(12) United States
`Scaife et al.
`
`Patent
`
`US006407128B1
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,407,128 B1
`Jun. 18, 2002
`
`(54)
`
`(75)
`
`METHOD FOR INCREASING THE
`BIOAVAILABILITY OF METAXALONE
`
`Inventors: Michael Scaife, Poway; Jaymin Shah,
`Sunnyvale, both of CA (US)
`
`(73)
`
`Assignee:
`
`Elan Pharmaceuticals, Inc., South San
`Francisco, CA (US)
`
`(*)
`
`Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21)
`
`(22)
`
`(51)
`(52)
`(58)
`
`(56)
`
`Appl. No.: 09/998,206
`
`Dec. 3, 2001
`Filed:
`Int. Cl.7 ................................................
`U.S. Cl ........................................................
`Field of Search ..........................................
`
`A61K 31/42
`514/376
`514/376
`
`References Cited
`
`5,977,175 A
`5,989,583 A
`6,030,988 A
`6,099,859 A
`6,103,269 A
`6,114,379 A
`6,143,325 A
`6,197,757 B1
`6,207,178 B1
`6,265,438 B1
`2001/0024659 A1
`
`Lin
`11/1999
`11/1999 Amselem
`2/2000 Gilis et al.
`8/2000 Cheng et al.
`8/2000 Wunderlich et al.
`9/2000 Wheelwright et al.
`11/2000 Dennis et al.
`3/2001
`Perrier et al.
`3/2001 Westesen et al.
`7/2001
`Steward
`9/2001 Chen et al.
`
`OTHER PUBLICATIONS
`Monograph No. 5838 of the Merck Index (11t~’ ed., 1989) for
`metaxalone.
`Lunsford et al., 82 J. Am. Chem. Soc. 1166 (1960).
`Skelaxin® monograph, 2001 Physicians’ Desk Reference.
`
`* cited by examiner
`
`Primary Examiner~Raymond Henley, III
`(74) Attorney, Agent, or Firm~innegan, Henderson,
`Farabow, Garrett & Dunner
`
`U.S. PATENT DOCUMENTS
`
`(57)
`
`ABSTRACT
`
`3,062,827 A
`3,993,767 A
`4,036,957 A
`4,058,621 A
`4,208,405 A
`4,784,852 A
`4,792,449 A
`4,820,690 A
`5,785,976 A
`5,840,688 A
`
`* 11/1962 Lunsford ....................
`11/1976 Alphin et al.
`7/1977 Alphin et al.
`11/1977 Hill
`6/1980 Fouad
`11/1988
`Johansson
`12/1988 Ausman et al.
`4/1989 Gregory et al.
`7/1998 Westesen et al.
`11/1998
`Tso
`
`260/307
`
`A method of increasing the bioavailability of metaxalone by
`administration of an oral dosage form with food is provided,
`as well as an article of manufacture comprising an oral
`dosage form of metaxalone in a suitable container and
`associated with printed labeling which describes the
`increased bioavailability of the medication in the container
`when taken with food.
`
`22 Claims, 1 Drawing Sheet
`
`Medline Industries, Inc.; IPR2015-00511
`Exhibit 2106
`Page 1 of 6
`
`

`

`U.S. Patent
`
`Jun. 18, 2002
`
`US 6,407,128 B1
`
`Medline Industries, Inc.; IPR2015-00511
`Exhibit 2106
`Page 2 of 6
`
`

`

`US 6,407,128 B1
`
`H3C
`
`2
`1
`METHOD FOR INCREASING THE
`elapsed from administration of the dosage form. Two (2)
`BIOAVAILABILITY OF METAXALONE
`plots are shown for the 400 mg dosage form administered
`with and without food.
`FIELD OF THE INVENTION
`SUMMARY OF THE INVENTION
`The invention relates to methods for increasing the bio-
`availability of a medicinal agent, namely metaxalone (5-[(3,
`The subject of this invention is the unexpected finding
`5-dimethylphenoxy)methyl]-2 oxazolidinone).
`that administration of metaxalone with food increases both
`the rate and extent of absorption via the oral dosage form in
`BACKGROUND OF THE INVENTION
`human subjects.
`Metaxalone (Skelaxin®) has the following chemical
`s0 One aspect of this invention is a method of increasing the
`structure and name:
`bioavailability of metaxalone in a human patient receiving
`metaxalone therapy wherein the metaxalone is contained in
`a pharmaceutical composition, which method comprises
`administering a therapeutically effective amount of metaxa-
`25 lone to the patient with food.
`Another aspect of the invention is providing a method of
`increasing rate and extent of metaxalone absorption as
`measured by the drug concentration attained in the blood
`stream over time of a patient receiving, the drug in an oral
`20 dosage form which method comprises administering a thera-
`5-[(3,5 -dimethylphenoxy)methyl]-2 oxazolidinone
`peutically effective amount of metaxalone to the patient with
`Skelaxin is indicated as an adjunct to rest, physical
`food.
`therapy, and other measures for the relief of discomforts
`Preferably the therapeutic amount is between about 200
`associated with acute, painful musculoskeletal conditions.
`mg to about 900 mg, and more preferably between about 400
`The mode of action of this drug has not been clearly
`25 mg to about 800 mg. Unit dosage forms are preferred.
`identified, but may be related to its sedative properties.
`Metaxalone does not directly relax tense skeletal muscles in
`Preferably the food is a solid food with sufficient bulk and
`fat content that it is not rapidly dissolved and absorbed in the
`man. The commercially available tablet contains:
`stomach. More preferably the food is a meal, such as
`metaxalone, 400 mg along with inert compression tableting
`breakfast, lunch or dinner. Advantageously the dosage is
`excipients.
`3o administered to the patient between about 30 minutes prior
`Metaxalone is further described at Monograph no. 5838
`to about 2 hours after eating a meal, most advantageously
`of the Merck Index (Eleventh Addition, Merck & Co., 1989)
`the dosage is administered within 15 minutes of eating a
`and is also identified by CAS Registry Number: 1665- 48-1.
`meal. The terms "without food", "fasted" and "an empty
`It is also known by the drug code, AHR-438; and the drug
`stomach" are defined to mean the condition of not having
`product containing it is marketed as Skelaxin® (a trademark
`35 consumed solid food for about 1 hour prior to until about 2
`of Elan Pharmaceuticals, Inc.).
`hours after such consumption.
`Preparation of metaxalone is described in Lunsford et al.,
`J. Am. Chem. Soc. 82, 1166 (1960) and U.S. Pat. No.
`Yet another aspect of this invention is providing infor-
`3,062,827 to Lunsford Nov. 6, 1962 Assignee A. H. Robins),
`mation to prescribing physicians and patients receiving
`which is incorporated herein in its entirety by reference. The
`metaxalone therapy useful in maximizing the therapeutic
`4o effect of the oral dosage form, by recommending that
`’827 patent discloses the compound and related species as
`anticonvulsants and antispasmodics, however, these activi-
`metaxalone be taken within about half an hour of consuming
`ties have not been borne out by clinical experience.
`food.
`Metaxalone is a central nervous system depressant that
`Another aspect of this invention is an article of manufac-
`has sedative and skeletal muscle relaxant effects. Metaxa-
`ture that comprises a container containing a pharmaceutical
`45 composition comprising metaxalone wherein the container
`lone is indicated as an adjunct to rest, physical therapy and
`other measures for the relief of discomforts associated with
`holds preferably the metaxalone composition in unit dosage
`acute, painful muscoloskeletal conditions. See Skelaxin®
`form and is associated with printed labeling instructions
`monograph, 2001 Physicians’ Desk Reference®, Medical
`advising of the differing absorption when the pharmaceutical
`Economics Company, Inc. (publisher) Montvale, N.J.
`50 composition is taken with and without food.
`The most frequent reactions to metaxalone include
`The effect of food on metaxalone absortpion was identi-
`nausea, vomiting, gastrointestinal upset, drowsiness,
`fied in a study designed to compare the bioavailability of 400
`dizziness, headache, and nervousness or "irritability." Other
`mg of metaxalone in the formulation the drug product
`adverse reactions are: hypersensitivity reaction, character-
`Skelaxin® administered to healthy volunteers with and
`ized by a light rash with or without pruritus; leukopenia;
`without food.
`hemolytic anemia; jaundice.
`An objective was to evaluate the bioavailability of
`Pharmacokinetic studies have not previously been con-
`metaxalone when administered to subjects with and without
`ducted to date to evaluate the effect of food on the pharma-
`food. A single center, single dose, open-label, two-period,
`cokinetics of metaxalone. The hydrophobicity of the
`randomized, crossover trial in healthy subjects was con-
`metaxalone molecule and the dosage amount required for a
`60 ducted over a period of approximately 32 days.
`therapeutic effect both point to probably limited absorption
`The two study drug treatments were as follows:
`from the gut when administered orally. More oral bioavail-
`Treatment A: metaxalone tablet (400 mg) administered
`ability of the drug substance has been sought to increase
`with food
`both speed of onset and amount of therapeutic effect.
`Treatment B: metaxalone tablet (400 mg) administered
`BRIEF DESCRIPTION OF THE DRAWINGS
`without food
`In fed treatment condition A, study drug was taken 15
`FIG. 1 is a plot of the mean plasma concentration of
`minutes after the test meal. The test meal was consumed
`metaxalone in nanograms per milliliter versus the time
`
`5
`
`55
`
`Medline Industries, Inc.; IPR2015-00511
`Exhibit 2106
`Page 3 of 6
`
`

`

`US 6,407,128 B1
`
`3
`4
`over a 15 minute time period. There was a 6-day washout
`product, the subject’s oral cavity was checked to con-
`period between study drug administrations. Seventeen blood
`firm complete medication and fluid consumption. Dos-
`samples were collected, starting with baseline (0 hour) and
`ing was completed as scheduled in 42 of 44 subjects.
`at the following time points: 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5,
`The drug substance, metaxalone; was dosed in tablet
`5, 6, 8, 12, 16, 24, and 36 hours.
`form. Content: 400 mg; Route: Oral, Batch/Lot No.:
`Atotal of 44 subjects (31 males/13 females) were enrolled
`SKLWW263F; Expiration Date: FEB03; Manufacturer:
`and dosed. Only the plasma of subjects who completed the
`West-Ward Pharmaceutical Covp
`study were assayed and used for the pharmacokinetic analy-
`All pharmacokinetic parameters were analyzed by non-
`sis.
`A single center, single dose, open label, two-period cross- compartmental methods. The following PK parameters were
`over trial was devised for study in healthy subjects. Each 10 calculated for the two PKprofiles and are defined as follows:
`administration was a single oral dose of one Skelaxin® 400
`Tmax: Time to maximum concentration;
`mg tablet with or without food. The study drug was admin-
`Cmax: Observed maximum concentration;
`istered as follows:
`kel: Slope of terminal linear portion of concentration/time
`Treatment A: One (1) 400 mg tablet of metaxalone with
`curve;
`240 mL of room temperature water with food: Break- 15
`fast was given to the subjects 30 minutes prior to dosing
`T½: Half-life of metaxalone calculated as: 0.693/Kel;
`and eaten within a 15 minute period. The dose of study
`AUC(last): Area under the curve to last quantifiable
`drug was administered to the subjects 15 minutes after
`concentration as measured by the trapezoidal rule;
`the breakfast was finished.
`AUC(inf): The AUC value extrapolated to infinity calcu-
`The breakfast consisted of the following:
`lated as: auC(inf)=aUC(last)+C(01ast/Kel where C(t)
`2 eggs (fried in butter);
`last is the last measurable concentration.
`2 strips of bacon;
`2 slices of toast with butter;
`4 ounces of hash brown potatoes;
`1 glass whole milk (8 ounces).
`Treatment B: 1 tablet of metaxalone) with 240 mL of
`room temperature water without food. The study drug
`was administered with 240 mL room temperature
`water. A mouth check was performed to verify that the
`subjects swallowed the dose. Subjects were sequen-
`tially dosed at 1 minute intervals. The actual time of
`dosing was recorded on the Master Flow Sheet (refer to
`the Appendix 16.3.2 Clinical Study Data). Drug admin-
`istration (lx400 mg capsule) was assisted with 240 mL
`of room temperature water consumed under direct 35
`observation. Immediately after administration of
`
`2o
`
`25
`
`Statistical Analysis
`
`3O
`
`All statistical analyses were performed using SAS® soft-
`ware version 6.08 or higher. The PK parameters between the
`two treatments were compared using an appropriate ANOVA
`model (analysis of variance) that includes term for
`treatment, sequence, and period effect. Ninety percent con-
`fidence interval was computed for the Cmax and AUC
`values of the fed treatment with fasting as the reference
`treatment. During the study there were no protocol devia-
`tions to confound the pharmacokinetic and bioavailability
`analyses. Study results were not corrected for drug potency.
`The individual test results are summarized in table I
`
`TABLE I
`
`Summary of AUCi~f and Ln-Transformed AUCiIff for
`Skelaxin ® Administered With Food (A) vs. Skelaxin ® Administered Without Food (B)
`
`A: With
`Food
`(ng/mL)
`
`B: Without
`Food
`(ng/mL)
`
`% Ratio
`Ratio (A/B)
`(a- B) (A/B) "100
`
`Subj Seq.
`
`Loge
`Ratio
`Loge A Loge B Ln
`Ln(A) Ln(B) (Ratio)
`
`2
`3
`4
`5
`6
`7
`8
`9
`11
`12
`13
`14
`15
`16
`17
`18
`19
`20
`21
`22
`23
`24
`25
`26
`
`1
`2
`2
`1
`2
`2
`2
`2
`2
`1
`2
`1
`2
`1
`1
`1
`2
`2
`1
`2
`1
`1
`2
`1
`
`9031
`9609
`5011
`3389
`10456
`11217
`4025
`13708
`8122
`6739
`4614
`17347
`5488
`12327
`4070
`5296
`8022
`2962
`9143
`11873
`10456
`6507
`12143
`4519
`
`9855
`13103
`3867
`2530
`7302
`11103
`3857
`8876
`6570
`5470
`4360
`13467
`3535
`12025
`3320
`4365
`8271
`2874
`7173
`7742
`9983
`5529
`10272
`5391
`
`824
`3494
`1144
`859
`3154
`114
`168
`4832
`1552
`1269
`254
`3880
`1953
`302
`750
`931
`249
`88
`1970
`4131
`473
`978
`1871
`872
`
`0.916
`0.733
`1.296
`1.340
`1.432
`1.010
`1.044
`1.544
`1.236
`1.232
`1.058
`1.288
`1.552
`1.025
`1.226
`1.213
`0.970
`1.031
`1.275
`1.534
`1.047
`1.177
`1.182
`0.838
`
`91.64
`73.33
`129.58
`133.95
`143.19
`101.03
`104.36
`154.44
`123.62
`123.20
`105.83
`128.81
`155.25
`102.51
`122.59
`121.33
`96.99
`103.06
`127.46
`153.36
`104.74
`117.69
`118.21
`83.82
`
`9.108
`9.170
`8.519
`8.128
`9.255
`9.325
`8.300
`9.526
`9.002
`8.816
`8.437
`9.761
`8.610
`9.420
`8.311
`8.575
`8.990
`7.994
`9.121
`9.382
`9.255
`8.781
`9.405
`8.416
`
`9.196
`9.481
`8.260
`7.836
`8.896
`9.315
`8.258
`9.091
`8.790
`8.607
`8.380
`9.508
`8.170
`9.395
`8.108
`8.381
`9.021
`7.963
`8.878
`8.954
`9.209
`8.618
`9.237
`8.592
`
`0.087
`0.310
`0.259
`0.292
`0.359
`0.010
`0.043
`0.435
`0.212
`0.209
`0.057
`0.253
`0.440
`0.025
`0.204
`0.193
`0.031
`0.030
`0.243
`0.428
`0.046
`0.163
`0.167
`0.176
`
`Medline Industries, Inc.; IPR2015-00511
`Exhibit 2106
`Page 4 of 6
`
`

`

`US 6,407,128 B1
`
`6
`
`TABLE I-continued
`
`Summary of AUCi~f and Ln-Transformed AUCiiaf for
`Skelaxin ® Administered With Food (A) vs. Skelaxin ® Administered Without Food (B)
`
`A: With
`Food
`Seq. (ng/mL)
`
`B: Without
`Food
`(ng/mL)
`
`% Ratio
`Ratio (A/B)
`(a- B) (A/B) "100
`
`Subj
`
`Loge
`Ratio
`Loge A Loge B Ln
`Ln(A) Ln(B) (Ratio)
`
`27
`28
`29
`30
`31
`32
`33
`34
`35
`36
`37
`38
`39
`40
`41
`42
`43
`44
`
`1
`2
`1
`1
`1
`2
`2
`2
`2
`1
`1
`2
`1
`1
`1
`2
`1
`2
`
`5208
`5197
`10355
`7350
`7899
`6719
`11295
`13357
`10710
`19077
`6727
`19024
`3060
`5188
`7273
`3958
`8837
`11427
`
`5061
`5012
`11601
`6452
`7677
`4440
`11316
`13580
`10138
`19329
`4454
`9934
`3284
`4203
`6574
`3642
`4642
`11935
`
`147
`185
`1246
`898
`222
`2279
`21
`223
`572
`252
`2273
`9090
`224
`985
`699
`316
`4195
`508
`
`1.029
`1.037
`0.893
`1.139
`1.029
`1.513
`0.998
`0.984
`1.056
`0.987
`1.510
`1.915
`0.932
`1.234
`1.106
`1.087
`1.904
`0.957
`
`102.90
`103.69
`89.26
`113.92
`102.89
`151.33
`99.81
`98.36
`105.64
`98.70
`151.03
`191.50
`93.18
`123.44
`110.63
`108.68
`190.37
`95.74
`
`8.558
`8.556
`9.245
`8.902
`8.974
`8.813
`9.332
`9.500
`9.279
`9.856
`8.814
`9.853
`8.026
`8.554
`8.892
`8.283
`9.087
`9.344
`
`8.529
`8.520
`9.359
`8.772
`8.946
`8.398
`9.334
`9.516
`9.224
`9.869
`8.402
`9.204
`8.097
`8.344
`8.791
`8.200
`8.443
`9.387
`
`0.029
`0.036
`0.114
`0.130
`0.029
`0.414
`0.002
`0.017
`0.055
`0.013
`0.412
`0.650
`0.071
`0.211
`0.101
`0.083
`0.644
`0.043
`
`Differences were declared to be significant at the 5%
`level. The ratio of the geometric means for the
`in-transformed data and the corresponding 90% confidence
`intervals were calculated for AUC(last), AUC(inf), and 3o
`Cmax. The calculations for the confidence intervals used the
`least squares means (LSMEANS) and the standard error of
`the estimate, both generated by the SAS® software.
`The lower limit of quantitation for metaxalone was 10
`ng/mL. For statistical analysis, subject sample values below 35
`the lower limit of quantitation were reported as zero.
`Tables IIa and IIb summarize the results of the analyses
`performed on the pharmacokinetic parameters obtained
`from the fed and fasted states.
`
`4O
`
`TABLE IIa
`
`Ln-Transformed Ln-Transformed
`
`Ln-Transformed
`
`AUC(last)
`7525.00
`
`AUCinf
`7630.53
`
`Cmax
`1536.23
`
`45
`
`6094.12
`
`6615.24
`
`865.34
`
`123.48
`(116.40, 130.99)
`
`115.35
`(109.24, 121.80)
`
`177.53
`(156.62, 201.23)
`
`5O
`
`Metaxalone
`Treatment A
`Geometric
`Mean
`Treatment B
`Geometric
`Mean
`% Ratio
`90%
`Confidence
`Interval
`
`TABLE lib
`
`Metaxalone
`
`AUC(last) AUCinf Cmax Tmax T1/2
`
`Treatment ALeast Squares
`Mean
`Treatment B Least Squares
`Mean
`
`8439.62
`
`8541.31 1773.61
`
`4.29
`
`2.37
`
`6961.81
`
`7478.90 983.37
`
`3.32
`
`9.04
`
`55
`
`60
`
`With a 5% significance level, the ANOVA detected sta-
`tistically significant differences between treatments for 65
`in-transformed AUC(last), AUCinf, and Cmax, as well as for
`untransformed aUC(last), auC(inf), Cmax, Tmax, T½, and
`
`Kel. The ANOVA detected no statistically significant differ-
`ences between periods or between sequences.
`The mean Ta/2 (half-life) of metaxalone with food and
`without food were 2.37 and 9.04 hours respectively. The
`exact reason for this discrepancy is unclear. However, the
`AUC last is outside the confidence interval, indicating a
`significant food effect.
`Ratio (A/B) of least-squares means for AUC(last), AUC
`(inf) and Cmax were 123.48%, 115.35% and 177.53%,
`respectively demonstrating that metaxalone administered
`with food increased both its rate and extent of absocption.
`ANOVA detected statistically significant differences
`between treatments for In-transformed AUC(last), AUC
`(inf), and Cmax, as well as for untransformed AUC(last),
`AUC(inf),Cmax, T½, and Kel. ANOVA did not detect any
`statistically significant differences between treatments for
`untransformed Tmax.
`Conclusion: Administration with food increases both the
`rate and extent of absocption of metaxalone 400 mg tablets
`when administered as a single dose. The bioavailability of
`metaxalone 400 mg tablets increased when administrated
`with food.
`
`Article of Manufacture
`The article of manufacture comprises a container holding
`an immediate release pharmaceutical composition suitable
`for oral administration of metaxalone in combination with
`printed labeling instructions providing a discussion of when
`a particular dosage form should be administered with food
`and when it should be taken on an empty stomach. The
`composition will be contained in any suitable container
`capable of holding and dispensing the dosage form and
`which will not significantly interact with the composition
`and will further be in physical relation with the appropriate
`labeling advising that an immediate release tablet dosage
`form has less somnolence associated with its use if taken on
`an empty stomach and an immediate release multiparticulate
`dosage form has less somnolence associated with its use if
`taken with food. The labeling instructions will be consistent
`with the methods of treatment as described hereinbefore.
`
`Medline Industries, Inc.; IPR2015-00511
`Exhibit 2106
`Page 5 of 6
`
`

`

`US 6,407,128 B1
`
`7
`The labeling may be associated with the container by any
`means that maintain a physical proximity of the two, by way
`of non-limiting example, they may both be contained in a
`packaging material such as a box or plastic shrink wrap or
`may be associated with the instructions being bonded to the
`container such as with glue that does not obscure the
`labeling instructions or other bonding or holding means.
`While the invention has been described by discussion of
`embodiments of the invention and non-limiting examples
`thereof, one of ordinary skill in the art may, upon reading the
`specification and claims, envision other embodiments and
`variations which are also within the intended scope of the
`invention and therefore the scope of the invention shall only
`be construed and defined by the scope of the appended
`claims.
`We claim:
`1. A method of increasing the oral bioavailability of
`metaxalone to a patient receiving metaxalone therapy com-
`prising administering to the patient a therapeutically effec-
`tive amount of metaxalone in a pharmaceutical composition
`with food.
`2. The method of claim 1 wherein the therapeutically
`effective amount is 200 mg to 900 mg.
`3. The method of claim 1 wherein the therapeutically
`effective amount is 400 mg to 800 mg.
`4. The method of claim 1 wherein the administration to
`the patient occurs between 30 minutes prior to 2 hours after
`consuming food.
`5. The method of claim 1 wherein the administration to
`the patient is substantially at the same time as the consump-
`tion of the food.
`6. The method of claim 1 wherein the administration to
`the patient is immediately after the consumption of food up
`to 1 hour after said consumption.
`7. The method of claim 1 wherein the pharmaceutical
`composition comprises a tablet.
`8. The method of claim 7 wherein the tablet is in unit
`dosage form.
`9. A method of increasing the rate and extent of absorption
`of an oral dosage form of metaxalone as measured by the
`drug concentration attained in the blood stream over time in
`a patient in need of a therapeutic effect thereof comprising,
`administering to the patient a therapeutically effective
`amount of metaxalone in a pharmaceutical composition with
`food.
`l~l. The method of claim 9 wherein the therapeutically
`effective amount is about 200 mg to about 900 mg.
`
`15
`
`11. The method of claim 9 wherein the therapeutically
`effective amount is from about 400 mg to about 800 mg.
`12. The method of claim 9 wherein the administration to
`the patient occurs between about 30 minutes prior to about
`5 2 hours after consuming food.
`13. The method of claim 9 wherein the administration to
`the patient is substantially at the same time as the consump-
`tion of the food.
`14. The method of claim 9 wherein the administration to
`s0 the patient is immediately after the consumption of food up
`to about one hour after said consumption.
`15. The method of claim 9 wherein the pharmaceutical
`composition comprises a tablet.
`16. The method of claim 15 wherein the pharmaceutical
`composition comprises a unit dosage form.
`17. A method of increasing the oral bioavailability of
`metaxalone to a patient receiving metaxalone therapy com-
`prising administering to the patient a pharmaceutical tablet
`2o comprising 400 mg to 800 mg of metaxalone, with food,
`wherein the administration results in an increase in the
`maximal plasma concentration (Cmax) and extent of absorp-
`tion (AUC(last)) of metaxalone compared to administration
`without food.
`25 18. The method of claim 17 wherein the administration to
`the patient occurs between 30 minutes prior to 2 hours after
`consuming food.
`19. The method of claim 17 wherein the administration to
`the patient is substantially at the same time as the consump-
`3o tion of the food.
`20. The method of claim 17 wherein the administration to
`the patient is immediately after the consumption of food up
`to 1 hour after said consumption.
`21. The method of claim 1, further comprising informing
`35 the patient that the administration of a therapeutically effec-
`tive amount of metaxalone in a pharmaceutical composition
`with food results in an increase in the maximal plasma
`concentration (Cmax) and extent of absorption (aUC(last))
`of metaxalone compared to administration without food.
`4o 22. The method of claim 1, wherein the metaxalone is
`from a container with printed labeling advising that admin-
`istration with food results in an increase in the maximal
`plasma concentration (Cmax) and extent of absorption
`(aUC(last)) of metaxalone compared to administration
`45 without food.
`
`Medline Industries, Inc.; IPR2015-00511
`Exhibit 2106
`Page 6 of 6
`
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