PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`
`(51) International Patent Classification 5 :
`(11) International Publication Number:
`WO 94/12153
`A61K 9/08, 9/10, 31/195, 47/38
`
`
`9 June 1994 (09.06.94)
`(43) International Publication Date:
`
`
`(21) International Application Number:
`
`(22) International Filing Date:
`
`PCT/SE93/01029
`'
`-
`29 November 1993 (29.11.93)
`
`(30) Priority Data:
`9203594—8
`
`30 November 1992 (30.11.92)
`
`SE
`
`(81) Designated States: AT, AU, BB, BG, BR, BY, CA, CH, CZ,
`DE, DK, ES, FI, GB, HU, JP, KP, KR, KZ, LK, LU, LV,
`MG, MN, MW, NL, NO, NZ, PL, PT, RO, RU, SD, SE,
`SK, UA, US, UZ, VN, European patent (A , BE, CH, DE,
`DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI
`patent (BF, BJ, F, CG, CI, CM, GA, GN, ML, MR, NE,
`SN, TD, TG).
`
`(71)(72) Applicants and Inventors: NYSTROM, Christer [SE/SE]; Published
`Holmvagen 22 B, 8-756 51 Uppsala (SE). PAALZOW,
`With international search report.
`Lennart [SE/SE]; Kyrkogérdsgatan 11, S-753 10 Uppsala
`With amended claims.
`(SE). AQUILONIUS, Sten-Magnus [SE/SE]; Ropstensvagen
`6, 8-193 31 Sigtuna (SE).
`
`(74) Agents: ONN, Thorsten et a1.; AB Stockholms Patentbyré,
`Zacco & Bruhn, PO. Box 23101, 8-104 35 Stockholm (SE).
`
`
`
`
`(54) Title: A PHARMACEUTICAL FORMULATION
`
`1,2
`
`
`
`
`
`1
`
`\
`
`‘1-
`
`
`
`
`1,0
`
`0:8
`
`
`
`Levodopaoonwntration(Hg/ml)
`
`——0— Infusion 1
`———o—— Infusion 2
`
`8 am
`
`noon
`
`4 pm
`
`(57) Abstract
`
`A pharmaceut'lml formulation for inuaduodenal administration cmprising at least one pharmacologically active agent, with limited
`solubility in water and is dispersed in an aqueous carrier. According to the invention, the active agent has a particle size not exceeding 20
`um, and the aqueous carrier has a viscosity of at least 300 mPas, measured at a moderate shear rate.
`
`
`
`
`
`

`

`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCI‘ on the fi'ont pages of pamphlets publishing international
`applications under the PCT.
`
`AT
`AU
`BB
`BE
`BF
`36
`3.]
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`CS
`CZ
`DE
`DK
`B
`F1
`FR
`GA
`
`.
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`COte d'lvoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Spain
`Finland
`France
`Gabon
`
`_
`
`GB
`GE
`GN
`GR
`BU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People‘s Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`MR
`MW
`NE
`N'L
`N0
`NZ
`PL
`PT
`R0
`RU
`SD
`SE
`SI
`SK
`SN
`TD
`TG .
`TJ
`IT
`UA
`US
`UZ
`VN
`
`Mauritania
`Malawi
`Niga
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Fedaan‘on
`Sudan
`Sweden
`Slovenia
`Slovakia
`Senegal
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`United States of Amaica
`Uzbekistan
`Viet Nam
`
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`W0 94/12153
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`l
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`PCT/SE93/01029
`
`A Pharmaceutical formulation
`
`The present invention relates to a pharmaceutical
`
`formu—
`
`lation for intraduodenal administration. More specifically,
`
`the
`
`invention relates to such a formulation comprising at least one
`
`pharmacologically active agent having a limited solubility in
`
`water. Still more specifically,
`
`the invention relates to such a
`
`formulation for the treatment of Parkinson‘s disease and
`
`comprising L—DOPA or an agent having similar properties. The
`
`term "limited solubility" is used in this patent application to
`
`refer to substances with low solubility in water and pharma—
`
`cologically active substances for wich the therapeutically
`
`active unit dose exceeds the solubility in water. The solubili—
`
`ty of L—DOPA in water is about 5 mg/ml, and this patent covers
`
`drugs with both lower and higher solubility compared to L-DOPA.
`
`L-DOPA (L—3,4-dihydroxyphenyalanine) has found a wide use
`
`for the treatment of patients suffering from Parkinson’s
`
`disease, and good results are usually achieved by such a
`
`treatment. However, it is important in such a treatment that a
`
`stable level of the active agent is maintained in the patient’s
`
`blood, and this has often been difficult to achieve in more
`
`conventional ways of administration, such as orally by tablets
`
`or capsules.
`
`It has also been difficult to prepare liquid dosage forms
`
`of administration, as the compound L-DOPA has a very low
`
`solubility in water, so that large volumes of liquid have to be
`
`administered in order to give the patient an adequate dose.
`
`In
`
`seVeral reports,
`
`the use of intraduodenal administration of
`
`aqueous solutions of drugs have shown several advantageous
`
`features as compared to oral administration of both tablets,
`
`suspensions and solutions (e.g. Watari et al., J. Pharmaco—
`
`kinet. Biopharm, Oct. 1983 11 (5), p- 529—545). Especially,
`
`the
`
`variation of drug plasma concentration was substantially
`
`reduced by using the intraduodenal route, mainly due to
`
`avoidance of the effect of variations in gastric emptying
`
`the
`times. However, for drugs with limited solubility in water,
`drug in suspended form is also an interesting possibility for,
`intraduodenal administration. Furthermore,
`the compound L-DOPA
`
`is quite sensitive to oxidation and will decompose in solutions
`
`which are in contact with atmospheric air. These problems have
`
`practically ruled out the use of aqueous solutions of L—DOPA in
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`therapy.
`
`PCT/SE93/01029
`
`To eliminate the disadvantages mentioned, L—DOPA has been
`
`administered intraduodenally by an intraduodenal catheter
`
`through the abdominal wall of the patient, or by a naso—duode—
`
`nal catheter. The formulation administered has then consisted
`
`of a suspension of L—DOPA in an aqueous carrier,
`
`thereby
`
`avoiding the problem of the low drug solubility. This method
`
`has given very good results as regards the maintaining of a
`
`stable level of L—DOPA in the patient’s blood. But,
`
`to obtain a
`
`useful preparation still two further problems have to be
`
`considered. First,
`
`the risk of sedimentation of drug particles
`
`during storage and administration (referred to in this patent
`
`as the physical stability). Secondly,
`of L-DOPA due to oxidation.
`
`the chemical instability
`
`Through the present invention,
`
`the drawbacks mentioned
`
`above are eliminated to a large extent. According to the
`
`invention a pharmaceutical formulation for intraduodenal
`
`administration is provided, comprising at least one pharmacolo—
`
`gically active agent with a limited solubility in an aqueous
`
`carrier. What characterizes the invention is that the pharmaco—
`
`logically active agent has a particle size not exceeding 20 um,
`
`and that the aqeuous carrier has a viscosity of at least 300
`
`mPas, measured at a moderate shear rate. These two charac-
`
`teristics have to be carefully controlled to produce an suspen—
`
`sion with acceptable physical stability.
`
`Preferably,
`
`the active agent has a particle size within
`
`the range 0.1 to 20 um, and especially then between 0.1 and 5
`pm.
`
`The active agent is preferably L-DOPA and at least one of
`
`the agents, carbidopa or benserazide. It is preferably present
`
`in the formulation in an amount from 0.01 up to 20 weight
`
`percent, and especially then from 1 to 5 weight percent.
`
`In a preferred embodiment of the invention,
`
`the pharma—
`
`ceutical formulation is filled and stored under exclusion of
`
`oxygen.
`
`Through the present invention it has become possible to
`achieve a highly advantageous therapeutic effect against
`Parkinson’s disease by the intraduodenal administration of
`
`L—DOPA which has a very low solubility in water. The chemical
`
`stability of L-DOPA in an aqueous medium is also improved in a
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`PCT/SE93/01029
`
`highly unexpected degree by this invention.
`
`In the drawing, Figure 1 shows a graph over the plasma
`
`concentration of L—DOPA as a function of the time after
`
`repeated administrations of tablets of a prior art formulation
`
`of L-DOPA. Figure 2 shows the plasma concentrations of L—DOPA
`
`as a function of the time after intraduodenal infusion of an L—
`
`DOPA preparation according to the present invention.
`
`The use of a very fine particle size for the pharmaceuti—
`
`cal agent in the present invention must not be confused with
`
`the prior art use of pharmaceutical agents such as griseoful—
`vin,
`in a finely divided form. This prior art use has only
`
`served to increase the rate of dissolution and as a consequence
`
`the bioavailability of the active agent, and in this case, a
`
`high viscosity of the formulation has not been desired, as it
`
`could result in reduced bioavailability. Thus,
`
`the object of
`
`using a very fine particle size in the formulations of the
`
`present invention is not to achieve an increased bioavailabili-
`
`ty, but to increase the physical stability of the formulation.
`
`In the present formulation this was achieved by the use of a
`
`very fine particulate quality of the drug in combination with
`
`the viscous aqueous medium. It was also unexpected that the
`
`chemical stability of L-DOPA was acceptable in this aqueous
`medium. The good chemical stability was achieved by the exclu—
`sion of atmospheric oxygen and the use of an aqueous medium of
`
`high viscosity.
`
`In the work with the present invention the so-called
`
`volume diameter by weight as measured by the Coulter technique
`
`the particle size distribution mayr
`has been used. Furtherfmore,
`not only be calculated on a weight basis, but can also be
`
`expressed by number,
`
`length and surface, where the values will
`
`be lower than those given in the present description of the
`invention.
`'
`
`An alternative method of expressing particle fineness is
`
`the specific surface area, normally expressed as nF/g.
`
`In the
`
`present case such measurements have been carried out by a gas
`permeability technique. These values may be said to correspond
`
`to the external or envelop surface area of the particles.
`Expressed in this manner,
`the maximum particle size given above
`(20 um) would correspond to a value of at least 0.5 nfi/g. The
`
`interval 0.1 to 20 um would correspond to an interval of 0.5 to
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`PCT/SE93/01029
`
`25 nfi/g. As stated above,
`
`the pharmacologically active agent
`
`should be suspended in an aqueous carrier having a viscosity of
`
`at least 300 mPas, measured at a moderate shear rate, and
`
`preferably being of a plastic or pseudoplastic nature. The
`
`plastic or pseudoplastic properties means that the vehicle or
`
`carrier will lower its viscosity during agitation, i.e.
`
`so—
`
`called shear thinning. This reduction in viscosity makes the
`
`liquid aqueous carrier more easy to pump through tubes with a
`
`small inner diameter of the type used in this invention. The
`
`degree of plasticity or pseudoplasticity can be expressed by
`
`several measures, according to well establiShed and documented
`
`principles reported in the
`
`literature. Generally when a
`
`reference is made to a viscosity value in this invention,
`
`the
`
`value refers to the viscosity when the liquid carrier is
`
`moderately agitated, corresponding to a shear rate of less than
`
`approximately 500 s'1 but higher than approximately 20 s'1 i.e.
`
`the viscosity when the carrier is almost at rest. A typical
`
`shear rate representing such a condition at rest is 5 5*.
`
`Such a carrier is usually an aqueous dispersion or solu-
`
`tion of,a pharmaceutically acceptable colloid, such as a
`
`water-soluble or water-swellable colloid of the carbohydrate or
`
`polysaccharide type or of a synthetic or semi-synthetic nature.
`
`As examples of such colloids may be mentioned cellulose ethers
`
`and other derivatives, such as methyl cellulose, carboxymethyl
`
`cellulose and sodium carboxymethyl cellulose, starchesnand
`
`starch derivatives, and plant gums and colloids such as Xantan
`
`gum, Guar gum, pectin, agar, alginates, dextran and other
`
`polysaccharides and derivatives thereof. Furthermore, water-
`
`soluble and water-swellable colloids of a synthetic or semi-
`
`synthetic origin may also be used, such as carbomers (carboxy-
`
`polymethylenes,
`
`trade name Carbopol®), provided that they are
`
`pharmaceutically acceptable for the duodenal administering
`
`system.
`
`The aqueous carrier should preferably have a viscosity at
`
`moderate agitation (shear rates between 20 and 500 5*) within
`
`the range from 300 to 5000 mPas and especially then within the
`
`range from 500 to 2000 mPas. For higher agitation intensities
`
`(shear rate higher than 500 s”)
`
`the viscosity should preferably
`
`be within the range from 10 to 1000 mPas, and especially then
`
`within the range from 50 to 500 mPas. A suitable viscosity may
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`PCT/SE93/01029
`
`be obtained by adjusting the molecular weight of the colloid
`used into a suitable range. The molecular weight
`in its turn
`may be adjusted by selecting a suitable degree of polymer-
`ization, as is well—known to those skilled in the art. Further—
`
`more,
`
`the Viscosity may be adjusted by selecting a suitable
`
`concentration of the colloid in the aqueous system.
`
`The preferred colloids to be used in the aqueous carrier
`
`are methyl cellulose, sodium carboxymethyl cellulose, carboxy-
`methyl cellulose and carbomers (carboxypolymethylenes,
`trade
`name Carbopol®).
`
`The formulation of the invention is prepared by dis—
`persing the active agent finely in the aqueous carrier using
`methods and apparatus which are well-known to those skilled in
`
`the art. It has turned out to be unexpectedly easy to achieve
`
`the necessary fine dispersion. This is a further important
`advantage of the invention.
`
`The formulations of the invention may contain other
`
`additional agents which are well-known to those skilled in the
`
`art. As examples of such agents may be mentioned stabilizers,
`antioxidants, preserving agents and pH regulating agents. Such
`additional agents may be added to the formulations before,
`during or after the dispersion process.
`
`The prepared formulations of the invention are sub—
`
`sequently dispensed into suitable containers for intraduodenal
`
`administration. Such containers may have a volume of about 100
`
`ml, which in the evaluations performed has been a suitable
`volume of 2 weight percent h—DOPA for successful treatment of
`adult patients suffering from severe Parkinson‘s disease. The
`
`dose to be administered during a given period of time is
`
`determined by the physician on the basis of such criteria as
`
`the age and Weight of the patient,
`tion, and the like.
`
`the severity of the condi—
`
`As has been stated above, it is an important feature of
`
`the invention that the formulations are prepared and stored
`under exclusion of oxygen. Thus,
`the formulation may be dis—
`pensed into bag-like containers of a plastic sheet material
`having a low permeability for oxygen. Furthermore,
`the filling
`of these containers may be carried out in such a manner that
`
`all air is first sucked out of the containers, after which the
`
`desired amount of the dispersion is pumped into the containers,
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`PCT/SE93/01029
`
`and the containers are subsequently sealed. The containers are
`
`also provided with an outlet conduit, which is initially
`
`sealed, and is only opened immediately before the conduit is
`
`connected to a catheter for intraduodenal administration. By
`this arrangement,
`the container may also be emptied completely
`without any need for an air valve in the container.
`
`The container with the formulation of the invention is
`
`usually placed in a type of cassette adapted to be carried by
`the patient. Such cassettes are previously known, and are
`
`provided with a pumping device for administering a metered
`
`amount of the formulation over a given time.
`
`In a test,
`the stability was compared between a suspen—
`sion of L-DOPA prepared in accordance with the present inven-
`
`tion which had been stored under complete exclusion of air, and
`
`an aqueous suspension which had been stored in a container
`
`containing a certain amount of air. After ten weeks of storage,
`the amount of undegraded L—DOPA in the container which con-
`
`tained air had decreased to 75 %, while no degradation could be
`
`observed of the L-DOPA which had been stored under complete
`exclusion of air.
`
`Tests have also shown that it is the oxygen present in
`air above the suspension which is most responsible for the
`
`degradation. Oxygen dissolved in the aqueous phase only seems
`to be of minor importance for the degradation process.
`
`In foregoing specification,
`
`the invention has been
`
`described mainly with reference to L—DOPA as the pharmacologi-
`cally active agent. However, it is to be noted that the in-
`
`vention is not restricted to this agent only, but is applicablev
`to all cases where a pharmacologically active agent with
`
`limited solubility in water or which is more stable in dis-
`
`persed form is to be administered as a water based suspension.
`
`The present invention is further described below by two
`examples,
`including graphs with clinical results. However,
`the
`possible range of design and formulation of the present in-
`vention is not by any means limited to the given examples.
`mm
`
`In this example the active ingredients L—DOPA and carbi-
`
`dopa have been suspended in a viscous water solution of methyl
`cellulose and subsequently administered intraduodenally by a
`portable pump. The active ingredients L—DOPA and carbidopa were
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`7
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`PCT/SE93/01029
`
`dry milled in a high speed, double rotating pin disc mill
`
`(Alpine 63C, Germany). The degree of fineness of the milled
`
`drugs was tested by a permeametric technique (Alderborn, Duberg
`
`and Nystrom, Powder Technol. 41:49 (1985)), and found to be 1.3
`
`mz/g.
`
`It should here be noted that also other milling
`
`techniques, well known to the expert in the field, could be
`
`used to obtain the high degree of particulate fineness needed.
`
`The milled drugs were then suspended in a 1.8 weight
`
`percent water solution of methylcellulose—lsoo (quality E) at
`
`room temperature (22i2°C). The viscosity of the methyl cellu-
`
`lose solution was determined at a shear rate of approximately
`20 s‘1 to 1300 mPas. To achieve an adequate deagglomeration,
`the
`
`suspension was agitated by a magnetic stirrer and subsequently
`
`sonificated for two minutes. The concentrations of L-DOPA and
`
`carbidopa were 2.0 and 0.5 weight percent, respectively.
`
`The well-dispersed suspension was then filled in
`
`cassettes (with a flexible plastic bag) of 100 ml. Prior to
`filling the bags are evacuated, resulting in a minute head
`space and thus oxygen content of the filled casssette. The
`
`cassettes were then stored in a refrigerator for no longer than
`
`48 hours. This short storage time is however not a necessary
`
`requisite for the use of the present invention. On the contra-
`
`ry, it has been shown that chemical stability (mainly avoidance
`
`of oxidation of the active ingredients) could be maintained for
`
`longer than two months, without any significant degradation or
`
`even darkening of the suspension. Regarding the physical
`
`stability (sedimentation of suspended drug particles) it is
`
`related to the combination of drug particles fineness and the
`viscosity of the dispersion medium. For the present example no
`
`significant sedimentation was noted.
`
`The clinical effects of the present invention was com-
`
`pared with the conventional therapy with oral administration of
`
`Sinemet® tablets and Sinemet® depot tablets. Sinemet® is a
`
`registered trademark for a preparation of L-DOPA and carbidopa
`
`from Merck Sharp and Dohme, USA. The results are presented in
`
`Figures 1 and 2 of the drawing. The results show that the
`
`plasma concentrations of L-DOPA after administration of the
`
`tablet formulations varied substantially with high peak con—
`
`centrations after each tablet intake followed by a rapid fall
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`PCT/SE93/01029
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`of the concentrations until intake of next dose. Pronounced
`
`variations in the blood concentration profiles between and also
`
`within individuals is a complicating factor in the treatment of
`
`Parkinson’s disease. These variations are to a great deal
`
`caused by variations in gastric emptying times.
`
`After intraduodenal administration of the present in-
`
`vention the plasma concentrations of L—DOPA were stable during
`the period of administration.
`
`The patients mobility was better, with lower incidence of
`
`both hypomotility and hypermotility when L—DOPA was given as
`intraduodenal infusions during daytime compared to the patients
`
`optimized oral treatment with Sinemet® tablets.
`
`Exempel 2
`
`To further illustrate the possibility to obtain a physi-
`
`cally stable preparation,
`carrier was tested.
`
`the use of a pesudoplastic aqueous
`
`The physical stability of a L—DOPA suspension, prepared
`
`from 0,3 % w/w % Carbopol® 934p and 2 w/w % L—DOPA was in—
`
`vestigated during 14 days. The suspension was prepared in a way
`similar to that in Example 1. Four cassettes of the suspension
`
`were prepared, and two cassettes were stored at 37°C and the
`
`other two at room temperature. During the entire experiment
`
`period no agitation was applied,
`
`in order to simulate sedimen-
`
`tation during shelf storage of the suspension. Duplicate
`
`samples were collected and their concentrations of L—DGPA were
`
`determined. The results are given in Table 1. The concentra-
`
`tions of L—DOPA were assayed using an HPLC method with elec-
`trochemical detection.
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`Table 1
`
`(w/w) of L—DOPA suspension
`%
`Physical stability of a 2
`with 0.3 %
`(w/w) Carbopol® 934p as carrier. Mean (SD)
`
`Day of assay
`
`Temperature
`(°C)
`
`0
`
`1
`
`2
`
`7
`
`14
`
`‘
`
`20
`37
`
`20
`37
`
`20
`37
`
`20
`37
`
`,
`
`Conc L—DOPA
`% w/w (SD)
`
`1.87 (0.07)
`
`1.99 (0.12)
`1.99 (0.18)
`
`1.96 (0.05)
`1.99 (0.09)
`
`1.92 (0.05)
`1.92 (0.06)
`
`2.02 (0.04)
`2.06 (0.04)
`
`The result in Table 1 clearly show that no sedimentation
`
`of L—DOPA particles took place during the test period of 14
`days. At the same time the suspension based on Carbopol® 934P
`was easy to pump through tubing of the same inner diameter as
`
`o\°
`
`those used in the clinical application of this invention.
`In
`fact, Carbopol® 934P at concentrations much higher than 0.3
`(w/w) could be pumped without any problems, although this
`concentration clearly was sufficient to maintain the L—DOPA in
`suspension. This combined effect of Carbopol® 934P and other
`plastic or pseudoplastic carriers is due to the so called shear
`thinning effect. When at rest these carriers posses a highly
`viscous structure while this structure is changed instantane-
`ously upon application of agitation forces such as pumping.
`These results demonstrate that by the use of the present
`invention it is possible to administer high doses of drugs with
`limited solubility using a small volume of an aqueous carrier
`(in this example 100 ml) of the formulated drug. The un—
`expectedly small variations in the plasma concentrations after
`intraduodenal infusion according to the present invention was
`achieved by using an extremely fine particulate quality of the
`drugs in combination with a high viscosity of the dispersion
`medium at rest.
`
`Thus this invention not only facilitates the admi-
`nistration of high doses for long time infusions of drugs with
`limited solubulity in water. Administration of L—DOPA prepared
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`4O
`
`45
`
`

`

`W0 94/12153
`
`lO
`
`PCT/SE93/01029
`-
`
`with techniques described in this patent application also
`
`resulted in superior clinical effects in patients suffering
`from severe Parkinson’s disease.
`
`

`

`W0 94/12153
`
`PCT/SE93/01029
`
`.l .1
`
`Claims
`
`1.
`
`A pharmaceutical formulation for intraduodenal administration, comprising at
`
`least one pharmacologically active agent which has a limited solubility in water and which
`
`is suspended in an aqueous carrier, characterized in that said active agent has a particle
`
`size not exceeding 20 um, and that said carrier has a viscosity of at least 300 mPas, as
`
`measured at a moderate shear rate.
`
`2.
`
`A formulation according to claim 1, characterized in that the active agent has a
`
`10
`
`particle size in the range of 0.1 to 20 ,um, preferably then 0.1 to 5 pm.
`
`3.
`
`A formulation according to claim 1 or 2, characterized in that the active agent is
`
`L-DOPA and at least one of the agents carbidopa and benserazide.
`
`15
`
`4.
`
`A formulation according to any of claims 1—3, characterized in that it contains the
`
`active agent in an amount from 0.01 up to 20 weight percent, preferably then 0.1 to 5
`
`weight percent.
`
`5.
`
`A formulation according to any of claims 1-4, characterized in that the carrier is
`
`an aqueous dispersion or solution of a water—soluble or water-swellable colloid of the
`
`carbohydrate or polysaccharide type, or of a synthetic or semi-synthetic origin:—
`
`6.
`
`A formulation according to claim 5, characterized in that the carrier is of a plastic
`
`or pseudoplastic nature.
`
`20
`
`25
`
`7.
`
`A formulation according to claim 6, characterized in that the carrier is a solution
`
`of methyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose or carboxy-
`
`polymethylene, or a mixture of any of these materials.
`
`30
`
`8.
`
`A formulation according to any of claims 5-7, characterized in that the carrier has
`
`a viscosity, as measured at a moderate shear rate, in the range of 300 to 5000 mPas,
`
`preferably then 500 to 2000 mPas.
`
`

`

`W0 94/ 12153
`
`PCT/SE93/01029
`
`12
`
`'
`
`9.
`
`A formulation according to any one of claims 1—8, containing L—DOPA and at
`
`least one of the compounds carbidopa and benserazide as the active agents for the
`
`treatment of Parkinson ’5 disease.
`
`

`

`WO 94/12153
`
`.
`
`l3
`
`AMENDED CLAIMS
`
`PCT/SE93/01029
`
`[received by the International Bureau on 27 April 1994 (27.04.94);
`original claim 1 amended; remaining claims unchanged (1 page)]
`
`1.
`
`A pharmaceutical formulation for intraduodenal administration, comprising at
`
`least one pharmacologically active agent which has a low solubility in water and which is
`
`suspended in an aqueous carrier, characterized in that said active agent has a particle size
`
`not exceeding 20 um, and that said carrier has a viscosity of at least 300 mPas, as
`
`measured at a moderate shear rate.
`
`2.
`
`A formulau'on according to claim 1, characterized in that the active agent has a
`
`10
`
`particle size in the range of 0.1 to 20 um, preferably then 0.1 to 5 pm.
`
`3.
`
`A formulation according to claim 1 or 2, characterized in that the active agent is
`
`L-DOPA and at least one of the agents carbidopa and benserazide.
`
`15
`
`4.
`
`A formulation according to any of claims 1-3, characterized in that it contains the
`
`active agent in an amount from 0.01 up to 20 weight percent, preferably then 0.1 to 5
`
`weight percent.
`
`20
`
`25
`
`5.
`
`A formulation according to any of claims 1-4, characterized in that the carrier is
`
`an aqueous dispersion or solution of a water-soluble or water—swellable colloid of the
`
`carbohydrate or polysaccharide type, or of a synthetic or semi-synthetic origin.
`
`6.
`
`A formulation according to claim 5, characterized in that the carrier is of a plastic
`
`or pseudoplastic nature.
`
`7.
`
`A formulation according to claim 6, characterized in that the carrier is a solution
`
`of methyl cellulose, sodium carboxymethyl cellulose, carboxymethyl cellulose or carboxy-
`
`polymethylene, or a mixture of any of these materials.
`
`30
`
`8.
`
`A formulation according to any of claims 5—7, characterized in that the carrier has
`
`a viscosity, as measured at a moderate shear rate, in the range of 300 to 5000 mPas,
`
`preferably then 500 to 2000 mPas.
`
`AMENDED SHEET (ARTICLE 19l
`
`

`

`W0 94/12153
`
`PCT/81593101029
`
`1/1
`
`1,2
`
`—o———Tab|et 1
`——.——Tablet 2
`
`
`
`
`
`Levodopaconcentration(Hg/ml)
`
`8 am
`
`noon
`
`4 pm
`
`1,2
`
`1,0
`
`0'8
`
`
`
`Levodopaconcentration(Hg/ml)
`
`
`
`——o——|nfusion 1
`———o———lnfusion 2
`
`8 am
`
`noon
`
`4 pm
`
`FIG.2
`
`SUBSTITUTE SHEET
`
`

`

`A CLASSIFICATION OF SUBJECT MATTER
`
`1
`
`International application No.
`
`PCT/SE 93/01029
`
`Minimum documentation searched (classification system followed by classification symbols)
`
`INTERNATIONAL SEARCH REPORT
`
`
`
`
`IPC5: A61K 9/08 A61K 9/10, A61K 31/195, A61K 47/38
`According to International Patent Classification (IPC) or to both national classification and IPC
`B. FIELDS SEARCHED
`
`
`IP05: A61K
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`
`
`SE,DK,FI,N0 classes as above
`Electronic data base consulted during the international search (name of data base and, where practicable. search terms used)
`
`
`
`
`DIALOG: MEDLINE
`EMBASE WPI WPIL
`CLAIMS CA
`
`G._OCUMENTSCONSIDERED TO BE RELEVANT
`Citation of document, with indication, where appropriate, of the relevant passages
`Relevant to claim No.
`
`
`
`
`
`
`
`
`
`
`
`
`
`1980
`GB, A, 1567890 (BOEHRINGER MANNHEIM), 21 May
`(21. 05. 80), see page 1,
`line 1 - page 2, lin e 14,
`examples 3-4, the claims
`
`DE, A, 2416736 (SCHfiNWALD K. ET AL. ),
`17 October 1974 (17.10.74), see page 5,
`page 8,
`line 18, the claims
`
`line 26 -
`
`
`
`DE, A1, 3232873 (F. HOFFMANN- LA ROCHE & C0 AG),
`31 March 1983 (31. 03. 83), see page 1,
`l1ne 11 -
`page 2,
`line 21, the claims
`
`
`
`
`
`
`Special categories of cited documents:
`*
`4
`.
`.
`.
`”A” document defining the general state of the art which is not considered
`
`l
`to be of
`.
`rele
`ee
`
`erlier document but published on or after the international filing date
`.
`.
`.
`.
`.
`.
`document which may throw doubt: on pnonty claim(s) or which Is
`
`cited :1 ambush the publication date of another citation or other
`
`special reason (a: specified)
`'0' document referring to an oral disclosure. use. exhibition or other
`
`means
`
`document published prior to the international filing date but later than
`the priority date claimed
`
`‘13.”
`
`'L'
`
`”P”
`
`
`
`Date of the actual completion of the international search
`
`
`
`
`
`'1'"
`
`
`
`
`
`
`
`
`
`
`
`later document published alter the international filing date or priority
`date and not in conflict with the application but cited to uncle-stand
`-
`~
`-
`-
`1
`the principle or theory underlying the invention
`'X" docm'nent of particular relevance: the claimed invention mnnot be
`'du‘ed novel or cannot be considered to involve an inventive
`coast“ : 1
`r: a" 1: 1t -
`r 1
`alone
`the d
`step
`1‘ talr
`'Y' domment of particular relevance: the claimed invention cannot be
`considered In involve an inventive step when the dome-1! it
`combined with one or more other such documents. such combination
`being °b“°“3 to a person 5km“!“1 the art
`”&' domment member of the same patent family
`
`Date of mailing of the international search report
`
`
`
`18 ~03- 1994
`
`Name and mailing address of the ISA/
`Swedish Patent Office
`
`Box 5055. 8-102 42 STOCKHOLM
`
`Anneli Jonsson
`
`
`Facsimile No. +46 8 666 02 86
`Telethone No.
`+46 8 782 25 00
`
`
`
`Form PCT/ISA/210 (second sheet) (July 1992)
`
`Authorized officer
`
`
`
`

`

`
`ln.
`iiionsl application No.
`
`PCT/SE 93/01029
`
`
`Box 1 Observations where certain claims were found unsenrchablc (Continuation of item I of first sheet)
`
`INTERNATIONAL SEARCH REPORT
`
`
`
`This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:
`
`l. [3 Claims Nos.:
`because they relate to subject matter not required to be searched by this Authority, namely:
`
`
`
` 2.
`
`
`
`
`
`
`
`
`
`1 , 2
`Claims Nos;
`because they relste to puts of the internstional appliation that do not comply with the prescribed requirements to such
`an extent that no meaningful international search can be carried out. specificelly:
`
`See attached sheet!
`
`
`Claims Nos.:
`
`
`because they ere dependent claims and are not drafted in swords-ice with the second and third sentences of Rule 6.4(1).
`
`Box ll Observations where unity of invention is lacking (Continuation of item 2 of first sheet)
`
`This lnternuionsl Searching Authority found multiple inventions in this internstionsl spplication. as follows:
`
` As I.“ required cdditionsl sesrch fees were timely paid by the spplimnt. this intemstional search report covers ell
`searchcble claims.
`
`As all seuehsble claims could be searches without effort justifying In sdditionsl fee. this Authority did not invite payment
`of any additional fee.
`
`
`
` As only some of the required sdditionai search fees were timely paid by the applicant, this international sesrch report
`
`wvers only those clu'ms for which fees were paid, specifically claims Nos;
`
` No required additional search fees were timely paid by the applicant. Consequently. this international search report is
`restricted to the invention first mentioned in the claims; it is covered by claims Nos;
`
`
`
`
`E] The sdditional search fees Were ammpanied by the applicant‘s protesL
` D No protest accompanied the payment of additional search fees.
`
`Run-Ht on Protest
`
`'Form PCT/lSA/210 (continuation of first sheet (1)) (July 1992)
`
`

`

` INTERNATIONAL SEARCH REPORT
`
`Inlemational applimtion No.
`