United States Patent [19]
`Kohl et al.
`
`[11] Patent Number:
`[45] Date of Patent:
`
`5,073,376
`Dec. 17, 1991
`
`[54] PREPARATIO:SS C01'1AINI!',G
`L-CAR:SITil'.E
`
`[75]
`
`Inventors: Willibald E. Kohl, Muri bei Bern;
`Thomas Scholl, Visp, both of
`Switzerland
`
`[73] Assignee: Lonza Ltd., Gampel, Switzerland
`
`[21] Appl. No.: 499,629
`
`[22J Filed:
`
`Mar. 27, 1990
`
`Foreign Application Priority Data
`[30]
`Dec. 22. 1989 [CH) Switzerland ......................... 4633/89
`
`Int. CJ.s ................................................ A61K 9/48
`[51]
`[52] U.S. CI . .................................... 424/451; 424/464;
`514/551; 514/556
`[58] Field of Search ............... 424/451, 464. 465. 466,
`424/440; 514/551, 556
`
`[56]
`
`References Cited
`U.S. PA TENT DOCUMENTS
`3,810,994 5/1974 Wiegand ............................. 424/316
`4,255,449 3/1981 Cavazza .............................. 424/316
`4,537,772 8/1985 Alexander ............................... 514/9
`
`FOREIGN PATENT DOCUMENTS
`57-126420 1/1981 Japan ................................... 514/556
`Primary Examiner-Thurman K. Page
`Assistant Examiner-D. Gabrielle Phelan
`Attorney, Agent, or Firm-Fisher, Christen & Sabol
`ABSTRACT
`[57]
`Tablets, capsules and other preparation forms for oral
`administration are produced which contain L-carnitine(cid:173)
`L-tartrate. In comparison to preparations made with
`free L-carnitine, the invention preparations exhibit less
`hygroscopicity, longer stability and better capacity for
`being stored.
`
`10 Claims, No Drawings
`
`Apotex Exhibit 1019.001
`
`

`

`1
`
`5,073,376
`
`2
`include particularly all kinds of tablets, both those that
`are swallowed without being chewed, and tablets to be
`chewed or sucked on, as well as those that are dissolved
`in a liquid before being taken. The tablet forms include
`5 uncoated tablets, in one-layer or multilayer or encased
`form. effervescent tablets, and coated tablets, such as,
`film tablets or dragees. Further preferred forms of ad(cid:173)
`ministration are capsules of soft or hard gelatin. Of
`these, hard gelatin capsules in the form of hard-shell
`10 capsules are particularly preferred. Further,. L-carni(cid:173)
`tine-L-tartrate can be used advantageously as a powder.
`for example, with gas-producing additives as an effer(cid:173)
`vescent powder, or as granulated powder. Adju,:ants
`are, for example, fillers, binding agents, lubricants and
`15 mold release agents, flow-regulating agents and disinte(cid:173)
`grants for the production of tablets, as well as coloring
`and flavoring substances. Such adjuvants are known to
`persons skilled in the art, as well as their use and the
`technology for producing the above-named forms of
`20 administration.
`DETAILED DESCRIPTION OF THE
`INVENTION
`The examples below explain the execution of the
`25 invention.
`
`PREPARATIO~S CO~TAl~I~G L-CAR~ITl~E
`
`BACKGROUND OF THE INVENTI01'
`I. Field Of The Invention
`The invention relates to preparations containing L(cid:173)
`carnitine for oral use in the form of tablets, capsules or
`powder.
`2. Background Art
`L-carnitine plays an important role in lipometabolism
`and is used especially in food for athletes, but also for
`the treatment of diseases with metabolic disorders. Ath(cid:173)
`letic food preparations containing L-carnitine are
`widely used, since they contribute significantly to sup(cid:173)
`plying the muscles with energy and promote endurance
`performance. Such preparations have great importance
`since they improve muscle activity and thereby bring
`about increased endurance and stress tolerance as well
`as delaying fatigue and shortening recovery time. How(cid:173)
`ever. the use of preparations containing L-carnitine is
`not limited to food for athletes, as they can also be used
`for geriatric purposes and as general food additives.
`Thus, the application can basically take place both
`enterally and parenterally. For the preferred enteral,
`i.e., oral, application, suitable forms of administration,
`preferably in the form of tablets or capsules, optionally
`also in the form of powder or granulate, are thus neces(cid:173)
`sary. Here the production takes place according to
`methods of pharmaceutical technology. independently
`of whether the form of administration is to serve for 30
`food purposes or therapeutic purposes. The production
`and handling of such forms of administration up to now
`have been made considerably more difficult because of
`the high hygroscopicity of L-carnitine. Thus, for exam(cid:173)
`ple. tablets that contain L-carnitine must be produced 35
`with the exclusion of moisture and must be packaged
`hermetically and individually, since they would begin
`to liquefy in a short time even with the normal moisture
`in the air. Moreover, L-carnitine often contains traces
`of trimethylamine. which, because of its fishy odor, has 40
`a repulsive effect on the user.
`
`BROAD DESCRIPTION OF THE INVENTION
`The object of the invention is to make available a
`nonhygroscopic and odorless form of L-carnitine, 45
`which contains no physiologically unsafe additives and
`which is preferably suitable in particular for producing
`tablets or capsules.
`·
`According to the invention, the object is attained by
`the use of L-carnitine-L-tartrate for producing compo- 50
`sitions for oral administration. Herein. L-carnitine-L(cid:173)
`tartrate is to be understood as the salt of L-carnitine
`with L-tartaric acid in the molar ratio of 2: I.
`It has been found that L-carnitine-L-tartrate at nor(cid:173)
`mal air moisture ( ~ 60 percent relative humidity) is 55
`stable in storage and can be processed without special
`precautions. L-carnitine-L-tartrate forms a crystalline
`powder which can be easily processed and is particu(cid:173)
`larly suitable for processing with rapidly running ma(cid:173)
`chines, since it does not tend to stick t0gether or be(cid:173)
`come lumpy. Moreover, it is completely odorless and
`because of the bonded tartaric acid it has a refreshing.
`somewhat acidic taste.
`L-carnitine-L-tartrate is used advantageously alone
`or with additional actiYe ingredients, such as. vitamins, 65
`amino acids. trace elements or mineral substances, as
`well as optionally the adjuvants usual for the respective
`form of administration. The forms of administration
`
`60
`
`EXAMPLE 1
`Production of L-carnitine-L-tartrate
`L-tartaric acid was dissolved in the required quantity
`of hot 90 percent aqueous ethanol, the calculated quan(cid:173)
`tity of L-carnitine was added, the salt was brought to
`crystallization by cooling, filtered and dried. The prod(cid:173)
`uct showed the following characteristics: colorless
`crystals
`melting point: 169°-175° C.
`[a]d5: -10.9°±0.6° (25° C., c=lo/t: in water).
`composition: mo! ratio of carnitine: tartaric acid is 2: I
`(lH-NMR).
`water solubility: about 73 g/100 g of solution.
`water absorption when air humidity is 32 percent.
`
`After hours
`
`L-carnitine-L-tartrate
`percent
`
`L-carnitme
`percent
`
`0
`1.9
`1
`0
`3.6
`2
`0
`4
`6.3
`0
`8.6
`8
`0
`24
`12.3
`water absorption when air humidity is 66 percent
`1
`0
`6.0
`2
`0
`9.6
`4
`0
`21.6
`8
`0.1
`45.2
`N
`n7
`QJ
`
`EXAMPLE 2
`Sucking Tablets With Orange Flavoring
`Sucking tablets weighing individually 2,200 mg were
`produced according to the following formulation:
`
`L-carmtinc-L-tartrate
`fructose
`orange flavoring
`quinoline yellow lacquer
`carboxymethyl cellulose
`polyvinylpyrrohdone
`saccharo5)e stearate
`
`732 mg
`1.089 mg
`30 mg
`4 mg
`25 mg
`20 mg
`JOO mg
`
`Apotex Exhibit 1019.002
`
`

`

`3
`-continued
`
`talc
`magnesium stearate
`
`160 mg
`40 mg
`
`5,073,376
`
`4
`tablets. Circular tablets with a facette edge 13 mm in
`diameter and about 3.9 mm thick were pressed. The
`tablets exhibited a resistance to pressure of 60 to 70 N
`and disintegrated in water of 20° C. within 15 to 17
`S minutes.
`
`EXAMPLE 5
`Capsules for use as Food Supplement
`Hard gelatin capsules with L-carnitine-L-tartrate
`were produced, corresponding to the following compo(cid:173)
`sition:
`
`L-carnitine·L•tartrate
`magnesium stearate
`
`366 mg
`4 mg
`
`The mixture was prepared in the usual manner and
`pressed into tablets 20 mm in diameter. As a compari(cid:173)
`son, sucking tablets of the same kind were produced
`which contained 500 mg of L-carnitine and 232 mg of
`microcrystalline cellulose (for weight compensation) 10
`instead ofL-carnitine-L-tartrate. On the crushed tablets
`the water absorption in each case was determined under
`constant relativity humidity. When they were stored at
`a relative humidity of 56 percent the crushed tablets,
`which contained L-carnitine-L-tartrate, did not take up IS
`any water even after 10 days. In comparison to this,
`tablets that contained L-carnitine showed a water ab(cid:173)
`sorption of 12 percent under identical conditions. The
`use of L-carnitine-L-tartrate according to the invention
`resulted in tablets that could be stored even under ex- 20
`treme conditions.
`
`EXAMPLE 3
`Sucking Tablets With Peppermint Flavoring
`Analogously to Example 2 sucking tablets were pro- 25
`duced according to the following formulation:
`
`L-carnitine-L-tartrate
`mannitol
`aspartame
`peppermint navoring
`carboxymethyl cellulose
`polyvinyl pyrrolidone
`saccharose stearate
`tak
`magnesium stearate
`
`1.IOO mg
`73' mg
`13 mg
`10 mg
`25 mg
`20 mg
`100 mg
`160 mg
`40 mg
`
`____________________ _ ; ___ _
`
`Magnesium stearate was sifted with a sieve with 0.5 mm
`mesh size, L-camitine-L-tartrate was added, and both
`components were intensively mixed for 15 minutes.
`Afterwards the mixture was filled into CONI-SNAP ®
`capsules of size I. This resulted in capsules that were
`capable of being stored even under tropical conditions.
`366 mg of L-camitine-L-tartrate per capsule corre(cid:173)
`sponded to a quantity of 250 mg of L-carnitine.
`We claim:
`1. A preparation for enteral application comprising at
`least one tablet composed of the salt of L-carnitine with
`L
`·
`f
`"d · h
`)
`·
`-tartanc ac1 mt e mo ar ratio o 2:1, powder com-
`30 posed of the salt of L-carnitine with L-tartaric acid in
`the molar ratio of 2: 1 or at least one capsule containing
`the salt of L-carnitine with L-tartaric acid in the molar
`ratio of 2: I.
`2. The preparation as claimed in claim 1 wherein said
`35 at least one tablet includes or said powder includes or at
`least one said capsule also contains at least one member
`of the group consisting of vitamin. amino acid. trace
`element, mineral substance. inert edible carrier or filler,
`gas-producing additive, · disintegrant, binding agent.
`lubricant, mold release agent, flow regulating agent.
`colorant and flavorant, the at least one capsule being
`composed of soft or hard gelatin.
`3. The preparation as claimed in claim 1 wherein the
`preparation is said at least one tablet.
`4. The preparation as claimed in claim 3 wherein said
`at least one tablet includes a monosaccharide, a disac(cid:173)
`charide, a sugar alcohol or a trisaccharide.
`5. The preparation of claim 1 wherein the preparation
`is said powder.
`6. The preparation as claimed in claim 1 wherein the
`preparation is said at least one capsule.
`7. A process comprising preparing a preparation for
`oral administration, the preparation being composed of
`L-carnitine-L-tartrate, the L-carnitine-L-tartrate being
`55 the salt of L-carnitine with L-tartaric acid in the molar
`ratio of 2: I.
`8. The process as claimed in claim 7 wherein the
`preparation is at least one tablet composed of L-carni(cid:173)
`;ine-L-tartrate, and said process comprises tableting
`60 said L-carnitine-L-tartrate into at least one tablet.
`9. The process as claimed in claim 7 wherein the
`preparation is at least one capsule containing L-carni(cid:173)
`tine-L-tartrate, and said process comprise~ placing said
`L-carnitine-L-tartrate into said at least one capsule.
`10. Process comprising enterally consuming the prep-
`aration of claim 1 by a human.
`• • • • •
`
`As a comparison again as in Example 2, tablets were
`produced with L-carnitine and microcrystalline cellu(cid:173)
`lose. Also with these tablets, as in Example 2, the water
`absorption was determined. The use according to the 40
`invention of L-carnitine-L-tartrate yielded stable tablets
`capable of being stored, while tablets on the basis of
`L-carnitine, after storage for one week, formed a sticky
`mass because of water absorption.
`
`EXAMPLE4
`Tablets for Swallowing
`According to the following formulation 12,000 tab(cid:173)
`lets of 650 mg each were produced:
`
`L-carnttine-L-tartrate
`lactose monohydrate
`(that can be direct!>· tableted)
`wheat starch
`cellulose. microcrystalline
`silicon dioxide (Aerosil ® 200)
`talc
`magnesium stcarate
`
`4.392 kg
`2.028 kg
`
`420 g
`360 g
`60 g
`480 g
`60 g
`
`The L-carnitine-L-tartrate was homogeneously mixed
`with the wheat starch and the cellulose and sifted. The
`lactose was added, uniformly mixed in and the mixture
`was sifted again. Talc. magnesium stearate and silicon
`dioxide were thoroughly mixed with one another, sifted
`and sprinkled into the mixture of active ingredients. The
`whole mixture was again mixed thoroughly and kept in
`a hermetically sealed container until it was made into
`
`45
`
`so
`
`65
`
`Apotex Exhibit 1019.003
`
`

`

`I 1111111111111111 11111 1111111111 1111111111 111111111111111 lll111111111111111
`US005073376Cl
`(12) EX PARTE REEXAMINATION CERTIFICATE (4938th)
`us 5,073,376 Cl
`United States Patent
`(10) Number:
`Kohl et al.
`(45) Certificate Issued: May 18, 2004
`
`(54) PREPARATIONS CONTAINING L(cid:173)
`CARNITINE
`
`(75)
`
`Inventors: Willibald E. Kohl, Muri bei Bern
`(CH); Thomas Scholl, Visp (CH)
`
`(73) Assignee: Lonza Ltd., GampelNalais (CH)
`
`Reexamination Request:
`No. 90/006,513, Jan. 13, 2003
`
`Reexamination Certificate for:
`5,073,376
`Patent No.:
`Dec. 17, 1991
`Issued:
`07/499,629
`Appl. No.:
`Mar. 27, 1990
`Filed:
`
`(30)
`
`Foreign Application Priority Data
`
`Dec. 22, 1989
`
`(CH) .............................................. 4633/89
`
`(51)
`
`Int. CI.7 ............................ A61K 9/14; A61K 9/20;
`A61K 9/48
`(52) U.S. Cl. ....................... 424/451; 424/456; 424/464;
`424/489; 514/551; 514/556
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`2,784,100 A
`3,359,119 A
`3,480,185 A
`3,653,914 A
`4,172,072 A
`4,267,163 A
`4,362,719 A
`4,371,618 A
`4,602,039 A
`RE32,398 E
`4,687,782 A
`4,753,804 A
`4,801,453 A
`4,806,282 A
`4,855,289 A
`4,871,550 A
`
`3/1957 Endicott
`12/1967 Milton
`11/1969 Steinberg
`4/1972 Schmitt
`10/1979 Ashmead
`5/1981 De Felice ...................... 424/9
`12/1982 Cavazza
`2/1983 Cavazza
`7/1986 Cavazza
`4/1987 DeWitt
`8/1987 Brantman
`6/1988 Iaccheri
`1/1989 Kosuge
`2/1989 Tinti
`8/1989 Wester
`10/1989 Millman
`
`4,883,786 A
`4,895,980 A
`4,933,490 A
`4,968,517 A
`4,968,719 A
`5,030,657 A
`5,071,874 A
`
`11/1989 Puricelli
`1/1990 Walsdorf
`6/1990 Iannella
`11/1990 Gergely et al. ............. 426/285
`11/1990 Brevetti ...................... 514/556
`7/1991 Burtle
`12/1991 Scholl
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`DE
`DE
`DE
`DE
`EP
`EP
`EP
`FR
`FR
`
`23 217
`93 347
`93 347
`31 49 517 Al
`36 35 864 C2
`0 076 340
`0 150 688
`0 434 088 Al
`2 529 545
`2 552 308 Al
`
`1/1959
`10/1971
`10/1972
`12/1981
`10/1986
`8/1984
`8/1985
`12/1990
`7/1982
`9/1984
`
`OTHER PUBLICATIONS
`
`Muller, et al, Splitting of the Racemate of DL-Carnitine,
`Apr. 1972, Hoppe-Seyler'sA. Physiol. Chem., vol. 353, pp.
`618-622.*
`Erich Struck and Irmgard Lorenz Bd. 318 (1960), pp.
`120-137.
`George D. Clayton and Florence E. Clayton, Toxicology,
`vol. 2.
`Chem.Abstract, Choh Hao Li, Amino Acids, Peptides, and
`Proteins (1974).
`Chem.Abstract No. 33996x, Aliphatics, vol. 77 (1972).
`
`* cited by examiner
`
`Primary Examiner-James M. Spear
`
`(57)
`
`ABSTRACT
`
`Tablets, capsules and other preparation forms for oral
`administration are produced which contain L-carnitine-L(cid:173)
`tartrate. In comparison to preparations made with free
`L-carnitine, the invention preparations exhibit less
`hygroscopicity, longer stability and better capacity for being
`stored.
`
`Apotex Exhibit 1019.004
`
`

`

`US 5,073,376 Cl
`
`1
`EXPARTE
`REEXAMINATION CERTIFICATE
`ISSUED UNDER 35 U.S.C. 307
`
`NO AMENDMENTS HAVE BEEN MADE TO
`THE PATENT
`
`2
`AS A RESULT OF REEXAMINATION, IT HAS BEEN
`DETERMINED THAT:
`
`The patentability of claims 1-10 is confirmed.
`
`5
`
`* * * * *
`
`Apotex Exhibit 1019.005
`
`