(low molecular weight heparin (LMWH)) (1000 IU), in the
`presence of 35 mg of different enhancers such as sodium
`caprylate (C8), sodium nonanoate (C9), sodium caprate
`(C10), sodium undecanoate (C11), sodium laurate (C12) and
`different 50:50 binary mixtures of enhancers, to rats (n:8) in
`an open loop model. The reference product comprised admin-
`istering 250 IU parnaparin sodium subcutaneously. The con-
`trol solution comprised administering a solution containing
`1000
`IU parnaparin sodium without
`any
`enhancer
`intraduodenally.
`FIG. 10 shows the mean plasma levels of leuprolide over a
`period of eight hours following intraduodenal administration
`of solutions of leuprolide (20 mg) containing different levels
`of sodium caprate (0.0 g (control), 0.55 g, 1.1 g) to dogs.
`FIG. 11 shows the mean anti-factor Xa response in dogs
`over a period of eight hours following oral administration of
`parnaparin sodium (90,000 IU) in the presence of 550 mg
`sodium caprate, as both a solution (10 ml) and an instant
`release tablet dosage form.
`FIG. 12 shows the mean anti-factor Xa response in humans
`over a period of 24 hours following oral administration of
`parnaparin sodium (90,000 IU) in the presence of sodium
`caprate, as both a solution (240 ml) and an instant release
`tablet dosage form
`FIG. 13 shows the mean anti-factor Xa response in humans
`over a period of 24 hours following intrajejunal administra-
`tion of 15 ml solutions containing different doses parnaparin
`sodium (20,000 IU, 45,000 IU, 90,000 IU) in the presence of
`different doses of sodium caprate (0.55 g, 1.1 g, 1.65 g)
`FIG. 14 shows the mean anti-factor Xa response in dogs
`over a period of 8 hours following oral administration of
`45,000 IU parnaparin sodium as: (a) instant release capsules
`containing 0.55 g sodium caprate, (b) Eudragit L coated rap-
`idly disintegrating tablets containing 0.55 g sodium caprate
`and (c) Eudragit L coated rapidly disintegrating tablets with-
`out enhancer.
`
`FIG. 15 shows the mean anti-factor Xa response in dogs
`over a period of 8 hours following co-administration of
`45,000 IU LMWH and 0.55 g sodium caprate orally, intraje-
`junally and intracolonically compared to subcutaneous
`administration.
`FIG. 16 shows the non-dose normalized amount of alendr-
`
`onate excreted in the urine