United States Patent [19]
`Meezan et al.
`
`[54] ABSORPTION ENHANCERS FOR DRUG
`ADMINISTRATION
`
`[75] Inventors: Elias Meezan; Dennis J. Pillion. both
`of Birmingham, Ala.
`
`[73] Assignee: The UAB Research Foundation,
`Birmingham, Ala.
`
`[21] Appl. N0.: 83,074
`
`[22] Filed:
`
`Jun. 24, 1993
`
`_
`
`[51] Int. Cl.6 .......................... .. CMG 3/00; A61K 31/70;
`A61K 38/00; A61K 38/28
`[52] U.S. Cl. ............................... .. 514/25; 514/24; 514/53;
`514/54; 514/912; 514/2; 514/3; 514/8; 536/4.1;
`536/115; 536/116; 536/118; 536/120; 536/122;
`536/123.13
`[58] Field Of Search ........................... .. 536/4.1, 115, 116,
`536/118, 120, 122, 123.13; 514/24, 25,
`53, 54, 2, 3, 8,912
`
`[56]
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`9/1989 Magnusson et al. .................. .. 536/4.1
`4,868,289
`l/l993 Chiou ............... ..
`5,182,258
`5,369,095 11/1994 Kee et al. ............................... .. 514/24
`
`OTHER PUBLICATIONS
`
`Masahiro Murakami et al., “Assessment of Enhancing Abil
`ity of Medium-Chain Alkyl Saccharides as New Absorption
`Enhancers in Rat Rectum.” International Journal of Phar
`maceutics, 79:159-169 (1992).
`Lars Hovgaard et al., “Insulin Stabilization and GI Absorp
`n'on,” Journal of Controlled Release, 19299-108 (1992).
`Dennis J. Pillion et al., “Systemic Absorption of Insulin
`Delivered Topically to the Rat Eye,” Investigative Ophthal
`mology & Visual Science, 32(12):3021—3027 (Nov. 1991).
`Taro Ogiso et al., “Percutaneous Absorption of Elcatonin
`and Hypocalcemic Effect in Rat,” Chem. Pharm. Bull,
`39(2):449-453 (1991).
`
`USOO5661130A
`[11] Patent Number:
`[45] Date of Patent:
`
`5,661,130
`Aug. 26, 1997
`
`Akira Yamamoto et al., ‘The Ocular Route for Systemic
`Insulin Delivery in the Albino Rabbit,” The Journal of
`Pharmacology
`and
`Experimental
`Therapeutics,
`249(l):249—255 (1989).
`George C.Y. Chiou et al., “Systemic Delivery of Insulin
`Through Eyes to Lower the Glucose Concentration,” Jour
`nal of Ocular Pharmacology, 5(1):8 1-91 (1989).
`George C.Y. Chiou et al., “Improvement of Systemic
`Absorption of Insulin Through Eyes with Absorption
`Enhancers,” Journal of Pharmaceutical Sciences,
`78(10):815—818 (Oct. 1989).
`G. S. Gordon et al., “Nasal Absorption of Insulin: Enhance
`ment by Hydrophobic Bile Salts,” Proc. Natl. Acad. Sci,
`USA, 82:7419-7423 (Nov. 1985).
`Robert Salzman et al., “Intranasal Aerosolized Insulin,” The
`New England Journal of Medicine, 312(l7):l078-1084
`(Apr. 25, 1985).
`Alan C. Moses et al., “Insulin Administered Intranasally as
`an Insulin-Bite Salt Aerosol —Effectiveness and Reproduc
`ibility in Normal and Diabetic Subjects,” Diabetes,
`32:1040-1047 (Nov. 1983).
`
`Primary Examiner—-John Kight
`Assistant Examiner—Everett White
`Attomey, Agent, or Firm-Needle & Rosenberg, RC.
`[57]
`ABSTRACT
`
`The present invention relates to a method of increasing the
`absorption of a compound via the ocular, nasal, nasolacrimal
`or inhalation route into the circulatory system of a patient.
`In particular, a method comprising administering with the
`compound an absorption enhancer comprising a nontoxic,
`nonionic alkyl glycoside is provided. Additionally provided
`are methods of raising or lowering the blood glucose level
`by administering glucagon or insulin, respectively, with such
`absorption enhancers. Finally, compositions for raising or
`lowering the blood glucose level are provided.
`
`11 Claims, N0 Drawings
`
`AQUESTIVE EXHIBIT 1020 page 0001
`
`

`

`5,661,130
`
`1
`ABSORPTION ENHANCERS FOR DRUG
`ADMINISTRATION
`
`BACKGROUND OF THE INVENTION
`
`20
`
`25
`
`30
`
`35
`
`1. Field of the Invention
`The present invention relates to a method of increasing
`the absorption of a compound via the ocular, nasal, naso
`lacn'mal or inhalation route into the circulatory system of a
`patient. In particular. a method comprising administering
`with the compound an absorption enhancers comprising a
`nontoxic, nonionic alkyl glycoside is provided. Additionally
`provided are methods of raising or lowering the blood
`glucose level by administering glucagon or insulin.
`respectively, with such absorption enhancers. Finally, com
`positions for raising or lowering the blood glucose level are
`provided.
`2. Background Art
`The revolution in biotechnology has impacted on the
`pharmaceutical industry and on the practice of medicine by
`making available a variety of previously known and newly
`discovered proteins, e.g., insulin, growth hormone, interfer
`ons; peptides, e.g., cyclosporine, enkephalins and other
`synthetic peptides; as well as macromolecules, e.g., heparin
`and derivatives; drugs which open up an entirely new
`dimension to the treatment of disease. A serious limitation to
`the development and use of such agents. however. is the
`ability to deliver them safely and e?iciently to their thera
`peutic site of action (Lee, V. H. L. et at., in “Peptide and
`Protein Drug Delivery,” V. H. L. Lee ed. Marcel Dekker,
`New York, pp. 1-56 (1991)). Because these drugs are
`usually available in only small amounts. are expensive and
`are biologically fragile—subject to denaturation and
`degradation-a rapid and e?icient route of delivery is an
`important requirement for their successful use in therapy.
`Unfortunately. for the most part, the practical delivery of
`such agents has been limited to injectable routes such as
`intravenous, intramuscular and subcutaneous administra
`tion. Insulin is the classic example of such an agent whose
`obligatory use in insulin-dependent diabetes mellitus
`requires administration via injection. In the case of other
`established macromolecular drugs. such as heparin, the
`requirement for delivery by injection and the availability of
`alternative. but far from ideal agents, such as the oral
`anticoagulants. has restricted the use of the injectable agent
`to the clinic or hospital, thus denying its bene?ts to a large
`outpatient population. Although many attempts have been
`made to safely and efficiently administer insulin. heparin and
`other macromolecular drugs by non-injectable routes, none
`have proved successful, and it has become apparent that the
`success of such attempts depends on the discovery of a safe
`and e?icient agent to enhance absorption of the macromol
`ecules (see Lee et at).
`Buccal absorption of insulin is minimal in the absence of
`a surfactant agent. but it has been shown to be improved with
`penetration-enhancers such as glycocholate and Brij 35.
`However. the low bioavailabilty observed and the possible
`toxicity of the enhancing agents used previously have made
`this route impractical (Oh. C. K. et at. Meth. Find. Earp. Clin.
`PharmacoL, 12:205-212 (1990)). Similar ?ndings have
`been reported for insulin absorption across the rectal mucosa
`(Rytting. J. H. et al., (V. H. L. Lee, ed.) Marcel Dekker, New
`York pp. 579-594 (1991)). However. it has recently been
`reported that dodecylrnaltoside was e?ective in promoting
`the absorption of high molecular weight sugar compounds,
`such as dextrans. and other molecules. such as
`carboxy?uoroscein. across the rectal mucosa of rats without
`
`2
`producing any apparent histological change to the tissue
`(Murakami. M. et al., Int. J. Pharm., 79:159-169 (1992)).
`Hovgaard et al.. (J. Controlled Release, 19199-108 (1992))
`reported the use of high concentrations of dodecyl maltoside
`to increase the absorption of insulin across the rectal mucosa
`in rats. High concentrations were found to be necessary for
`rectal absorption (3.2%—12.8% dodecyl maltoside). It was
`concluded by Hovgaard et al. that rectal absorption enhanc
`ers function at least in part because they render the insulin
`- enhancer complex more resistant to enzymatic degradation
`10
`by intestinal digestive enzymes. The use of dodecyl malto
`side in the reported concentrations would be too irritating
`and toxic to the much more sensitive ocular and nasal
`mucosa and thus unsuitable for ocular and nasal absorption
`enhancers.
`A synthetic analogue of calcitonin, a hypocalcemic pep
`tide has been shown to be elfectively absorbed percutane
`ously in the rat by applying it in transdermal dosage form as
`a gel containing a combination of bile salts and the alkyl
`glycosides octylglucoside or octylthioglucoside (Ogiso, T. et
`al., Chem. Pharm. Bull, 39:449-453 (1991)).
`We had previously shown that systemic delivery of insu
`lin via the ocular and nasal-lacrimal route in amounts
`sufticient to lower blood sugar in experimentally diabetic
`rats was made possible by including 1% saponin in the eye
`drops with the insulin (Pillion, D. J. et al., Invest. Ophthal
`mol. Vis. Sci., 32:3021-3027 (1991)). However, saponins,
`which have also been used by others to promote ocular
`absorption of insulin (Chiou, G. C. Y. et al., J. Pharm. Sci.,
`78:815-818 (1989); Chiou, C. Y. et al., J. Ocular Phamza
`col. 5:81-91 (1989); U.S. Pat. No. 5.182.258 (Chiou et al.),
`are a large and complex class of compounds, derived from
`plants, which are difficult to prepare in pure form and have
`deleterious properties such as being irritants (Price, K. R. et
`al., CRC Crit. Rev. Food Sci. Nutn, 26127-135 (1987)).
`Another surfactant, Tween 20, which has the same 12 carbon
`alkyl side chain as dodecylrnaltoside, but which has a
`polyoxyethylene moiety in place of maltose, has been
`reported to be almost without e?°ect in allowing absorption
`of insulin in rabbit eyes (Chiou, et al., J. Pharm. Sci.,)
`Furthermore, saponin, fusidic acid. EDTA,
`polyoxyethylene-9-lauryl ether, glycocholate, taurocholate,
`deoxycholate and decamethoniurn as ocular absorption
`enhancers have met with limited success in promoting the
`ocular absorption of insulin (Pillion et al., Chiou et al., (J.
`Pharm. Sci.), Chiou et al. (J. Ocular Pharmacol.) and
`Yamamoto et al., J. Pharmacol. Exptl. Then, 249:249-255
`(1989)), but the toxicity of these agents makes their thera
`peutic usage problematic.
`Intranasal administration of insulin in the form of a nasal
`spray with bile salts or laureth-9 as absorption enhancers has
`been tested in clinical trials with normal and diabetic
`subjects. but also with only limited success (Moses, A. C. et
`al.. Diabetes, 32:1040-1047 (1983); Gordon, G. S. et al.,
`Proc. Natl. Acad. Sci. USA, 82:7419-7423 (1985);
`Salzmann, R. et al., New Engl. J. Med., 312:1078-1084
`(1985)). The major limiting factors which have prevented
`the practical development of this route for general use is the
`low e?iciency of absorption across the nasal mucosa and the
`local and systemic toxicity of the penetration-enhancing
`agents used (Moses et al., Gordon et al., Salzmann et al and
`Chadwick, U.S. et al., Gut, 17:10-17 (1976)). Aerosolized
`insulin has been absorbed via the respiratory route, but only
`at low ef?ciency. probably because no absorption enhancer
`was employed (Wigley, F. M. et al., Diabetes, 20:552-556
`(1971).
`Dodecylmaltoside and other alkyl glycosides can readily
`be obtained in pure form and have well de?ned, simple
`
`40
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`50
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`65
`
`AQUESTIVE EXHIBIT 1020 page 0002
`
`

`

`3
`structures (Neugebauer, J.. “A Guide to the Properties and
`Uses of Detergents in Biology and Biochemistry,” Calbio
`chem Corporation (1988)). They are mild nonionic surfac
`tants which have generally been shown to be nontoxic to
`several di?erent cell types (DiCorleto, P. E. et al., J.
`ImmunoL, 143:3666-3672 (1989) and LeGrue, S. J. et al., J.
`Natl. Cancer Inst, 69:131-136 (1982)). Octylglucoside had
`no effect on the viability or morphology of monocytes or
`endothelial cells (DiCorleto et al.) and was non-cytolytic to
`intact mouse ?brosarcoma cells (LeGrue et al.) Orally
`administered alkyl glycosides, including octyl [3-D
`glucoside and dodecyl [i-D-maltoside. have also been shown
`to be metabolized to nontoxic metabolites by cleavage to
`sugars and long chain alcohols which enter into the path
`ways of carbohydrate and lipid metabolism. It was sug
`gested that these compounds would be suitable for use as
`food additives because of their lack of toxicity (Weber, N. et
`al., J. Nutn, 114:247-254 (1984)). In contrast, other agents
`which have been shown to enhance the systemic absorption
`of insulin. such as bile salts or laureth-9, are known to be
`irritating to mucosal surfaces and are not metabolized to
`simple products in the body (Moses et al., Gordon et al., and
`Salzmann et al) In the case of bile salts, it is known that
`they are toxic to the gastrointestinal mucosa when admin
`istered orally and that they cause ultrastructural abnormali
`ties of the nasal mucosa when used to administer insulin by
`this route (Moses et al., Gordon et al., and Chadwick et al.).
`Thus. many attempts have been unsuccessfully made to
`obtain a suitable, effective absorption enhancer for drugs,
`and there is a great need for such an enhancer. The ideal
`absorption or penetration enhancer would preserve the bio
`logical activity of the protein or other drug and thus should
`be nonreactive and non-denaturing. It should enhance the
`passage of the drug through membrane barriers without
`damaging the structural integrity and biological functions of
`the membrane. Most importantly, both it and its metabolites
`should be nonirritating and nontoxic, both at the site of
`application, and also systemically, since it is likely that any
`enhancer of drug absorption will itself be absorbed and have
`to be metabolized and/or cleared from the body. Such an
`absorption enhancer is provided herein.
`
`10
`
`15
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`25
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`30
`
`35
`
`SUMIVIARY OF THE INVENTION
`
`The present invention relates to a method of increasing
`absorption of a compound into the circulatory system of a
`subject comprising administering via the ocular, nasal,
`nasolacrimal. or inhalation route the compound and an
`absorption increasing mount of a suitable nontoxic. nonionic
`glycoside having a hydrophobic alkyl joined by a linkage to
`a hydrophilic saccharide.
`The present invention also relates to a method of lowering
`blood glucose level in a subject comprising administering
`via the ocular. nasal, nasolacrimal or inhalation route, a
`blood glucose-reducing amount of a composition compris
`ing insulin and an absorption increasing amount of a suitable
`nontoxic. nonionic alkyl glycoside having a hydrophobic
`alkyl joined by a linkage to a hydrophilic saccharide, thereby
`increasing the absorption of insulin and lowering the level of
`blood glucose.
`The instant invention further relates to a method of raising
`blood glucose level in a subject comprising administering
`via the ocular, nasal. nasolacrimal or inhalation route a blood
`glucose-raising amount of a suitable composition compris
`ing glucagon and an absorption increasing amount of a
`suitable nontoxic, nonionic alkyl glycoside having a hydro
`phobic alkyl joined by a linkage to a hydrophilic saccharide,
`
`45
`
`50
`
`55
`
`65
`
`5,661,130
`
`4
`thereby increasing the absorption of glucagon and raising
`the level of blood glucose.
`The present invention also relates to a composition com
`prising (a) a nontoxic, nonionic alkyl glycoside having a
`hydrophobic alkyl joined by a linkage to a hydrophilic
`saccharide. in concentration in the range of 0.01% to 1.0%,
`capable of increasing absorption of a compound into the
`circulatory system of a patient and (b) an agent selected from
`the group consisting of insulin and glucagon.
`Accordingly. it is an object of the present invention to
`provide a method of increasing the absorption of a com
`pound into the circulatory system of a subject by utilizing
`the ocular, nasal and nasolacrimal or inhalation route.
`Another object of the present invention is to provide
`compositions and methods for raising or lowering the blood
`glucose level in a subject utilizing the provided method for
`increasing absorption of compounds. and thus treating
`hypoglycemia or diabetes mellitus, respectively.
`Finally, an object of the present invention is to provide
`compositions for raising and lowering blood glucose levels.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`The present invention may be understood more readily by
`reference to the following detailed description of speci?c
`embodiments and the Examples included therein.
`The present invention provides a method of increasing
`absorption of a compound into the circulatory system of a
`subject comprising administering via the ocular, nasal,
`nasolacrimal, or inhalation route the compound and an
`absorption increasing amount of a suitable nontoxic, non
`ionic alkyl glycoside having a hydrophobic alkyl joined by
`a linkage to a hydrophilic saccharide. The compound and the
`alkyl glycoside can be mixed prior to administration. or they
`can be administered sequentially, in either order. It is pre
`ferred that they be mixed prior to administration.
`As used in the claims, “a” can mean one or more.
`As used herein, “hypoglycemia” means a hypoglycemic
`crisis.
`“Nontoxic,” as used herein. means that the alkyl glycoside
`molecule has a su?iciently low toxicity to be suitable for
`human administration. Preferred alkyl glycosides are non
`irritating to the tissues to which they are applied. Any alkyl
`glycoside should be of minimal or nontoxicity to the cell,
`such as not to cause damage to the cell. Toxicity for any
`given alkyl glycoside may vary with the concentration of
`alkyl glycoside used. It is also bene?cial if the alkyl glyco
`side chosen is metabolized or eliminated by the body and if
`this metabolism or elimination is done in a manner that will
`not be harmfully toxic.
`As used herein, “alkyl glycoside” refers to any sugar
`joined by a linkage to any hydrophobic alkyl, as is known in
`the art. The hydrophobic alkyl can be chosen of any desired
`size, depending on the hydrophobicity desired and the
`hydrophilicity of the saccharide moiety. A preferred range of
`alkyl chains is from 9 to 24 carbon atoms. An even more
`preferred range is ?'om 9 to 14 carbon atoms.
`As used herein; “saccharide” is inclusive of
`monosaccharides, oligosaccharides or polysaccharides in
`straight chain or ring forms. oligosaccharides are saccha
`rides having two or more monosaccharide residues.
`As used herein. a “suitable” alkyl glycoside means one
`that ful?lls the limiting characteristics of the invention, i.e..
`that the alkyl glycoside be nontoxic and nonionic, and that
`it increases the absorption of a compound when it is admin
`
`AQUESTIVE EXHIBIT 1020 page 0003
`
`

`

`5,661,130
`
`5
`
`25
`
`35
`
`45
`
`50
`
`55
`
`65
`
`5
`istered with the compound via the ocular, nasal. nasolacri
`mal or inhalation route. Suitable compounds can be deter
`mined using the methods set forth in the examples.
`Also as used herein. “hydrophile-lipophile balance num
`ber” (HLB) is a characteristic of individual surfactants that
`can be either calculated or determined empirically, as pre
`viously described (Schick. M. J. Nonionic Surfactants. p.
`607 (New York: Marcel Dekker. Inc. (1967)). HLB can be
`calculated by the formula: ZOXMW hydrophilic component!
`(MW hydrophobic c0mp0nent+MW hydrophilic
`component). where MW=mo1ecular weight (Rosen, M. J .,
`Surfactants and Interfacial Phenomena. pp. 242-245. John
`Wiley, New York (1978)). The HLB is a direct expression of
`the hydrophilic character of the surfactant. i.e., the larger the
`HLB. the more hydrophilic the compound. A preferred
`surfactant has an HLB of from 10 to 20 and an even more
`preferred range of from 11 to 15.
`Compounds whose absorption can be increased by the
`method of this invention include any compounds now
`known or later discovered, in particular drugs that are
`di?icult to administer by other methods, for example, drugs
`that are degraded in the gastrointestinal (GI) tract or that are
`not absorbed well from the GI tract, or drugs that subjects
`could administer to themselves more readily via the ocular.
`nasal, nasolaq‘imal or inhalation route than by traditional
`self-administration methods such as injection. Some speci?c
`examples include peptides, polypeptides. proteins and other
`macromolecules, for example, peptide hormones, such as
`insulin and calcitonin. enkephalins, glucagon and hypogly
`cemic agents. such as tolbutamide and glyburide, and agents
`which are poorly absorbed by enteral routes, such as
`griseofulvin, an antifungal agent.
`The saccharide can be chosen, for example, from any
`currently commercially available saccharide species or can
`be synthesized. The saccharide can be a monosaccharide, a
`disaccharide. an oligosaccharide or a polysaccharide, or a
`combination thereof to form a saccharide chain. Some
`examples of the many possible saccharides to use include
`glucose, maltose, maltotriose, maltotetraose, sucrose and
`trehalose. Preferable saccharides include maltose, sucrose
`and glucose.
`Additionally, various oxygen atoms within the com
`pounds can be substituted for by sulfur in order to decrease
`susceptibility to hydrolytic cleavage by glycohydrolases in
`the body (Defaye, J. and Gelas, J. in Studies in Natural
`Product Chemistry (Atta-ur-Rahman, ed.) Vol. 8, pp.
`315-357, Elsevier. Amsterdam, 1991). For example. the
`heteroatom of the sugar ring can be either oxygen or sulfur,
`or the linkage between monosaccharides in an oligosaccha
`ride can be oxygen or sulfur (Horton, D. and Wander, J. D.,
`"I‘hio Sugars and Derivatives.” The Carbohydrates: Chem
`istry and Biochemistry, 2d. Ed. Vol. [8, (W. Reyman and D.
`Horton eds.). pp. 799-842, (Academic Press, New York),
`(1972)). Oligosaccharides can have either ot (alpha) or [5
`(beta) anomeric con?guration (see Pacsu, E.. et al. in Meth
`ods in Carbohydrate Chemistry (R. L. Whistler. et al.. eds.)
`Vol. 2. pp. 376-385. Academic Press. New York 1963).
`Many alkyl glycosides can be synthesized by known
`procedures. i.e., chemically, as described, e.g.. in Rosevear
`et al.. Biochemistry 19:4108-4115 (1980) or Koeltzow and
`Urfer. J. Am. Oil Chem. Soc., 61:1651-1655 (1984). US.
`Pat. No. 3.219.656 and US. Pat. No. 3.839.318 or
`enzymatically. as described. e.g., in Li et al.. J. Biol. Chem,
`266:10723-10726 (1991) or Gopalan et al.. J. Biol. Chem.
`267:9629-9638 (1992).
`The linkage between the hydrophobic alkyl and the
`hydrophilic saccharide can include. among other
`
`6
`possibilities. a glycosidic, thioglycosidic (Horton), amide
`(Carbohydrates as Organic Raw Materials, F. W. Licht
`enthaler ed., VCH Publishers. New York, 1991). ureide
`(Austrian Pat. 386,414 (1988); Chem. Abstr. 110:137536p
`(1989); see Gruber. H. and Greber, G.. “Reactive Sucrose
`Derivatives” in Carbohydrates as Organic Raw Materials.
`pp. 95-116) or ester linkage (Sugar Esters: Preparation and
`Application, J. C. Colbert ed., (Noyes Data Corp., New
`Jersey). (1974)).
`Examples from which useful alkyl glycosides can be
`chosen for the therapeutic composition include: alkyl
`glycosides, such as octyl-, nonyl-, decy1-, undecyI-,
`dodecyl-, tridecyl-, tetradecyl. pentadecyl-, and octadecyl ot
`or [S-D-maltoside, -glucoside or -sucroside (synthesized
`according to Koeltzow and Urfer; Anatrace Inc., Maumee,
`Ohio; Calbiochem, San Diego, Calif; Fluka Chemie,
`Switzerland); alkyl thiomaltosides, such as heptyl, octyl,
`dodecyl-, tridecyI-, and tetradecyl-B-D-thiomaltoside
`(synthesized according to Defaye. J. and Pederson, C.,
`“Hydrogen Fluoride, Solvent and Reagent for Carbohydrate
`Conversion Technology” in Carbohydrates as Organic Raw
`Materials, 247-265 (F. W. Lichtenthaler, ed.) VCH
`Publishers, New York (1991); Ferenci. T., J. Bacteriol,
`144:7-11 (1980)); alkyl thioglucosides, such as heptyl- or
`octyl l-thio ot- or B-D-glucopyranoside (Anatrace, Inc.,
`Maumee, Ohio; see Saito, S. and Tsuchiya, T. Chem. Pharm.
`Bull. 33:503-508 (1985)); alkyl thiosucroses (synthesized
`according to. for example, Binder, T. P. and Robyt, J. F.,
`Carbohydr. Res. 14029-20 (1985)); alkyl maltotriosides
`(synthesized according to Koeltzow and Urfer); long chain
`aliphatic carbonic acid amides of sucrose [i-arnino-alkyl
`ethers; (synthesized according to Austrian Patent 382,381
`(1987); Chem. Abstr., 1082114719 (1988) and Gruber and
`Greber pp. 95-116); derivatives of palatinose and isomal
`tamine linked by amide linkage to an alkyl chain
`(synthesized according to Kunz, M., “Sucrose-based Hydro
`philic Building Blocks as Intermediates for the Synthesis of
`Surfactants and Polymers” in Carbohydrates as Organic
`Raw Materials, 127-153); derivatives of isomaltamine
`linked by urea to an alkyl chain (synthesized according to
`Kunz); long chain aliphatic carbonic acid ureides of sucrose
`B-amino-alkyl ethers (synthesized according to Gruber and
`Greber, pp. 95-116); and long chain aliphatic carbonic acid
`amides of sucrose B-amino-alkyl ethers (synthesized accord
`ing to Austrian Patent 382,381 (1987), Chem. Abstrz,
`1082114719 (1988) and Gruber and Greber, pp. 95-116).
`Some preferred glycosides include maltose. sucrose, and
`glucose linked by glycosidic linkage to an alkyl chain of 9,
`10, 12 or 14 carbon atoms, i.e., nonyl-, decyl-, dodecyl- and
`tetradecyl sucroside, glucoside, and maltoside. These com
`positions are nontoxic, since they are degraded to an alcohol
`and an oligosacchan'de, and amphipathic.
`The above examples are illustrative of the types of
`glycosides to be used in the methods claimed herein; the list
`is not exhaustive. Derivatives of the above compounds
`which ?t the criteria of the claims should also be considered
`when choosing a glycoside. All of the compounds can be
`screened for e?icacy following the methods taught in the
`examples.
`Preferred concentrations of alkyl glycosides are those
`within the range of 0.01-1%, as such low concentrations
`reduce any potential irritability or damage to the tissues
`while still increasing absorption. Even more preferred are
`concentrations within the range of 0.125-0.5%. From a
`medical standpoint, the less absorption enhancer used, that
`is still as effective as desired. the better for the subject.
`The method of this invention can also include the
`administration. along with the alkyl glycoside and a protein
`
`AQUESTIVE EXHIBIT 1020 page 0004
`
`

`

`5,661,130
`
`10
`
`15
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`20
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`25
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`35
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`45
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`7
`or peptide. a protease or peptidase inhibitor, such as
`aprotinin, bestatin, alphal proteinase inhibitor, recombinant
`secretory leucocyte protease inhibitor, captopril and other
`angiotensin converting enzyme (ACE) inhibitors and
`thiorphan, to aid the protein or peptide in reaching its site of
`activity in the body in an active state (i.e., with degradation
`minimal enough that the protein is still able to function
`properly). The protease or peptidase inhibitor can be mixed
`with the alkyl glycoside and compound and then
`administered, or it can be administered separately, either
`prior to or after administration of the glycoside and com
`pound.
`The amount of compound administered will, of course, be
`dependent on the subject being treated. the subject’s weight.
`the severity of symptoms and the judgment of the prescrib
`ing physician. Generally. however, dosage will approximate
`that which is typical for known methods of administration of
`the speci?c compound. For example, for intranasal admin
`istration of insulin. an approximate dosage would be about
`0.5 unit/kg regular porcine insulin (Moses et al.). Dosage for
`compounds affecting blood glucose levels optimally would
`be that required to achieve proper glucose levels, for
`example, to a normal range of about 5-6.7 mM.
`Additionally, an appropriate amount may be determined by
`one of ordinary skill in the art using only routine testing
`given the teachings herein (see Examples).
`The compound can be administered in a format selected
`from the group consisting of a drop. a spray, an aerosol and
`a sustained release format. The spray and the aerosol can be
`achieved through use of the appropriate dispenser. The
`sustained release format can be an ocular insert, erodible
`microparticulates, swelling mucoadhesive particulates, pH
`sensitive microparticulates, nanoparticles/latex systems,
`ion-exchange resins and other polymeric gels and implants
`(Ocusert, Alza Corp., California; J oshi, A.. S. Ping and K. J.
`Himmelstein, Patent Application WO 91/19481). These sys
`tems maintain prolonged drug contact with the absorptive
`surface preventing washout and nonproductive drug loss.
`Also provided is a method of lowering blood glucose
`level in a subject comprising administering via the ocular,
`nasal, nasolacrimal or inhalation route, a blood glucose
`reducing amount of a composition comprising insulin and an
`absorption increasing amount of a suitable nontoxic, non
`ionic alkyl glycoside having a hydrophobic alkyl joined by
`a linkage to a hydrophilic saccharide, thereby increasing the
`absorption of insulin and lowering the level of blood glu
`cose. A “blood glucose-reducing amount” of such a com
`position is that amount capable of producing the effect of
`reducing blood glucose levels, as taught herein. Preferred is
`an amount that decreases blood glucose to norrnoglycemic
`or near normoglycemic range. Also preferred is an amount
`that causes a sustained reduction in blood glucose levels.
`Even more preferred is an amount su?icient to treat diabetes
`mellitus by lowering blood glucose level. Thus. the instant
`method can be used to treat diabetes mellitus. Preferred alkyl
`glycosides are the same as those described above and
`exempli?ed in the Examples.
`Also provided is a method of raising blood glucose level
`in a subject comprising administering via the ocular. nasal.
`nasolacrimal or inhalation route a blood glucose-raising
`amount of a suitable composition comprising glucagon and
`an absorption increasing amount of a suitable nontoxic,
`nonionic alkyl glycoside having a hydrophobic alkyl joined
`by a linkage to a hydrophilic saccharide, thereby increasing
`the absorption of glucagon and raising the level of blood
`glucose. A “blood glucose-raising amount” of such a com
`position is that amount capable of producing the effect of
`
`55
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`60
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`65
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`8
`raising blood glucose levels. Preferred is an amount that
`increases blood glucose to normoglycemic or near
`normoglycemic range. Also preferred is an amount that
`causes a sustained raising of blood glucose levels. Even
`more preferred is an amount su?icient to treat hypoglycemia
`by raising blood glucose level. Thus this method can be used
`to treat hypoglycemia. Preferred alkyl glycosides are the
`same as those described above and exempli?ed in the
`Examples.
`Also provided is a composition comprising (a) a nontoxic,
`nonionic alkyl glycoside having a hydrophobic alkyl joined
`by a linkage to a hydrophilic saccharide, in concentration in
`the range of 0.01% to 1.0%, capable of increasing absorption
`of a compound into the circulatory system of a patient and
`(b) an agent selected from the group consisting of insulin
`and glucagon. When this composition includes insulin. it can
`be used to cause the lmown effect of insulin in the
`bloodstream. i.e., lower the blood glucose levels in a subject,
`by administering it by, for example, the administration
`means of this invention, i.e., via the ocular, nasal, nasolac
`rimal or inhalation route. Such administration can be used to
`treat diabetes mellitus. using the concentrations of insulin
`known to those of skill in the art to properly lower blood
`glucose.
`Similarly, when this composition includes glucagon. it
`can be used to cause the known effect of glucagon in the
`bloodstream i.e., to raise the blood glucose levels in a
`subject. Such administration can therefore be used to treat
`hypoglycemia, including hypoglycemic crisis.
`The present invention is more particularly described in the
`following examples which are intended as illustrative only
`since numerous modifications and variations therein will be
`apparent to those skilled in the art.
`EXAMPLES
`Hypoglycernic Effects of Insulin Delivered by the Ocular
`Route
`All of the experimental results described were obtained in
`normal rats in which blood glucose values have been
`elevated as a consequence of anesthesia produced by
`xylazine/ketamine. This mimics the hyperglycemic state
`seen in diabetic animals and humans. The elevated levels of
`D~glucose that occur in response to anesthesia provide an
`optimal system in which to measure any systemic hypogly
`cemic action of insulin-containing eye drops. Hence, anes
`thetized rats given eye drops containing insulin can be
`compared to anesthetized animals given eye drops without
`insulin, and the differential systemic responses should accu
`rately re?ect the effect of insulin absorbed via the ocular
`route of administration.
`Adult male Sprague-Dawley rats (250-350g) were fed ad
`libitum, and experiments were conducted between 10:00
`am. and 3:00 pm. Rats were anesthetized with a mixtu