Pl 1170170
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`APPLICATION NUMBER:60/458,922
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`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and Trademark Office
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`May 17, 2004
`
`APPLICATION NUMBER:60/458,922
`FILING DATE:March 28, 2003
`RELATED PCT APPLICATION NUMBER: PCT/US04/09387
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`REC'D 21 MAY 2004
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`By Authority ofthe
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`FILING DATE: March 28, 2003
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` Pl 1170170
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`LO ALL,TOWHOMTHESE; PRESEN
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`UNITED STATES DEPARTMENT OF COMMERCE
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`APPENDIX
`
`CONTENTS
`
`APIDissolution Analysis
`
`“1.1.
`1.2
`1.3.
`14
`
`Dissolution in 0.1N HCl (UV and HPLC)
`Dissolution in Phosphate buffer pH 6.8 (UV and HPLC)
`Dissolution in DI Water (UV)
`Dissolution in Buffer pH 4.5
`
`Intrinsic Dissolutions
`
`API Related Substances (Comparison to Cilag)
`
`Finished Product Related Substances
`
`Freeze-dried complexes FB Related Substances
`4
`
`Formulations based on Fludaribine
`4.1
`Fludaribine Formulation: RDT0385
`4.2
`Enteric-coated tablets: (Fludaribine Formulation). RDT0O385b
`4.3
`20% Carbomer Formulation: RDT0398a
`5.4
`Cyclodextrin Formulation: RDT0398b
`
`Buccal and granule Formulations using Diclofenac as API
`6.1
`Buccal / Sublingual
`°
`6.2
`Mucoadhesive granule for HGC fill
`6.3.
`Mucoadhesive Direct compression tablet
`6.4—Tablet within a tablet formulation:
`
`Phasesolubility testing
`
`Cladribine freeze-dried Cyclodextrin complexes
`9.1
`Cyclodextrin Complex Formulations for Buccal/Sublingual Dosage forms
`9.2.
`Manufacturing Process
`9.3.
`Physical Parameters
`9.4
`Dissolution profiles of Cladribine freeze-dried buccal tablets in water and salivary
`buffer
`Results
`9.5
`9,6 Dissolution and Degradation profiles ofCladribine freeze-dried Cyclodextrin buccal
`tablets in 0.1N HCl
`
`
`
`API ANALYSIS
`
`
`
`Ta Dissolution in 0.1N HCl
`
`Initial analysis of active by UV showed 10% degradation of API over 2 hours.
`Following from this HPLC analysis ofactive in 0.1N HCL showed degradation of Cladribine
`and growth of Impurity D (RRT 0.701). Approx 3% Cladribine remaining after 120 minutes
`dissolution.
`
`
`Dissolution of RDT0385 in 0.1NHCI
`
`90.000
`80.000
`
`70.000
`
`60.000 -
`50.000
`40.000
`
`30.000
`20.000
`
`10.000
`
`0.000.
`
`0
`
`30
`
`
` T a
`60
`"90
`120
`
`
`
`Time (mins)
`
`
`
`
`
`—e— % Cladribine
`
`—m— % Impurity D
`
`150
`
`
`
`%Dissolved
`
`=
`
`=
`
`:
`
`
`
`
`ei)
`seal
`
`8
`
`2
`§
`¢
`
`oo
`
`4.00
`
`“A Npbh r FeBeggaraENaEETTE
`
`
`
`= Sra
`
`8.00
`
`10.00
`
`12,00
`
`14,00
`
`6.00
`
`
`
`Chromatogram of Cladribineafter 2 hours dissolution in 0.1N HCI. Growth of impurity
`D at retention time 5.936 minutes
`
`
`
`Dissolution in Phosphate buffer pH 6.8 HPLC
`1.2
`102%dissolved after 2 hours. No observed degradation after 5 hours. No increase in related
`
`substances.
`
`% Cladribine / % Impurities Dissolution in Buffer pH 6.8
`
`400.000 a80.000
`
`Timepoint (Hours)
`
`420.000
`
`60.000
`
`40.000
`
`20.000
`
`0.000
`
`1 Hour
`
`2 Hours
`
`3 hours
`
`4 Hours
`
`:
`
`5 Hours
`
`—@— % Cladribine
`3
`—g-— % Impurities
`
`LC
`Water
`Dissolution in DI
`13
`102% dissolved after 2 hours. No observed degradation after 5 hours. Increase in assay of
`Cladribine after 72 hours due to evaporation ofmedium. Noincrease in related substances
`
`140.000
`
`420.000
`
`s
`
`% Cladribine / % Impurities Diss in H20
`
`
`.. 100.000 ee
`
`
`x 60.000
`Impurities
`
`
`
`
`
`4 Hour
`2 Hours
`72 hours
`
`
`
`Timepoint (Hours)
`
`
`40.000
`
`20.000
`
`0.000
`
`
`
`
`
`1.4
`
`Dissolution in Buffer pH 4.5 (HPLC)
`
`102% dissolved after 2 hours. No observed degradation after 2 hours. Increase in impurities
`(0.1%) of Cladribine after 24 hours.
`
`
`
`%Cladribine / % Impurities Dissolution in Buffer pH 4.5
`
`Timepoint (Hours)
`
`120.000
`
`80.000
`
`60.000
`
`40.000
`
`20.000
`
`0.000
`
`—_
`
`—e— %Cladribine
`a
`—m— % Impurities
`
`>
`
`4 Hour
`
`2 Hours
`
`3 hours
`
`24 Hours
`
`
`
`
`
`2
`
`INTRINSIC DISSOLUTIONS
`
`Note:
`
`IDR of 0.1 mg/min/cm’correspondsto solubility of 1 mg/ml.
`Cilag estimate solubility of 5mg/ml in water
`
`IDR of APIin DIwater:
`IDR of Gamma-CD complex in DI water:
`IDR of HP-CD complex in DI water:
`
`0.3316 mg/min/em’?
`0.6026 mg/min/cm’
`0.8246 mg/min/em’?
`
`Intrinsic Dissolution of Cladribine API, HP-CD Complex and Gamma-CD
`Complex in DI Water
`
`y = 0.8246
`
`Time (Minutes)
`
`
`Amountdissolvedperunitarea
`Time (minutes)
`o-NWwWfFoaAN@
`
`
`amountdissolvedperunitarea
`
`4
`
`6
`
`IDRof API in phosphate buffer pH 4.5:
`IDR of Gamma-CD complexin salivary buffer pH 7.0:
`IDR of HP-CD complex in salivary buffer pH 7.0:
`
`0.2395 mg/min/em”
`0.6637 mg/min/em’
`0.8313 mg/min/cm’
`
`Intrinsic Dissolution of AP! in buffer 4.5 and HP-CD and Gamma-CDin
`salivary buffer pH 6.8
`
`y = 0.2395x
`
`4
`
`6
`
`
`
`eS a GCAee see TSCER ep ree ae
`
`3.
`
`API RELATED SUBSTANCES
`
`
`
`{2.824
`
`j
`.
`anne"
`
` -0.0001-} eslinnTeSn etar OT
`0.00
`15.00
`40.00
`5.00
`16.00
`20.00
`25.00
`30,00
`36.00
`
`
`Specification
`RRT
`Cilag Assay
`IVAX Assay
`
`2-Amino-2 deoxyadenosine
`(Impurity B)
`
`NMT0.3%
`
`0.563
`
`2-Chloro-adenine
`(impurity D)
`
`NMT0.3%
`
`0.701
`
`2-Methoxy-2-deoxyadenosine
`(impurity E)
`
`NMT0.2%
`
`0.821
`
`0.200
`
`<0.1
`
`0.200
`
`0.060
`
`0.002
`
`0.082
`
`
`
`2-Chloro-9-(2 deoxy-a-D-|NMT 0.2% 0.951 <0.1 0.01
`
`ribofuranosyl)-adenine
`:
`J
`,
`?
`(Impurity F)
`Cladribine
`
`98.5
`
`
`
`Name
`
`98% - 102%
`
`1.000
`
`99.8
`
`Unknown1
`
`Unlnown Impurity RRT
`(Cilag RRT)= 1.85
`Impurity G
`RW4J-47753-000
`
`NMT0.1%
`
`NMT 0.2%
`NMT 0.1%
`NMT0.1%
`
`RW4J-47754-000
`
`NMT 0.1%
`
`1.763
`
`1.85
`2123
`3.877
`
`4.511
`
`0.088
`
`ND
`ND
`0.043
`
`0.056
`
`
`
`TOTAL IMPURITIES|NMT 1.0% 0.6% 0.3%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`RDT0398a
`RDT0385
`(Carbomer
`(Fludaribine
`
`formulation
`formulation
`0.067
`0.059
`
`
`
`RDT039
`(Cyclode
`formulat
`0.056
`
`0.002
`
`0.076
`
`0.009
`
`90
`
`0.082
`
`*
`
`0.000
`0.039
`
`0.047
`
`0.24%
`
`0.002
`
`0.083
`
`0.002
`
`0.093
`
`0.010
`
`0.012
`
`96
`
`0.086
`
`0.001
`0.042
`
`0.049
`
`0.33%
`
`114
`
`0.104
`
`0.000
`0.050
`
`_
`
`0.059
`
`0.38%
`
`,
`
`NMT 0.3%
`
`NMT 0.3%
`
`NMT 0.2%
`
`NMT0.2%
`
`98% - 102%
`
`NMT 0.1%
`
`NMT 0.2%
`
`NMT 0.1%
`NMT 0.1%.
`
`NMT 0.1%
`
`NMT1.0% ©
`
`Name
`
`RRT
`
`Specification
`
`
`
`
`2-Amino-2
`deoxyadenosine
`(Impurity B)
`
`2-Chloro-adenine
`(impurity D)
`2-Methoxy-2-
`deoxyadenosine
`(Impurity E)
`
`2-Chloro-9-(2 deoxy-c-
`D-ribofuranosyl)-
`adenine
`(Impurity F)
`
`Cladribine
`
`Unknown1
`
`Unlnown Impurity
`RRT (Cilag RRT)
`= 1.85
`
`Impurity G
`RW4J-47753-000
`
`RW4J-47754-000
`
`TOTAL
`IMPURITIES
`
`0.701
`
`0,821
`
`0.951
`
`1.000
`
`1.763
`
`2:123
`3.877
`
`4.511
`
`
`
`RsES
`“
`
`5.
`
`ASSAY AND RELATED SUBSTANCES OF FREEZED DRIED COMPLEX RAW
`MATERIAL AND TABLETS ~
`
`
`
`
`
`Identity|Chemical Name RRT CD Raw
`
`
`
`2-Amino-2’-
`
`es
`
`2-Methoxy-2'-
`deoxyadenosine
`
`0.1
`
`0.13
`
`0.13
`
`Imp F
`
`adenine
`
`Cladribine
`
`2-Chloro-9-(2’-
`
`deoxy-a.-D-
`ribofuranosyl)-
`y
`
`Theoretical
`% Active
`Cladribine
`
`in Complex
`
`Material fa
` Gamma —
`deaxyadenasmeetartet a
`08
`|
`He
`
`
`
`
`
`RWI-
`zscicoos:|Bakeaonm
`
`
`|
`
`
`
`Actual %
`| Active in
`Complex
`
`Cladribine
`
`2
`
`Unknown
`
`Not Known
`
`Unknown
`Unknown
`
`Not Known
`"Not Known
`
`2|e=andanae)
`
`zo
`
`* To be investigated. Possible solventor carryover.
`
`
`
`
`
`
`
` Pamir menainoded kk, 11°hRTR £ 2 NASD PE rm. kL AFM AIAARA
`
`
`
`
`
`SUMMARY
`
`Nodifferences observed in assay for related substances for API and any formulations.
`Recommended PDAanalysis on APIalso.
`
`6.
`
`FORMULATIONSBASED ON FLUDARIBINE
`
`Three 100g batches using Cladribine API have been manufactured using the following formulations:
`
`
`
`6.1_Fludaribine Formulation: RDT0385
`
`101.4%
`-
`e Assay
`100.5%, RSD = 3.17%
`-
`e CU
`Max 91% 30 minutes.
`-
`¢ UY Dissolution (0.1N HCl)
`¢ HPLC analysis carried out on dissolution in HC] showed breakdownof Cladribine into impurity
`D. Only 3% Cladribine remaining after 2 hours dissolution.
`e UV Dissolution (buffer pH 6.8)
`-
`Slow release. 85% after 240 minutes
`e UV Dissolution (Water)
`-
`Fast release. 101% after 2 hours.
`
`
`
`
`
`7
`
`an WAS
`re ay
`
`6.2
`
`Enteric-coated tablets: (Fludaribine Formulation). RDTO385b
`
`UV Dissolution in 0.1N HCl followed by buffer pH 6.8 - 7.0.
`7% dissolution after 2 hours in acid, (min 5%, max 18%). On addition of pH 7.0 conditions
`dissolution increased to 97% after 2 hours (min 84%, Max 107%). After 4 hoursin acid,
`dissolution was 116%.
`20% Carbomer Formulation: RDT0398a
`6.3
`
`Results mayberelatedto tablet weighti.e. heavier tablet gives higher dissolutions
`
`ee@8 Assay
`
`cu
`UV Dissolution (0.1N HCl)
`UV Dissolution (buffer pH 6.8)
`
`UV Dissolution (Water)
`
`~
`-
`-
`-
`
`.
`
`113.9%
`+ 105.7%, RSD = 6.4%. Oneresult at 123.1%
`Max 80%, 240 minutes. Slow release profile
`Slow release. 86% after 10 hours. 0.1%
`Carbomerinterference. Further HPLC analysis
`showspossible Carbomer peak at 4 —5 minutes.
`0.2% - 1.0%.
`Fast release. 97% after 2 hours.
`
`6.4
`
`Cyclodextrin Formulation: RDT0398b
`
`Cyclodextrin formulation is sub-potent due to extra Mag Stearate added. Estimated potency at 95%.
`
`Assay
`CU .
`DV Dissolution (0.1N HC})
`UV Dissolution (buffer pH 6.8)
`UV Dissolution (Water)
`
`-
`_-
`~
`-
`-
`
`89.9%
`83.2%, RSD = 3.3%
`Max 83%, 48 minutes. Degradation occurs.
`Max 76%, 1 hour. No Cyclodextrin interference
`Max 86% after 1 hour.
`
`SUMMARY
`
`Cladribine APIis acid labile. Formulation needed to avoid acidic stomach conditions.
`
`No degradation observed in water, buffer pH 4.5 and buffer pH 6.8
`
`API IDR matchesCilag estimated solubility. Best IDR in water.
`
`Solubility issue in buffer pH 6.8. Dissolution values are less than assay results.
`
`Solubility does not seem to be a problem in water. Dissolution results matching assay and CU.
`
`Fludaribine formualtion shows fast release in water and slowreleasein buffer pH 6.8.
`
`Carbomer formulation allows for slow release. Carbomer impurity ( approx 1.0%) present in
`chromatography.
`
`10
`
`
`
`
`
`Somespurious CUresults (121%) indicating possible processing problems with Carbomer o74P
`or high levels of Carbomer.
`® Possible potency issue with Cyclodextrin formulation. Only getting 90%assay and dissolution.
`
`Immediate release in buffer and water.
`
`7
`
`BUCCAL AND GRANULE FORMULATIONS WITH DICLOFENACAPI
`
`Six batches using Diclofenac Sodium in place of Cladribine API were manufactured to explore the
`development of buccal / sublingual and mucoadhesivetablets as patentable cladribine formulations.
`
`Formulation:
`
`
`
`Seeee
`
`10.00
`10.00
`
`S|
`
`eae
`5.00
`2.50
`|
`| __87.00__|84.50 __[F
`
`ey0.‘Smp/tablet added to minimise picking.
`
`RDT0399¢c was manufactured as RDT0399a placebo.
`
`Physical parameters:
`
`peena a07
`
`4min 45sec
`
`2min 34sec
`
`*Tablet formed a soft globular mass with adhesive properties
`** Tablet formed a globular mass with strong adhesive properties. Mass wasdry in center after 15
`mins.
`
`NOTE:
`
`Diclofenac has solubility problems in 0.1N HCl.
`Diclofenac Na dissolves 16% ~ 20% in 0.1N HCI.
`
`11
`
`
`
`
`
`Tal
`
`Buccal/ Sublingual:
`
`RDT0399a + RDT0399b:
`Manufactured using Sodium CMCat2.5 — 5 % respectively.
`e UV Dissolution of approx 70% after 10 hours in simulated saliva solution. 68% dissolution after
`30 minutes.
`e Assay of 70%.
`e No obviousreasonfor low results.
`e
`Poortaste from tablets. Possible Diclofenac Na taste. Recommend 2mg drug formulation per 100
`mgtablet to inhibit possible taste issues.
`
`7.2___ Mucoadhesive granule forHGC fill:
`
`NOTE:
`
`Carbopol 71G mayoffer better flow properties due to its granular nature which may
`alleviate possible processing problems.
`
`RDT0399d:
`Manufactured using Carbopol OTAP at 2.5%.
`e
`5% dissolution in 0.1N HCI after 2 hours. 97% dissolution after 3 hours in pH 7.0 buffer.
`
`RDT0399e:
`Manufactured using Carbopol 974Pat 10%.
`e
`6% dissolution in 0.1N HCI after 2 hours. 91% - 99% after 3 hours in pH 7.0
`
`7.3
`
`Mucoadhesive Direct compressiontablet:
`
`RDT0399f:
`Manufactured using Carbopol 71G at 2.5%.
`e
`5% dissolution in 0.1N HClafter 2 hours. 76% after 3 hours in pH 7.0
`
`RDT0399¢:
`Manufactured using Carbopol 71G at 10%.
`e
`2% dissolution in 0.1N HClafter 2 hours. 90% after 3 hours in pH 7.0
`
`All tablet formulations flowed and compressed well.
`The granulated product produced a good strong granule. Milled through a 0.075 inch comilscreen.
`
`TA
`
`Tablet within a tablet formulation:
`
`
`
`i
`Sess aya ar
`tae
`“Sse ee
`
`at a
`
`Outer tablet coat used to protect Cladribine from acidic stomach conditions.
`
`Dissolution in 0.1N HCLfollowed by buffer pH 6.8. Tablets completely disssolved in acid (86% -
`95%) after 25 minutes. No advantage.
`
`8
`
`PHASE SOLUBILITY TESTING
`
`Table 1. Solubility of cyclodextrins in water (g/100 ml)
`
`
`
`n emperatur¢ ~ ACD BCD | GCD [
`ICC
`
`
`|20.0fot 155
`
`icca NO dOMe
`
`
`
`
`
`PROTOCOL FOR PHASE SOLUBILITY STUDIES OF CLADRIBINE IN PRESENCE OF
`CYCLODEXTRIN
`
`Reported Solubility of Cladribine in Water is 5 mg / ml
`
`TABLE1
`
`
`
`
`
`
`Solution of CD,
`
`800
`mgin 4ml B.soln
`
`
`
`
`
`:
`
`DRUG ADDED
`
`2 mi soln.B +2 mlD.Water (100mg)|25 mg
`
`
`‘DD—Cs«éD;[- 2 ml soln.C +2 mlD.Water (50 mg 25 meg
`
`2mlisoln.D+2mlD.Water (25mg)*|25mg
`
`* Use only 2 mlof solutionfortesting
`0.0 mg
`[FoF
`
`25 mg
`2 ml D.Water
`
`
`Cyclodextrin
`B.soln. — Bulk Solution
`D.Water — Deionised Water
`Methodfor preparation.
`
`OyBideGihef=
`
`In screw capped vials take 2 ml Cyclodextrin solutions as mentioned in Table 1.
`Add respective quantity of drug in each vial.
`Allow the samples to sonicate for 30 minutes.
`Remove the samples from sonicator and place on shakerfor 8 hrs.
`The sample after shaking is filtered to get clear supernant.
`Analyse the sample by UV at 265 nm wavelength.
`
`13
`
`
`
`
`
`
`
`RESULTS:
`
`
`
`
`
`
`
`
`
`
`
`Cladribine —HP betaCD2cone (TrialA)
`Cladribine -HP betaCD +
`
`
`
`Cladribine -gama- CD
`HPMC(0.1%)
`’
`(Trial C)
`
`
`(Trial B)
`
`Absorbance| mg/mi
`
`
`:
`0.00
`
`|—_o073
`:
`:
`.
`:
`f
`0.0095
`i
`:
`
`
`
`|0.0100
`0.035
`5;
`:
`i
`‘
`‘
`0.0114
`0.1531
`2.852
`
`
`
`0.245 4.570|0.016 4.449 00148|0.182|a80.223
`
`
`
`
`
`
`
`
`
`0.142] 6.211|0.0217 6.185|0.0216(0.333 0.332 0.1965 3.661 |0.0128
`
`
`
`
`
`
`
`
`
`
`
`0.514 4.831|0.01699.581 0.0335 0.259 0.4688 8.733 |0.0306
`
`
`
`
`
`CladribineMolarConc,
`
`PHASE SOLUBILITY STUDIES
`
`0.071
`
`0.142
`
`0.285
`
`—@—HP-Beta-CD
`
`CD- Molar Conc.
`
`—i— Gama-Cd
`
`—M—HPCD+HPM
`c
`
`Observations:
`
`Thebest solubility results are obtained with HP-beta CD as complexing agent.
`e
`e With HP-beta CD + HPMC (0.1%) results are similar to HP-beta CD,at higher concentration
`
`fine precipitation was observed in the vials at the end ofthe study.
`
`Absorbanceof this sample is low andindicates precipitation of solubised drug
`
`e Absorbance with Gama-Cyclodextrin is low as compared with HP-beta CD.
`
`‘e Bail park solubility of 9.581 mg/ml in comparison to 5 mg/mlsolubility with API alone.
`
`.
`
`_
`
`14
`
`
`
`SUMMARY
`
`Cyclodextrin/Cladribine complex showed increased Cladribine solubility
`
`Complex sent for freeze-drying.
`
`Cladribine API groundto decreaseparticle size (10g)
`
`Process buccal and sublingual tablets using freeze-dried material
`Issues regarding taste and poorassay, dissolution on previous buccaltablets.
`Information on buccal formulation work in Miami.
`
`Continued investigation into oral dosage formulations:
`
`1. Tablet-within-tablet:
`High viscosity HPMCin outer formulation for protection against
`acidic stomach conditions.
`
`2. Soft gel capsule:
`10g APIsent to Czechslovakiafortrials.
`
`.
`3. Dry emulsion formulation:
`Dummy emulsion to be made with freeze-dried sample
`
`
`
`sj
`
`CLADRIBINE FREEZE-DRIED CYCLODEXTRIN COMPLEXES
`
`9.1_Cyclodextrin Complex Formulations for Buccal/Sublingual Dosage forms
`
`
`
`
`
`
`Code} no.|Mg/ Tablet | Mg/Tablet|Mp/ Tablet| Mg /Tableten ot
`
`
`
`pea
`hc aes
`|FD-01|Gamma-cD|NA|213)|213|
`
`
`sean
`-
`N/A
`__218
`|1F290| -
`1F2
`RE0484
`REO541
`10130.
`
`+Cladribine
`
`9.2 Manufacturing Process
`
`-Cyclodextrin FD / Complex
`
`(18 Mesh)
`
`Magnesium Sterate / Lactose pre-mix
`(40 Mesh)
`
`Turbula Mixer (5 min)
`
`Manesty Single station F-press
`(220 mg, 10.0 mm round concave UP/ Flat Bevelled LP)
`
`e Flow and compressibility goodforall fractions.
`
`OBSERVATIONS
`
`
`
`
`
`e No picking noticed
`
`9.3 Physical Parameters
`
`e Average weight: A) 215 mg, B) 220 mg, C) 237mg, D)220mg.
`
`« Average Hardness: 3- 4 Kp
`
`e Thickness :3.2mm - 3.4mm
`
`« - Disintegration Time : 6 — 7 minutes ( Water/ Simulated Saliva Buffer)
`
`Dissolution profiles of freeze-dried buccaltablets in water and simulated salivary
`9.4
`buffer solution
`
`Dissolution of Cladribine freeze-dried Cyclodextrin-complex tablets in DI water
`and simulated salivary buffer pH 6.8. Comparison to Fludaribine formulation
`tablets (RDT0385).
`
`
`
`—@— RDT0385 (water)
`—@-—-HPCD (water)
`iim Gamma (water)
`—r¢-HPCD (buffer)
`—*— Gamma(Buffer)
`—@—RDT0385(buffer 6.8)
`
`0
`
`10
`
`20
`
`50
`
`
`(AU)
`
`Absorbance
`
`
`40
`30
`Time (minutes)
`
`
`60
`
`70
`
`Simulated Saliva Solution:2.38g Na,HPO,, 0.19¢ KH2PO, and 8g NaClin1litre ofdistilled water, pH 6.75, at 37°C
`
`9.5
`
`Results
`
`e
`
`Increased Dissolution time.
`HP-CD. 100% dissolution in salivary buffer after 10 minutes.
`Gamma-CD. 100% dissolutionin salivary buffer after 15 minutes
`
`HP-CD. 100% dissolution in water after 10 minutes.
`Gamma-CD.100% dissolution in salivary buffer after 15 - 18 minutes
`
`e
`
`Increased Solubility.
`
`
`
`U
`z
`
`a 2iefetTegk
`
`aeSar inet
`
`=
`
`100% dissolution attained for both tablet types in both buffers. Comparison to Fludaribine
`formulation dissolution in water and buffer show faster dissolution and greater solubility.
`
`Dissolution and Degradation profiles of freeze-dried Cladribine-Cyclodextrin
`9.6
`
`complex buccaltablets in 0.1N HCl
`
`Dissolution/Degradation of HP-CD tablets and Gamma-CDtablets in 0.1N
`Hydrochloric Acid
`
`120
`
`100
`
`
`
`
`
`—¢e— Dissolution od FD03 (HPCD)
`—#i—Degradation of FD03 (HPCD)
`
`—i-~ Dissolution of FD02 (Gamma)
`—»<— Degradation of FD02 (Gamma)
`
`
`
`0
`
`.
`
`5
`
`10
`
`15
`
`30
`
`‘Time (minutes)
`
`
`« Degradation ofCladribine peak to Impurity D CEE 10— 15% after 10 minutes. 100%
`
`dissolution after 10 — 15 minutes.
`
`e By optimising complexation, we can further inhibit acidic degradation of the drug in the stomach
`whilst increasing drug availability for absorption.
`
`areas
`
`|
`|
`
`|
`
`|
`
`
`
`80
`| Sw
`
`40.
`
`20
`
`
`0
`
`
`
`
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