SCHEDULE A 

Case 3:11-cv-03788-FLW-LHG Document 122-2 Filed 04/23/13 Page 1 of 9 PageID: 2577
(12) United States Patent 

Pettersson et ai. 

(54) PHARMACEUTICAL COMPOSITION FOR 

THE TREATMENT OF ACUTE DISORDERS 

(75) Inventors: Anders Pettersson, Kode (SE); 

Christer Nystrom, Uppsala (SE) 

(73) Assignee: Diabact AB, Uppsala (SE) 

( * ) 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) Appl. No.: 09/787,888 

(22) PCT Filed: Sep.24,1999 

(86) PCTNo.: PCT/SE99/0l687 

§ 371 (c)(l), 

(2), (4) Date: Jun. 8, 200l 

(87) PCT Pub. No.: WOOO/16750 

PCT Pub. Date: Mar. 30, 2000 

(30) Foreign Application Priority Data 

Sep. 24, 1998 (SE) .............................................. 9803240 

(51) Int. CI? ............................ A61K 9/14; A61K 9/16; 

A61K 9/50 

(52) U.S. CI. ....................... 424/489; 424/490; 424/500; 

424/492; 424/493; 424/494; 424/496; 424/497; 

424/435 

(58) Field of Search ................................. 424/440,441, 

424/434, 435, 485, 489, 490, 500 

(56) References Cited 

U.S. PATENT DOCUMENTS 

5,288,498 A * 2/1994 Stanley et al. .............. 424/440 

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US006761910Bl 

(10) Patent No.: 

(45) Date of Patent: 

US 6,761,910 Bl 

Jui. 13,2004 

FOREIGN PATENT DOCUMENTS 

o 144243 6/1985 

o 324 725 A1 * 1/1989 ............ A61K/9/18 

0324725 7/1989 

OTHER PUBLICATIONS 

Fine et ai, An open label study of oral transmucosal fentanyl 

citrate (OTFC) for the treatment of breakthrough cancer 

pain, 1991, Pain, 45, 149-153.* 

Farrar IT et al. "Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment 

of breakthrough pain in cancer patients", 1 N atl Cancer Inst 

(United States) Apr. 15, 1998, vol. 90, No.8, pp 611-6. 

* cited by examiner 

Primary Examiner-lames M. Spear 

Assistant Examiner-Micah-Paul Young 

25 

(74) Attorney, Agent, or Firm-Young & Thompson 

(57) ABSTRACT 

A pharmaceutical composition for the treatment of acute 

disorders is described. The composition comprises an essentially water-free, ordered mixture of at least one pharmaceutically active agent in the form of microparticles which 

are adhered to the surfaces of carrier particles which are 

substantially larger than the particles of the active agent or 

agents, and are essentially water-soluble, in combination 

with the bioadhesion and/or mucoadhesion promoting agent. 

The invention also relates to a method for preparing the 

composition and to the use of the composition for the 

treatment of acute disorders. 

21 Claims, 1 Drawing Sheet 

30 60 120 180 240 

Time (min) 

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u.s. Patent Jui. 13,2004 US 6,761,910 Bl 

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Case 3:11-cv-03788-FLW-LHG Document 122-2 Filed 04/23/13 Page 3 of 9 PageID: 2579
US 6,761,910 B1 

1 

PHARMACEUTICAL COMPOSITION FOR 

THE TREATMENT OF ACUTE DISORDERS 

2 

effects of opiates such as morphine and meperidine. 

However, compared to these opiates, fentanyl exhibits little 

hypnotic activity, rarely induces histamine release, and 

respiratory depression is more short-lived. Fentanyl is cornFIELD OF THE INVENTION S mercially available for intravenous, intrabucchal (lozengetransmucosal) and transdermal administration. 

The present invention relates to a rapidly acting pharmaceutical composition for sublingual administration of a 

pharmaceutical agent, to a method for preparing such a 

composition, and to a method for the treatment of acute 10 

disorders by the use of such a composition. 

BACKGROUND OF THE INVENTION 

Following parenteral administration of fentanyl, the analgesic action is more prompt and less prolonged than that of 

morphine and meperidine. The onset of analgesia following 

i.v. administration is rapid. Peak analgesia is obtained within 

a few minutes. Following transbucchal administration by a 

lozenge, consumption of the lozenge is usually complete 

within 30 min and peak plasma concentrations appear after 

Acute and/or severe disorders are a common cause of around 20 minutes, as described by e.g. Farrar et aI., 1. NatI. 

emergency treatment or hospitalization. One of the most 

common disorders of this type is acute or breakthrough pain. 

15 Cancer Inst., 1998, 90(8), p. 611-616. Analgesia is apparent 

within 5-15 min and peaks at about 20-50 min. While this 

is an improvement over oral administration for gastrointestinal uptake, a quicker onset of analgesia would be of 

substantial benefit to the patient. In addition, substantial 

In cancer patients, pain is usually treated with non-steroid 

anti-inflammatory drugs (NSAIDs) and opiates alone or in 

combination. Opioid-requiring cancer pain patients are usually given slow-release opiates (slow-release morphine or 

ketobemidone or transdermal fentanyl). A characteristic 

feature of cancer pain are periods of inadequate analgesia 

(breakthrough pain). Most often they are due to increased 

physical activity of the patient. However, treatment of 

breakthrough pain by administration of increased time con- 25 

tingent doses of long -acting analgesics causes adverse side 

effects such an excess sedation, nausea, and constipation. 

20 amounts of lozenge-administered fentanyl are swallowed by 

the patient. This is not desirable and results in the administration of excessive amounts of the drug, which may give 

rise to side effects. 

OBJECTS OF THE INVENTION 

Other disorders and conditions which require a fast-acting 

treatment are, for example, pulmonary edema, gastroesophageal reflux, insomnia and nephrolitiasis. 

It is one object of the invention to provide for the 

treatment of acute disorders by perorally administering at 

least one pharmaceutically active agent in a manner giving 

30 rise to pharmacologically effective plasma levels of said 

agent or agents within a short time after administration. 

It is another object of the invention to provide a pharmaceutical composition suitable for that purpose. 

Presently available oral, rectal, or sublingual formulations 

have relatively lengthy onset times or erratic absorption 

characteristics that are not well suited to control acute 

disorders. It is a further object of the invention to provide a method 

35 of making such a composition. Conditions of acute operative/postoperative or traumatic/ 

posttraumatic pain as well as pain due to severe disease (e.g. 

myocardial infarction, nephrolithiasis, etc.) is usually treated 

with opioid analgesics which are administered parenterally 

(by intravenous or intramuscular administration) to obtain a 40 

rapid onset of analgesia. In such cases, rapid-onset oral 

alternatives are of considerable therapeutic interest. Also for 

the treatment of other acute disorders, it is of considerable 

interest to provide fast-acting therapeutic compositions 

which may be administered orally instead of parenterally or 45 

rectally. 

However, many pharmaceutically active agents which 

would be advantageous to adminster orally are not suitable 

to be swallowed. They may, for example, be inactivated by 

the gastro-intestinalliquids, have a slow action because of a 50 

low solubility in the aqueous medium, or be highly susceptible to metabolism by gastro-intestinal enzymes and have 

poor absorptiom properties, as exemplified for peptide hormones. It is therefore more preferable to arrange for the 

active component to be taken up through the mucous mem- 55 

branes of the oral cavity. Here, the most preferred way of 

administration is via the sublingual route. In this 

administration, a dosage unit of the pharmaceutical composition is placed under tongue, and the active component is 

absorbed through the surrounding mucous membranes. 60 

However, with this way of administration the risk that the 

patient swallows the medication by swallowing saliva is 

well known. 

It is an additional object of the invention to provide a 

method of manufacture of a medicament for sublingual 

administration containing a physiologically effective dose of 

at least one pharmaceutically active compound useful in the 

treatment of acute disorders. 

DESCRIPTION OF THE DRAWING 

The sole FIGURE of the drawing shows the result of a test 

of the bioavailability of the active agent in a composition 

according to the invention. It is a diagram showing the 

plasma concentration of the agent against the time after 

administration. 

SUMMARY OF THE INVENTION 

According to the invention, the peroral treatment of acute 

disorders comprises sublingual administration of an ordered 

mixture comprising a pharmacologically effective amount of 

at least one pharmaceutically active agent. Said agent or 

agents is administered sub lingually in combination with a 

bioadhesion and/or mucoadhesion promoting compound. 

Further according to the invention, there is also provided 

a single-dose pharmaceutical composition for sublingual 

administration, comprising a pharmacologically effective 

amount of at least one pharmaceutically active agent. Said 

composition also contains a bioadhesion or mucoadhesion 

promoting compound. This composition reduces erratic drug 

absorption via swallowed saliva and enables the adminisFor the treatment of acute pain may be used fentanyl, tration of small amounts of said agent or agents. Therefore, 

N-(1-phenethyl-4-piperidyl)-propioanilide, or one of its 

pharmaceutically acceptable salts. This compound is an 

opioid agonist and shares many of the pharmacodynamic 

65 it substantially reduces the risk of side effects and intrapatient as well as interpatient variation of therapeutic response. 

Thereby the risk of drug accumulation is reduced, making 

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US 6,761,910 B1 

3 

the pharmaceutical preparation well suited for repeated 

dosing in patients suffering from acute disorders. 

The amount of active agent or agents contained in the 

pharmaceutical composition of the invention is obviously 

dependent on a number of factors, which are to be evaluated 

by the treating physician. Among such factors may be 

mentioned the specific agent used and the type of disorder 

being treated, the medical status of the patient, and others. 

When fentanyl is used for the treatment of acute or 

breakthrough pain, the composition of the invention should 

contain from 0.05 up to 20 weight percent of fentanyl or one 

of its pharmaceutically acceptable salts. More preferably, the 

compositions contains from 0.05 to 5 weight percent of 

fentanyl, and especially from 0.1 to 1 weight percent. The 

contents can also be expressed as the amount of fentanyl in 

a dose unit of the composition, such as a tablet. In this case, 

a dose unit should contain from 0.05 to 20 mg, and preferably 0.1 to 5 mg of fentanyl. When the fentanyl is used in 

the form of a salt, these percentages and amounts should be 

recalculated accordingly. 

Still further according to the invention, the sublingual 

composition comprises an ordered mixture of one or more 

bioadhesive andlor mucoadhesive carrier substances coated 

with the pharmaceutically active agent or agents in a fine 

particulate form. 

It is preferred to formulate the composition according to 

the invention by use of the technology for formulating 

rapidly dissolving ordered-mixture compositions disclosed 

in European patent EP 0 324 725. In these compositions, the 

drug in a finely dispersed state covers the surface of substantially larger carrier particles. Such compositions disintegrate rapidly in water, thereby dispersing their contents of 

microscopic drug particles. 

However, this prior art technique of using an ordered 

mixture for rapid drug dissolution has hitherto only been 

reported to be suitable for conventional oral drug therapy, 

4 

mucus, such as those in the oral cavity, while the expression 

"bioadhesion" is meant to denote an adhesion to biological 

surfaces more in general, including mucous membranes 

which are not covered by mucus. These expressions gener5 ally overlap as definitions, and may usually be used 

interchangeably, although the expression "bioadhesive" has 

a somwhat wider scope. In the present specification and 

claims, the two expressions serve the same purpose as 

regards the objects of the invention, and this has been 

10 expressed by the use of the common term "bioi 

mucoadhesion" . 

Suitably the carrier particles contain from 0.1 up to 25 

weight percent of biolmucoadhesion promoting compound, 

based on the total composition. In practice, contents below 

15 1 weight percent have been found to give an insufficient 

biolmucoadhesive effect. The preferred range of bioi 

mucoadhesion promoting agent content is from 1 to 15 

weight percent. 

It is preferred that the biolmucoadhesion promoting agent 

20 is a polymeric substance, preferably a substance with an 

average molecular weight above 5,000 (weight average). 

The level of hydration of the mucosa adhesion promoting 

agent interface is of importance in the development of 

biolmucoadhesive forces. Therefore, the faster the swelling 

25 of the polymer, the faster is the initiation of bioi 

mucoadhesion. The hydration of bioadhesive compounds 

also makes them useful as absorption enhancers according to 

the invention. 

Preferably, the carrier particle size is from 50 to 750,um, 

30 and more preferredly from 100 to 600 ,urn. Although particle 

sizes outside the indicated range can be used, practical 

difficulties are experienced when formulating pharmaceutical preparations from particles having such sizes. The carrier 

used may comprise any substance which is pharmaceutically 

35 acceptable, is highly soluble in water, and which can be 

formulated into particles fit for incorporating a bioi 

mucoadhesion promoting agent. A number of such substances are known to the person skilled in this art. As 

suitable examples may be mentioned carbohydrates, such as 

i.e. for solid dosage forms which are to be swallowed. For 

such preparations, the dissolution of the drug particles takes 

place in the stomach, i.e. in an environment where there 

exists a relatively large volume of liquid which can dissolve 

the drug particles. In the entire prior art literature, dissolution testing of ordered mixtures has been conducted with a 

large volume of water, typically 1 liter. The possibility to use 

ordered mixtures for sublingual administration, where the 45 

volume of liquid available as a solvent is limited to a few 

milliliters, has not been considered as a feasible approach. It 

was therefore unexpected that the present form of a solid 

dosage form preparation and administration route gives 

positive and useful results. In such an ordered mixture, the 50 

active agent or agents have a mean particle size below 10 

,urn. This size is determined on a weight basis, as obtained 

directly by e.g. dry sieving analysis, as is known by those 

skilled in the art. 

40 sugar, mannitol and lactose, or pharmaceutically acceptable 

inorganic salts, such as sodium chloride or calcium phosphate. 

In accordance with one particularly preferred aspect of the 

invention, the carrier also comprises a fragmentation promoting agent. By a fragmentation promoting agent is meant 

a brittle material which is readily crushed or broken up when 

a pharmaceutical composition of which it forms a part is 

compacted into tablets. If a biolmucoadhesion promoting 

agent also is incorporated within the carrier as well as being 

added to the carrier surface, further surfaces of bioi 

mucoadhesion promoting agent may then exposed for hydration. This effect is especially pronounced when the bioi 

mucoadhesion promoting agent also serves as a disintegrant. 

Mannitol and lactose have been found to be particularly 

A bioadhesion andlor mucoadhesion promoting agent is 

additionally added to the carrier particles according to the 

invention. The bioadhesion andlor mucoadhesion promoting 

agent is effective in making the active agent or agents adhere 

to the oral mucosa and may, in addition, possess properties 

to swell and expand in contact with water and thus make the 

tablet or the carrier particles disintegrate when wetted with 

saliva. The biolmucoadhesion promoting agent must then be 

present on the surface of the carrier particles, but it may 

optinally also be present within these particles, as described 

below. 

The expression "mucoadhesion" is meant to denote an 

adhesion to mucous membranes which are covered by 

55 suitable as fragmentation promoting agents. 

The addition of a pharmaceutically acceptable surfactant 

to the composition is also a preferred feature of the invention. The increased wetting effect of the surfactant enhances 

the hydration of the carrier particles, which results in faster 

60 initiation of the bio/mucoadhesion. The surfactant should be 

in a finely dispersed form and intimately mixed with the 

active agent or agents. The amount of surfactant should be 

from 0.5 to 5 weight percent of the composition, and 

preferably then from 0.5 to 3 weight percent. 

65 As examples of suitable surfactants may be mentioned 

sodium lauryl sulfate, polysorbates, bile acid salts and 

mixtures of these. 

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US 6,761,910 B1 

5 

A variety of polymers known in the art can be used as 

bio/mucoadhesion promoting agents. In addition to their 

polymeric nature, their ability to swell is important. On the 

other hand, it is also important that they are substantially 

insoluble in water. Their swelling factor by volume when 

brought into contact with water or saliva should preferably 

6 

orientation on the surfaces of the carrier particles, also be 

incorporated into the carrier particles in various ways. For 

example, the finely dispersed carrier can be granulated 

together with finely dispersed bio/mucoadhesive in a liquid 

5 which does not dissolve the bio/mucoadhesive agent or 

cause it to swell. In this case, the dry constituents are first 

mixed, and the resultant mix is then moistened with a 

non-dissolvinglnon-swelling liquid, such as absolute ethanol. The resultant mass is granulated, for instance by forcing 

be at least 10, while a factor of at least 20 is more preferred. 

Examples of such bio/mucoadhesion promoting agents 

include cellulose derivatives such as hydroxypropylmethyl 

cellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), methyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose and sodium carboxymethyl cellulose (NaCMC); starch derivatives such as 

moderately cross-linked starch; acrylic polymers such as 

carbomer and its derivatives (Polycarbophyl, Carbopol®, 

etc.); polyethylene oxide (PEO); chitosan (poly(Dglucosamine)); natural polymers such as gelatin, sodium 

alginate, pectin; scleroglucan; xanthan gum; guar gum; poly 

co-(methylvinyl ether/maleic anhydride); and crosscaramellose. Combinations of two or more bio/mucoadhesive polymers can also be used. More generally, any physiologically 

acceptable agent showing bio/mucoadhesive characteristics 

may be used successfully to be incorporated in the carrier. 

Bio/mucoadhesiveness can be determined in vitro, e.g. 

according to G. Sala et aI., Proceed. Int. Symp. Contr. 25 

Release. Bioact. Mat. 16:420, 1989. 

10 it through a filter. It is then dried and finely ground. 

Alternatively, the moist mass can he dried and then granulated. Another way of producing the carrier particles according to the invention is by dissolving the carrier agent in a 

solvent which will not dissolve the bio/mucoadhesion pro15 moting agent or cause it to swell, followed by the addition 

or the bio/mucoadhesion promoting agent to the solution, 

evaporation of the solvent, and granulation of the residue. 

Other methods are also conceivable to the person skilled in 

this art. Irrespective of the method applied, a suitable grain 

20 size fraction of the carrier agent containing bioi 

mucoadhesion promoting agent is prepared in a final stage, 

e.g. by passing the particulate mixtures through an screen or 

sieve of an appropriate mesh size, for instance a U.S. mesh 

size from 35 to 170. 

The bio/mucoadhesion promoting agent suitably has a 

particle size between 1 and 100 ,urn. When the particles of 

this agent are to be mixed with the carrier particles to form 

an ordered mixture, their size lies within the lower part of the 

size interval, and suitably their size is then below 10 ,urn. 

Some suitable commercial sources for representative bioi 

mucoadhesive polymers include: 

Carbopol® acrylic copolymer-BF Goodrich Chemical 

Co, Cleveland, Ohio, USA; 

HPMC-Dow Chemical Co., Midland,), Mich., USA; 

NEC (Natrosol)-Hercules Inc., Wilmington, Del., USA; 

HPC (Klucel®)-Dow Chemical Co., Midland, Mich., 

USA; 

NaCMC-Hercules Inc. Wilmington, Del. USA; 

PEO-Aldrich Chemicals, USA; 

Sodium Alginate,-Edward Mandell Co., Inc., Carmel, 

N.Y., USA; 

30 When the bio/mucoadhesion promoting agent is to be incorporated in the carrier particles, its particle size may be within 

the upper part of the size interval. 

The invention is particularly directed to the administration 

of drugs which are used for the treatment of medical 

35 conditions where a rapid and transient effect is desirable, 

such as pain, insomnia, allergic conditions and pulmonary 

oedema. As non-limiting examples of such drugs may be 

mentioned morphine (analgetic), fentanyl (analgetic), alfenPectin-BF Goodrich Chemical Co., Cleveland, Ohio, 40 

USA; 

tanyl ( analgetic), sufentanyl (analgetic), buprenorphine 

(analgetic), pizotifen (analgetic), sumatriptan (analgetic), 

indomethacin ( analgetic), sulindac ( analgetic), diclofenac 

Ac-Di-Sol® (modified cellulose gum with a high 

swellability)-FMC Corp., USA; 

Actigum,-Mero-Rousselot-Satia, Baupte, France; 

Satiaxane-Sanofi Biolndustries, Paris, France; 

Gantrez®-ISP, Milan, Italy; 

Chitosan-Sigma, St Louis, Miss., USA; 

Depending on the type and the proportion of the bioi 

mucoadhesion promoting agent used, the rate and intensity 

ofbio/mucoadhesion may be varied. According to one of the 

preferred aspects of the invention, substances with high and 

rapid capacity for swelling are preferred. 

In order for the pharmaceutical composition of the invention to function properly when a bio/mucoadhesion promoting agent is added thereto, this agent must be positioned at 

the surfaces of the carrier particles. The bio/mucoadhesion 

promoting agent can then be admixed to the carrier particles 

in several ways. In a preferred embodiment of the invention, 

a fine particulate quality of the bio/mucoadhesion promoting 

agent is mixed together with the coarse carrier for a sufficient time to produce an ordered mixture, where the finer 

particles exist as discrete primary particles adhered to the 

surfaces of the carrier particles. Thus, the bio/mucoadhesion 

promoting agent is admixed in the same way as the active 

compound described in European patent No. 0 324 725. 

In yet another embodiment of the invention, the bioi 

mucoadhesion promoting agent may, besides it peripheral 

( analgetic), ketorolac ( analgetic), piroxicam (analgetic), 

tenoxicam (analgetic), ibuprofen (analgetic), naproxen 

(analgetic), ketoprofen (analgetic), butazolidine (analgetic), 

45 phenylbutazone (analgetic), diazepam (insomnia), 

oxazepam (insomnia), zopiclone (insomnia), zolpidem 

(insomnia), propiomazin (insomnia), valeriana (insomnia), 

levomepromazin (insomnia), cyclizine (allergy), cetirizine 

(allergy), terfenadine (allergy), acrivastine (allergy), fex50 ofenadine (allergy) and furosemide (diuretic). 

Other drugs which benefit from an enhanced absorption 

and which may be used for medical conditions where a rapid 

onset of the action is desirable include, without any limiting 

sense, various pep tides and enzymes, such as atrial natri55 uretic peptides (ANP, ANF, auriculin) (diuretics), brain 

natriuretic pep tides ( diuretics), platelet aggregation inhibitors (anticoagulants), streptokinase (antocoagulant), heparin 

(anticoagulant), urokinase (anticoagulant), renin inhibitors 

(hypertension), insulin (antidiabetic), and sleep inducing 

60 peptide (insomnia). 

Further examples of drugs where exposure to gastric acid 

has to be avoided and where the swallowing of active drug 

containing saliva can be minimised by means of the bioi 

mucoadhesive properties of the present formulations 

65 include, without any limiting sense, benzimidazole derivatives used as H+, K+ and ATPase inhibitors (gastric acid 

reduction), such as omeprazole, pantoprazole, perprazole 

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US 6,761,910 B1 

7 

and lansoprazole. Other H+, K+ and ATPase inhibitors 

include alyll isothiocyanate, trifluorperazide, nolinium 

bromide, RP 40749 and fenoctimine. 

The invention is particularly suitable for the administration of fentanyl and its pharmacologically acceptable salts, 5 

such as the citrate or maleate, which are not readily soluble 

in water. The particles of fentanyl or salt thereof will suitably 

have a maximum particle size of about 24 ,urn but will 

preferably not be greater than about 10 ,urn. Fentanyl is 

caused to adhere to the carrier particles by dry mixing of the 10 

ingredients during a period of time of sufficient length. This 

time period can vary according to the mixing equipment 

used. A person skilled in the art will have no difficulty in 

determining by experimentation a suitable mixing time for a 

given combination of active substance, bio/mucoadhesion 

promoting agent, and carrier, by using a particular mixing 15 

equipment. 

Another preferred aspect of the invention comprises the 

incorporation of a disintegrating agent in the composition of 

the invention. Such an agent which will accelerate the 

dispersion of the carrier particles. Examples of disintegrat- 20 

ing agents according to the invention include cross-linked 

polyvinylpyrrolidone, carboxymethyl starch, natural starch, 

microcrystalline cellulose, cellulose gum and mixtures of 

these. A preferred content of disintegrating agent is from 1 % 

to 10% of the composition. As can be seen, the definitions 25 

of the disintegrating agent and the bio/mucoadhesion promoting agent overlap somewhat, and it may be preferred that 

both functions are served by the same substance. However, 

it is important to note that these two categories of excipients 

are not equivalent, and there are efficiently functioning 30 

disintegrants which do not possess bio/mucoadhesive 

properties, and vice versa. 

The ordered mixtures prepared in accordance with the 

present invention can be incorporated into various kinds of 

pharmaceutical preparations intended for sublingual admin- 35 

istration. Irrespective of the form given to the preparation, it 

is important that the preparation is essentially free from 

water, since its bio/mucoadhesion promoting character 

results from its practically instantaneous hydration when 

brought into contact with water or saliva. Premature hydra- 40 

tion would drastically decrease the mucoadhesion promoting properties and result in a premature dissolution of the 

active substance. 

8 

EXAMPLE 1 

Preparation of a Rapidly Disintegrating Tablet with 

Bio/Mucoadhesion Promoting Properties 

A batch of 1000 tablets was produced from the following 

compositions: 81.5 g of mannitol and 2.0 g of Ac-Di-Sol® 

(disintegrant and bio/mucoadhesion promoting agent) were 

mixed with about 170 ml of absolute ethanol. The dried 

mixture was forced through a metal sieve of 1 mm mesh 

width and the resultant fraction, having a particle size from 

about 250 to 450 microns, was mixed with 500 mg of 

micronized fentanyl and with 1.0 g of finely ground sodium 

lauryl sulfate (surfactant) over a period of 50 hours. The 

resulting mixture was admixed with 5.0 g of Avicel® Ph 101 

and 10.0 g sodium alginate (bio/mucoadhesion promoting 

agent and disintegrant) over a period of 60 minutes. The 

resulting mixture was compacted into tablets at a compaction pressure of 200 MPa, each tablet having a weight of 100 

mg and containing 0.5 mg of fentanyl. 

The dissolution rate of the tablets thus produced was 

investigated in accordance with USP XXIII (Paddle 

Method) at two different stirring speeds, 25 and 100 rpm. 

EXAMPLE 2 

Preparation of a Rapidly Disintegrating Tablet with 

Bio/Mucoadhesion Promoting Properties 

A batch of 1000 tablets was produced from the following 

composition: 91.0 g of mannitol (granular quality of a 

particle size from 250 to 450,um) and 1.0 g of sodium lauryl 

sulfate and 500 mg of micronized fentanyl were mixed in a 

V-mixer over a period of 24 hours. Thereafter, 5.0 g of 

Avicel® PH 101 and 2.0 g of Ac-Di-Sol® (here used both 

as a disintegrant and as a bio/mucoadhesion promoting 

agent) was admixed for an additional 2 hours. Finally, 0.5 g 

of magnesium stearate was admixed for 2 minutes. The 

resulting tablet mass was compacted into tablets at a compaction pressure of 130 Mpa, each tablet containing 0.5 mg 

of fentanyl. 

The disintegration time was tested with the use of the 

apparatus described in Ph. Eur. (latest edition) 

It was found that the disintegration time was less than 15 

seconds. 

For comparison, conventional rapidly dissolving tablets 

were also produced. Dry mannitol having a particle size of 

250-450 microns was dry mixed with micronized fentanyl 

without any further addition of excipients. The mixing time 

was 50 hours. The resulting mixture was compacted into 

tablets at a compaction pressure of 200 MPa, each tablet 

containing 0.5 mg of fentanyl. 

The results from this investigation showed that the 

ordered mixture with bio/mucoadhesive properties accordA pharmaceutical composition for the preferred sublingual route of administration can be obtained by combining 45 

an aforementioned ordered mixture with conventional pharmaceutical additives and excipients used in the art for 

sublingual preparations. Appropriate formulation methods 

are well known to the person skilled in the art; see, for 

instance, Pharmaceutical Dosage Forms: Tablets. Volume 1, 50 

2nd Edition, Lieberman H A et al.; Eds.; Marcel Dekker, 

New York and Basel 1989, p. 354-356, and literature cited 

therein. Suitable additives comprise additional carrier 

agents, preservatives, lubricants, gliding agents, 

disintegrants, flavorings, and dyestuffs. 55 ing to the invention (Example 1) has a dissolution rate equal 

to that of a conventional rapidly dissolving tablet formulation. The entire tablet was dissolved within 2 minutes. 

Furthermore, the rapid disintegration found for the tablets of 

Example 2 was equal to or better than for the conventional 

Thus, the invention provides a dosage form which is easy 

and inexpensive to manufacture, enables rapid active substance release, promotes a rapid uptake of the active agent 

or agents through the oral mucosa, and enhances the upptake 

of otherwise poorly soluble substances, such as peptides. 

The use of a low dose of active agent is provided for, 

supporting a short duration of action while enabling a 

repeated dosing schedule for patients in need of treatment of 

recurrent acute disorders. 

60 tablets. 

The invention will now be illustrated in more detail by 65 

reference to examples showing preferred but not limiting 

embodiments. 

EXAMPLE 3 

Evaluation of Uptake in Sublingual Administration 

To one patient suffering from breakthrough pain due to 

cancer was administered 400 ,ug of fentanyl as a sublingual 

tablet formulated as described in Example 1. The plasma 

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US 6,761,910 B1 

9 

concentration of fentanyl was monitored for a time of 240 

minutes after the administration, and the results are shown 

in the accompanying FIGURE. It will be seen that the uptake 

10 

of fentanyl was rapid, with the maximum value attained 

already after 5 minutes. This shows that a sublingual prep a- 5 

ration according to the invention gives a rapid uptake of the 

active agent, even though a very small volume of liquid is 

available for dissolution in this route of administration. 

molecules in sublingual administration were prepared 

according to Example 1, each tablet containing 0.7 mgANP. 

The tablets show a rapid release of ANP and an enhanced 

uptake of ANP through the oral mucosa in comparison with 

conventional peroral formulations. The preparation may be 

used for the treatment of pulmonary edema. 

EXAMPLE 7 

EXAMPLE 4 

Evaluation of BiolMucoadhesive Properties 

For in vitro evaluation of the bio/mucoadhesive properties 

of the formulation according to the present invention, a 

method permitting evaluation of bio/mucoadhesion promoting properties directly on finished dosage forms (Sala, G. E. 

et aI., Proc. Int. Symp. Contr. Release Bioact. Mat. 16:420, 

1989) was used. The evaluation was based on measurements 

of the flow of water required to remove the active substance 

from a rabbit intestinal membrane. A strip of rabbit mucosa 

was placed horizontally in a suitable temperature controlled 

chamber set at 37° C. The tissue was first washed with 

predetermined volumes of water by means of a peristaltic 

pump. Pre-compressed compositions according to Example 

10 Preparation of Rapidly Disintegrating Tablets for 

the Administration of Omeprazole 

Rapidly disintegrating tablets with bio/mucoadhesive 

properties for sublingual administration were prepared 

according to example 1, each tablet containong 10 mg of 

15 omeprazole. The tablets show a rapid release of omeprazole 

and an enhanced uptake of omeprazole through the oral 

mucosa, as well as a reduced swallowing of omeprazole in 

the saliva, in comparison with conventional peroral formulations. The preparation may be used for the treatment of 

20 gastroesophageal reflux. 

EXAMPLE 8 

1 (5-15 mg) were then placed on the tissue and allowed to 25 

remain there for 2 minutes to ensure proper dissolution. 

Upon this followed an elution with water fed by a peristaltic 

pump during 10 minutes. Rinsed-off fentanyl was collected, 

and its amount determined by radioimmunoassay (RIA) in 

order to establish the percentage of fentanyl removed. Sub- 30 

sequent tests were carried out using increasing elution flow 

rates. The results are shown in Table 2; percentages of 

removal at a high flow rate are listed for. 

Preparation of Rapidly Disintegrating Tablets for 

the Administration of Diclofenac 

Rapidly disintegrating tablets with bio/mucoadhesive 

properties for sublingual administration were prepared 

according to example 1, each tablet containinh 50 mg of 

diclofenac. The tablets show a rapid release of diclofenac 

and an enhanced uptake of diclofenac through the oral 

mucosa in comparison with conventional peroral formulations. The preparation may be used for the treatment of 

painful conditions such as neprolithiasis. 

A Bio/mucoadhesive mixture according to the invention 

(Example 1); 

B Bio/mucoadhesive mixture according to the invention 

(Example 2); 

C Conventional mixture for rapid dissolution containing 

no bio/mucoadhesion promoting agent. 

TABLE 2 

% fentanyl removed 

Flow rate (m1!min) A B c 

>15 <50 <50 >95 

EXAMPLE 5 

Preparation of Rapidly Disintegrating Tablets for 

the Administration of Furosemide 

Rapidly disintegrating tablets with bio/mucoadhesive 

properties for sublingual administration were prepared 

according to Example 1, each tablet containing 20 mg of 

furosemide. The tablets show a rapid release of furosemide 

and a promoted uptake of furosemide through the oral 

mucosa in comparison with conventional peroral formulations. The preparation may be used for the treatment of 

pulmonary edema. 

EXAMPLE 6 

Preparation of Rapidly Disintegrating Tablets for 

the Administration of Atrial Natriuretic Peptide 

(ANP) 

Rapidly disintegrating tablets with bio/mucoadhesive 

properties which in addition enhance absorption of large 

In the foregoing specification, the present invention has 

35 been described with reference to various examples and 

preferred embodiments. However, for a person skilled in the 

art, it is clear that the scope of the invention is not limited 

to these examples and embodiments, and that further modifications and variations are possible without departing from 

40 the inventive idea, The scope of the invention is thus only 

limited by the appended claims. 

What is claimed is: 

1. A pharmaceutical composition for the treatment of 

acute disorders by sublingual administration, comprising an 

45 essentially water-free, ordered mixture of microparticles of 

at least one pharmaceutically active agent adhered to the 

surfaces of carrier particles, said particles being substantially larger than said microparticles and being watersoluble, and a bioadhesion and/or mucoadhesion promoting 

50 agent mainly adhered to the surfaces of the carrier particles. 

2. A composition according to claim 1, wherein the 

microparticles of said active agent or agents have a weight 

based mean diameter of less than 10 ,urn. 

3. A composition according to claim 1, wherein the mean 

55 sieve diameter of the carrier particles is between 100 and 

600,um. 

4. A composition according to claim 1, wherein the carrier 

particles comprise a brittle material which will fragmentize 

easily when compressed. 

60 5. A composition according to claim 1, wherein the carrier 

particles contain from 0.1 to 25 weight percent of the 

bio/mucoadhesion promoting agent. 

6. A composition according to claim 5, wherein the 

bio/mucoadhesion promoting agent is selected from the 

65 group consisting of acrylic polymers, cellulose derivatives, 

natural polymers having bio/mucoadhesive properties, and 

mixtures thereof. 

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7. A compositlon according to claim 6, wherein the 

bio/mucoadhesion promoting agent is selected from the 

group consisting of cellulose derivatives and comprising 

hydroxypropylmethyl cellulose, hydroxyethyl cellulose, 

hydroxypropyl cellulose, sodium carboxymethyl cellulose, 5 

methyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose, and modified cellulose gum; crosscaramellose; modified starch; acrylic polymers comprising carbomer and its derivatives; polyethylene oxide; chitosan; 

gelatin; sodium alginate; pectin; scleroglucan; xanthan gum; 10 

guar gum; poly-co-(methyl vinyl ether-maleic anhydride); 

and mixtures thereof. 

8. A composition according to claim 1, further comprising 

a pharmaceutically acceptable surfactant in a finely dispersed form and intimately mixed with the active agent or 15 

agents. 

9. A composition according to claim 8, wherein the 

surfactant is present in an amount from 0.5 to 5 weight 

percent of the composition. 

10. A composition according to claim 8, wherein the 20 

surfactant is selected from the group consisting of sodium 

lauryl sulfate polysorbates, bile acid salts and mixtures 

thereof. 

12 

14. A composition according to claim 13, wherein the 

disintegrating agent is selected from the group consisting of 

cross-linked polyvinylpyrrolidone, carboxymethyl starch, 

natural starch, microcrystalline cellulose, cellulose gum, and 

mixtures thereof. 

15. A composition according to claim 13, wherein the 

disintegrating agent is present in an amount from 1 to 10 

weight percent of the composition. 

16. A composition according to claim 1, wherein the 

pharmaceutically active agent is fentanyl or a pharmaceutically acceptable salt thereof. 

17. A composition according to claim 1, for the treatment 

of acute disorders by sublingual administration. 

18. A composition according to claim 16, for the treatment 

of acute or breakthrough pain by sublingual administration 

of fentanyl or a pharmaceutically acceptable salt thereof. 

19. A method for the treatment of acute disorders, wherein 

to an individual afflicted with said disorder is administered 

sub lingually at least one dose unit of an essentially waterfree pharmaceutical composition containing an effective 

amount of at least one pharmaceutically active agent in the 

form of microparticles adhered to the surfaces of carrier 

particles, which are substantially larger than said micropar- 11. A composition according to claim 1, wherein the 

carrier particles comprise a water-soluble, pharmaceutically 

acceptable carbohydrate and/or an inorganic salt. 

12. A composition according to claim 11, wherein the 

carrier particles comprise at least one of the materials 

mannitol, lactose, calcium phosphate and sugar. 

25 ticles and are essentially water-soluble, and a bioadhesion 

and/or mucoadhesion promoting agent. 

13. A composition according to claim 1, wherein the 

carrier particles contain at least one pharmaceutical disintegrating agent promoting the dispersion of the microparticles of the active agent or agents over the sublingual 

mucosa. 

20. A method according to claim 19, wherein the pharmaceutically active agent is fentanyl or a pharmaceutically 

30 acceptable salt thereof. 

21. A method according to claim 20, wherein the fentanyl 

is administered in an amount from 0.05 to 20 mg. 

* * * * * 

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