MEDICAMENT UPTAKE

TECHNICAL FIELD

The present invention relates to medicament uptake.

BACKGROUND ART

One of the most common routes of drug administration is oral delivery.

While other methods of administration, including injections, patches, topical creams, topical drenches and boluses are available, they all have considerable disadvantages. As such, oral delivery has remained the preferred delivery route for most medicaments.

One considerable advantage of oral delivery is that the medicament is consumed by the animal such that it can be absorbed in the gastrointestinal tract. Unlike patches, creams and drenches the administrator can be quite certain that the required dose has been taken.

A further advantage of oral delivery over other administration techniques, such as boluses and injections, is that the former requires very little intervention and discomfort to the animal.

Regardless, one of the major disadvantages associated with oral delivery is the unpalatable taste of many of the constituents within medicaments.

Relevant prior art discloses numerous methods of hiding or disguising unpalatable tastes of medicaments. For example, people have attempted to hide medicaments within a pocket of meat, hoping that the animal will not notice it. Alternatively, many people have chosen to sedate the animal in attempt to overcome the animals stubbornness. These are inefficient and sometimes unpleasant procedures, and can still result in animals refusal to consume the medicament. This can result in ineffective treatment as the required dose may not be delivered. Similarly, the caregiver may simply give up trying to force the animal to eat it due to its unpalatability.

Some medicaments are formulated to be chewable, with the intention that animals are more likely to accept such a medicament as it mimics the chewiness of certain food. However, the active ingredient may be lost in the saliva that is spat out (i.e. not ingested). This could lead to inadequate treatment for the animal. Alternatively, if extra medicament is administered to account for the potential loss of the medicament being spat out in the saliva, this could instead lead to potential overdosing of the drug.

Many formulations may contain excipients to try mask the unpleasant taste or smell of certain components, however the poor taste/smell problem can often persist. Alternatively, excipients effective enough to achieve the desired goal may instead cause deleterious effects on pharmacokinetic properties of formulations or even side-effects to the consumer.

Also, unpleasant tasting drugs have previously been masked by infusing the drugs into meat, for example beef cubes. Alternatively, a simpler option has been to provide the drug within food such as a beef casserole. In this sense, the drug is a part of the food such that the animal will receive the medicament with each bite. In this case, the medicament is not in a concentrated form, but is "diluted" within the food. However, the correct dosage is only taken if the animal consumes the entire portion of food. If the animal discontinues consuming the food prior to its completion, the animal will not receive the correct dosage. A further disadvantage is that, in order to be sure the intended animal is consuming the medicament, the animals caregiver must be present while the food is being eaten, or the animal must be kept in isolation while consuming the food.

Also, a major disadvantage of masking unpalatable drugs within food items such has been that the food item often has a limited shelf life, usually considerably more limited than the drug itself. Therefore, storing the drug-food mixture for long periods of time may lead to the food turning rancid. This is particularly relevant to meat.

To avoid this problem, one could mix the drug with the food just prior to administration. However, this can increase handling time, errors in the measurement and administration of the drug, and costs (for example, the need to purchase the food itself, as well of course the hands-on time required to prepare and supply the medicament to the animal).

Good examples of unpalatable formulations are those which include non-steroidal anti-inflammatory drugs (NSAID's), used to treat of degenerative inflammatory diseases.

Non-steroidal anti-inflammatory drugs (NSAID's) have been developed that specifically inhibit cyclooxygenase-2 (COX-2) activity without inhibiting cyclooxygenase-1 (COX-1 ) activity.

NSAID activity, including the characteristics of COX-1 and COX-2 enzymes, are extensively described in the prior art, for example the article 'Practical COX-1 and COX-2 Pharmacology: What's it all About?' by C. Jones.

By way of example, one COX-2 selective drug remedy widely used for treatment of joint problems is carprofen, sold by Pfizer under the trade name Rimadyl ^® with related patents US 4,264,500 and US 6,013,808. Carprofen has the formula:

Carprofen is a NSAID of the propionic acid class that includes ibuprofen, maproxen and ketoprofen. Carprofen is the non-proprietary designation for a substituted carbozole, 6-chloro-alpha-methyl-9H-carbozole-2-acetic acid. Carprofen has been widely used in veterinary treatments.

While NSAIDs such as carprofen are extremely effective anti-inflammatory drugs with only limited side-effects, palatability of these drugs largely remains poor. Many consumers and/or care-givers object to the bitter taste associated with NSAIDs, leading to an overall dissatisfaction with the drug.

Thus it is an object of the present invention to provide an alternative therapy that addresses the foregoing problems or at least to provide the public with a useful choice.

All references, including any patents or patent applications cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the Applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents form part of the common general knowledge in the art, in New Zealand or in any other country. It is acknowledged that the term 'comprise' may, under varying jurisdictions, be attributed with either an exclusive or an inclusive meaning. For the purpose of this specification, and unless otherwise noted, the term 'comprise' shall have an inclusive meaning - i.e. that it will be taken to mean an inclusion of not only the listed components it directly references, but also other non-specified components or elements. This rationale will also be used when the term 'comprised' or 'comprising' is used in relation to one or more steps in a method or process.

Further aspects and advantages of the present invention will become apparent from the ensuing description which is given by way of example only.

DISCLOSURE OF INVENTION

According to one aspect of the present invention there is provided a composition including at least one therapeutic agent characterised in that the composition includes at least one seafood flavouring agent.

According to a further aspect of the present invention there is provided a method of treatment or prevention of a connective tissue disease or the symptoms thereof in an animal,

characterised by the step of

administering to the animal a composition containing a therapeutically effective amount of at least one therapeutic agent

wherein the composition includes at least one seafood flavouring agent.

According to a further aspect of the present invention there is provided the use of a therapeutically effective amount of at least one therapeutic agent characterised in that the composition includes at least one seafood flavouring agent in the manufacture of a medicament for the treatment or prevention of a connective tissue disease or the symptoms thereof.

According to a further aspect of the present invention, there is provided a method of making a composition containing a therapeutically effective amount of at least one therapeutic agent and at least one seafood flavouring agent

wherein the seafood flavouring agent is derived by the steps of

a) centrifuging a soft part of a sea dwelling organism to form a pellet;

b) freeze-drying the pellet;

c) powdering the freeze-dried pellet; and

d) adding at least one powdered freeze-dried pellet to the composition.

The term 'therapeutic agent' should be taken as meaning any molecule, compound or material that is used to treat or cure at least one disease, or condition, or any of their symptoms.

In a preferred embodiment, the therapeutic agent is a NSAID.

The term 'NSAID' should be taken as meaning any non-steroidal anti-inflammatory drug, compound or agent.

In a particularly preferred embodiment, the NSAID is cyclooxygenase-2 (COX-2) selective.

In a preferred embodiment the COX-2 selective NSAID compound is selected from: carprofen, (naproxen, ibuprofen, ketoprofen, piroxicam, diclofenac, etodolac, flunixin, deracoxib, meloxicam, celecoxib, rofecoxib, and combinations thereof. In a particularly preferred embodiment , the COX-2 selective NSAID compound is carprofen.

The term 'seafood flavouring agent' should be taken as meaning any component derived from a water-dwelling organism. Therefore, this term should be taken as including organisms from either salt water and/or fresh water.

The seafood flavouring agent is utilised to increase the palatability of the composition and hence the uptake of the associated medicament.

The Applicants have surprisingly observed considerable advantages in a medicament formulated to include a seafood flavouring agent and a therapeutic agent. The use of the seafood flavouring agent as described in the specification results in a medicament with a considerably higher level of palatability than the same medicament lacking the seafood flavouring agent.

In a preferred embodiment, the seafood flavouring agent is an extract from mussel meat.

The term 'mussel' should be taken as meaning any of several marine bivalve molluscs, especially edible members of the family Perna and Mytilus.

In a preferred embodiment, the mussel may be of Perna or Mytilus genus. Most preferably, the mussel may be Perna canaliculus.

The term 'extract' should be taken as meaning a preparation of one or more components separated from its source(s).

In a preferred embodiment, the mussel 'extract' is a powdered form of the mussel meat (not including the shell).

In an alternative embodiment the mussel extract is a concentrated preparation of the lipid portion of the mussel meat. However, it should be appreciated that the term 'extract' also encompasses other powdered or liquid forms of the mussel meat or a specific portion or portions thereof.

In a preferred embodiment, the ratio (w/v) of therapeutic agent to seafood flavouring agent is between 30:1 to 2:1.

The Applicants have unexpectedly discovered that a medicament with a ratio of therapeutic agent to seafood flavouring agent between approximately 30:1 to 2:1 provides sufficient palatability for a medicament that typically would be unpalatable without inclusion of seafood flavouring agent. The Applicants appreciate that greater amounts of seafood flavouring agent relative to therapeutic agent in a given medicament (e.g. less than 1:2) may provide increased palatability of the medicament. However, it has been found that many of the advantages discussed below are lost as the ratio of seafood flavouring agent to therapeutic agent decreases below 1:2.

In a particularly preferred embodiment, the ratio (w/v) of therapeutic agent to seafood flavouring agent is approximately 10:1.

Having a low ratio of seafood flavouring agent to therapeutic agent may also help to avoid allergenic reactions that some animals have against seafood products.

The Applicants also notes the having a low ratio of flavouring agent to therapeutic agent also helps to avoid the dilution of the active ingredient such that it may be kept in a concentrated form (such as a pill) rather than diluted within a meal (for example).

This also is advantageous as the medicament is not provided in a chewy vehicle like many foods. This avoids potential loss of the medicament in saliva or food/drug being spat out during the chewing process;

The Applicants also note that the current invention preferably uses only small amounts of a seafood flavouring agent which helps to avoid exposure to potential heavy metal poisoning. Although unlikely, excessive consumption of some forms of seafood may lead to mercury poisoning, for example. However, by using only only a low ratio of seafood flavouring agent to therapeutic agent in the medicament, this risk is minimalized.

Some further advantages of the present invention are discussed below.

The avoidance of land based meat such as beef prevents the medicament going rancid during storage. Instead, the seafood flavouring agent is very stable on its own and in combination with therapeutic agents within the medicament.

Unlike many previous methods to entice an animal to consume unpalatable drugs, the current invention avoids a meal needing to be consumed by the animal during administration.

Further, the Applicants have surprisingly discovered that the medicament is palatable for animals that typically are known for disliking seafood products (e.g. dogs). Typical flavouring agents used for animals such as dogs have tended to be for example, from land based meat such as beef, chicken and pork, not seafood.

Additionally, the components used for the seafood flavouring agent are relatively inexpensive to source, process and then incorporate into a medicament as the flavouring agent. This makes excellent use of seafood that usually would not typically be consumed by humans, yet still can be used to make components used in the present invention.

Also, the aroma provided by the seafood flavouring agent has a strong influence on the animal's decision to accept the medicament. It is well known that a large factor of taste is actually due to smell perception. No doubt, the aroma of a seafood flavour agent has an enormous impact on taste with other animals such as dogs.

Because the invention most preferably uses natural seafood flavouring agents, this helps to avoid the need for synthetic (or unnatural) flavouring enhancers.

As discussed above, the increased uptake of a normally unpalatable composition is a significant advantage. With commercially available formulations, many animals simply refuse to take the medicament due to the medicament being unpalatable.

In a preferred embodiment, the composition may be in any form suitable for oral administration. For example, the composition may be in capsules, suspensions, drinks or tonics, powders, or food ingredients. Most preferably, the composition may be formulated for oral administration in the form of a tablet or capsule.

In a particularly preferred embodiment, the composition may further include: carriers, diluents, fillers, flavourings, colourings, excipients, modifiers, humectants, stabilisers, emulsifiers, and other known formulation components.

In a preferred embodiment the connective tissue disease treated or prevented is selected from: osteoarthritis, joint inflammation, cartilage degradation, hip dysplasia, or combinations thereof.

The term 'symptom' refers to any subjective evidence of disease or patient's condition.

In a preferred embodiment, the composition may be used for treatment of both the underlying cause and symptoms associated with connective tissue afflictions. Most preferably, the symptoms may include pain and reduced mobility of the joint and the underlying cause is primarily due to degradation of cartilage from the joint. However, this should not be seen as limiting as it should be appreciated by those skilled in the art that, due to the potent anti-inflammatory nature of the composition, other inflammation related disorders may also be able to be treated using the composition of the present invention such as rheumatoid arthritis inflammation. Such disorders include strained ligaments or muscles, or for postoperative use to control pain associated with soft tissue and orthopaedic surgeries.

In a particularly preferred embodiment, the composition of the present invention is used for treatment of hip dysplasia.

In a preferred embodiment, the animal to be treated is a companion animal.

In a particularly preferred embodiment, the animal may be from the species canine, feline or equine.

In a particularly preferred embodiment, the animal may be a domestic pet dog.

However, this above preferences should not be seen as limiting as those skilled in the art would appreciate that based on previous results found for COX-2 selective NSAID compounds when used alone and mussel extracts when used alone, the combination therapy of the present invention may be used in other animals, including humans. For example, Carprofen has been used to treat cats, rabbits, chinchillas, rats and birds.

Typically, a therapeutically effective dose of COX-2 selective NSAID compound is between 1-4 mg NSAID per kg of animal weight per day (mg/kg/day). Therefore, if a 20 kg animal is administered a NSAID medicament once-daily, the composition would include between 20-80 mg NSAID. If the dosage was 4 mg NSAID/ kg/day, the composition would include 80 mg NSAID.

The Applicants have found that the above exemplary composition preferably would include between 2.7 mg to 8 mg seafood flavour agent such as mussel extract (representing 1 :30 to 1 : 10 ratio of flavour agent to therapeutic agent) in order to make this composition considerably more palatable.

The Applicant acknowledges that depending on how unpalatable a medicament is, differing levels of the seafood flavouring agent (e.g. mussel extract) may be required. The Applicant has discovered that to provide an acceptable level of palatability for particularly unpalatable drugs, the ratio would likely be closer to 10:1 than 30:1 , and vice versa (therapeutic agent to seafood flavouring agent.

It is envisaged that the composition of the present invention may be used as a palatable and effective 'first line of treatment' for connective tissue afflictions including joint inflammation, osteoarthritis and/or cartilage degradation.

The composition which includes at least one therapeutic agent and at least one seafood flavouring agent is made by the steps previously discussed (see page 6 of the specification).

The term 'soft part of a sea dwelling organism' should be taken as meaning any soft tissue of an organism that resides, in at least part of its normal life-cycle in salt water or fresh water.

In a preferred embodiment, the soft part of the sea dwelling organism is first manually separated from the hard parts of the organism. This may help to avoid having to separate out these unwanted parts of the organism during the latter stages of the process. In a preferred embodiment, the soft part of the sea dwelling organism includes muscle, fat, cartilage, and/or tendon. The Applicant envisions that it is preferable to separate the bone and / or shell of sea-dwelling organisms from the soft parts listed above but not bone or shell.

In a particularly preferred embodiment, the soft part of the sea dwelling organism is the fatty tissue.

In a particularly preferred embodiment, the sea dwelling organism is green lipped mussel.

Preferably, the mussel is Perna or Mytilus genus. Most preferably, the mussel is Perna canaliculus.

For example, the soft part of the organism may be centrifuged at between 1000 - 2000 r.p.m. for 10 - 20 minutes at 3 - 20 ⁰ C. These centrifugation conditions have been found to be sufficient to effectively separate the portion to be used for the seafood flavouring agent. However, depending on, for example, the tissue type and the centrifuge/rotor size and model, someone skilled in the art would appreciate that there many alternatives to this step which should not be considered beyond the scope of the invention.

A considerable advantage of the above method is that the method provides a concentrated (i.e. potent) and semi-purified seafood flavouring agent to be used for increasing the palatability of a medicament (which otherwise would be unpalatable). There are many advantages in providing this seafood flavouring agent within a medicament as previously discussed in the specification.

Some considerable advantages in the above method are as follows:

• removes many unwanted parts of the organism prior to use in the medicament. This may help to avoid allergic reactions.

• provides a concentrated "potent" palatability agent that, when added to the medicament, will not overly bulk up the volume/weight of the composition. For example, this may allow the medicament to be provided in a pill opposed to a meal supplement or a gravy.

• The process may be adapted to a large scale to produce large amounts of the seafood flavouring agent.

• Preferably uses unwanted parts of the sea dwelling organism such as the fatty tissue. Therefore, parts that are usually discarded after the meat is used for human consumption can instead be harvested and used for the current invention.

• The powdered freeze-dried pellet may be stored at -20 ⁰ C to 30 ⁰ C for long a period of time prior to use without significant decreases in overall effectiveness of the agent.

• Even within the medicament, the seafood flavouring agent is very stable at room temperature, such that it will not rot or deteriorate

BEST MODES FOR CARRYING OUT THE INVENTION

The invention will now be described with reference to examples of preferred formulations known to the inventors.

A preliminary trial conducted by the applicant has suggested that the composition (composition A) containing 2 mg of a mussel extract (GLME) and 20 mg of NSAID (Carprofen), which represents a 1:10 ratio of a seafood flavouring agent to therapeutic agent, showed similar palatability scores in dogs to a chewable composition containing 25 mg of Carprofen (Rimadyl chewable tablets).

Rimadyl Chewable Tablets have an improved palatability component due to the increased chewiness of the medicament. However the Applicant wishes to increase palatability whilst avoiding the need to make the composition chewy. As discussed previously in this specification, there are considerable disadvantages of having a chewy composition. Therefore these preliminary studies have identified that the seafood flavouring agent can, for example, increase palatability of a typically non-palatable medicament to levels similar to Rimadyl Chewable Tablets, yet without the need to formulate the medicament to have chewy characteristics.

The applicant envisions that similar to above, this increased palatability of composition will extend to a ratio range of 1 :30 to 1 :10 of seafood flavouring agent to therapeutic agent.

Similarly, the applicant envisions that the seafood flavouring agent is likely to provide increased palatability effects with other non-palatable therapeutic agents, and should not be limited specifically to NSAID's.

Summary

The objective of the study was to compare the palatability of tablets containing GLME and carprofen against Rimadyl Chewable Tablets for Dogs (carprofen), in dogs. Thirty healthy dogs between the ages of four months and ten years (average age 3.9 years), of both sexes (twenty females and ten males) and a range of breeds participated in the study. The most common breeds represented were Labradors or Labrador cross (14 dogs), Greyhounds (four dogs) and Huntaways (three dogs).

Study Design Thirty healthy dogs between the ages of four months and ten years, of both sexes and a range of breeds participated in this crossover design study. Older dogs (greater than ten years) and dogs with poor health were excluded to minimise the likelihood of encountering adverse effects to carprofen. Owners were also questioned about the dog's history, including previous bleeding disorders, vomiting or diarrhoea, liver and kidney disease and intolerance to non-steroidal antiinflammatory drugs. Dogs were given a veterinary exam prior to inclusion.

Dogs were offered both Rimadyl Chewable Tablet and GLME + carprofen tablet by the dog's owner, at the dogs' normal residence. The treatments were not mixed with food and the dogs were fasted for at least six hours prior to being offered a tablet. Dogs were offered one product daily on two consecutive days, then the alternative product daily on following two consecutive days. The order that the treatments were offered to dogs was randomised.

Each dog weighing approximately 12 kg or more was offered one 25 mg tablet of Rimadyl Chewable Tablet at an offering (this is enough to treat a 12 kg dog at the low end of the recommended dose rate) or one GLME + carprofen tablet (containing 20 mg carprofen and 2 mg GLME). Smaller dogs were offered half a tablet of either treatment. Thus small dogs were treated at below the therapeutic dose range to minimise the risk of adverse effects to carprofen occurring.

Each owner monitored and recorded the time from the dog noticing the tablet to swallowing it. Owners were asked to document any other notable behavioral responses (e.g., salivation, repeated spitting out, chewing). If a dog failed to accept a tablet after two minutes, it was withdrawn. The proportion of any tablet uneaten was also recorded. The time taken for the dog to consume a treatment was graded as follows

Grade I: Dog swallowed the tablet within 10 seconds of it being offered. Grade 2: Dog swallowed the tablet within 11-30 seconds of it being offered. Grade 3: Dog swallowed the tablet within 31-120 seconds of it being offered. Grade 4: Dog did not consume the entire tablet by 120 seconds after being offered.

The palatability of treatments was compared using a simple Chi-squared statistical analysis.

Treatment Regime

Dogs were fasted for at least 6 hours prior to a product being offered. Any other dogs at the premises were restrained away from the dog being tested. The dose for a dog weighing 12 kg or more was one 25 mg Rimadyl Chewable Tablet or one GLME + carprofen tablet (containing 20 mg carprofen and 2 mg GLME). Smaller dogs were offered half a tablet of either product. The owner offered the tablet to the dog and the response of the dog was observed and recorded. The owner offered another dose of the same product the following day according to the same instructions. Following at least 24 hours, the alternative product was offered using the same schedule and instructions. Owners recorded the time from the dog noticing the tablet to swallowing it. Owners were asked to document how much of the tablet had been eaten any other notable behavior (e.g., salivation, repeated spitting out, chewing). If the dog did not voluntarily consume the tablet after two minutes, the tablet was withdrawn.

Test and Reference Item

Name: GLME + carprofen tablet Active ingredient: 2 mg green lipped mussel extract and 20 mg carprofen per tablet

Dose: Dogs weighing 12 kg or more were offered one tablet, orally. Smaller dogs were offered half a tablet.

Dosing was repeated once, the following day

Storage conditions: Refrigerate

Name: Rimadyl Chewable Tablets for Dogs

Active ingredient: 25 mg Carprofen

Dose: Dogs weighing 12 kg or more were offered one tablet, orally. Smaller dogs were offered half a tablet.

Dosing was repeated once, the following day

ACVM Registration N ⁰ A8023

Batch number: OAJWU

Manufacture Date: Not supplied

Expiry date: May 10

Storage conditions: Store below 25 ^C C out of direct sunlight

Statistical Analysis A Chi-squared analysis of the data was performed, testing the null hypothesis that the difference in the proportion of dogs that accepted Rimadyl and GLME + carprofen tablet is no different from what could have occurred randomly (statistical significance p<0 05). The number of dogs refusing one dose of a product, number of dogs refusing both doses of a product, the total number of refusals of a product, the number of grade I and grade 2 responses were investigated and a p-value generated.

The grade I acceptance rate and the rejection rate of both products were compared with what could occur by random chance, in the pet dogs Table I: Score of dog's response to each treatment offered.

Table 2: Percent-wise Analysis of palatability scores

Pet dogs (52 scores)

The GLME + carprofen tablet was very palatable to dogs, with only one refusal to 52 offerings (2% refusal rate) Compared with what may have occurred randomly, the Likelihood to this difference occurring by chance is p=0.002.

The probability that the difference between the number of refusals to GLME + carprofen tablet (one refusal) and Rimadyl Chewable Tablet (no refusals) is caused by random chance is p=0 31. In addition, the probability that the difference between the number of dogs that consumed GLME + carprofen tablets and Rimadyl Chewable Tablets within ten seconds of offering of is caused by random chance is p=060 Thus these two products were considered to be comparable and to both be highly palatable in the pet dog population studied.

It should be appreciated by those skilled in the art that the above described invention provides an animal treatment for joint disorders that is effective at treating both the symptoms of the disorder as well as the underlying cause of the disorder i.e. cartilage degradation and associated inflammation. It is also envisaged that the combination formulation also acts quickly to treat the disorder and is more cost effective long term with fewer potential side effects.

Aspects of the present invention have been described by way of example only and it should be appreciated that modifications and additions may be made thereto without departing from the scope thereof as defined in the appended claims.