WO2009010707A1

WO2009010707A1 - Injectable pharmaceutical compositions containing panthenol

Info

Publication number: WO2009010707A1
Application number: PCT/GB2007/050406
Authority: WO
Inventors: Paul Sherwood; Keith Davies
Original assignee: Prototype Bioforum Limited
Priority date: 2007-07-13
Filing date: 2007-07-13
Publication date: 2009-01-22
Also published as: EP2178526A1

Abstract

Use of panthenol in the preparation of a pharmaceutical composition for administration by intraarticular or periarticular injection to a joint which is inflamed or painful due to traumatic arthritis.

Description

INJECTABLE PHARMACEUTICAL COMPOSITIONS CONTAINING PANTHENOL

This invention relates to injectable pharmaceutical compositions containing panthenol and their use in the alleviation of inflammation and pain in joints affected by traumatic arthritis.

Pain or loss of movement in joints is a common occurrence for those who have suffered damage to cartilage, bone surfaces or ligaments, particularly among the elderly. Standard methods of treatment include the administration of corticosteroids by injection into the site of the inflammation. However, relief tends to be temporary and long term use carries a number of contraindications.

Pantothenic acid (sometimes known as vitamin B5) and its salts have been used as a dietary supplement and for treatment of bronchial asthma, hay-fever, sinusitis and neurodermatitis.

European Patent No. 1 276 477 discloses that pantothenic acid salts may be used in an injectable formulation for treatment of joint pain.

It has now been found that panthenol, the alcohol derivative of pantothenic acid, is of value in reducing pain and inflammation when injected into or adjacent to an affected joint.

According to the present invention there is provided use of panthenol in the preparation of a injectable pharmaceutical composition for administration by injection into a joint, or into a body region closely adjacent to the joint, for alleviation of inflammation or pain caused by traumatic arthritis.

The alcohol is optically active and the dextro-rotatory isomer dexpanthenol is the preferred active agent. Dexpanthenol is commercially available in forms approved by the European Pharmacopiea. There is no evidence of toxicity associated with the ingestion of panthenol. Dexpanthenol has rarely been associated with contact dermatitis when applied topically, and pain, numbness and difficulty breathing following injection. Suitably the injectable composition contains a dose of at least about 250 mg, typically at least about 400 mg of dexpanthenol, preferably at least about 500 mg, more preferably at least about 800 mg, and most suitably about 1000 mg i.e. about 1 gram of dexpanthenol. The exact dosage will vary with the condition treated, and the age and condition of the patient. A course of injections may be required, given at intervals of about one week. Reduced inflammation and increased freedom of movement is usually noticeable shortly after administration and a review of the response can be made after about a week of treatment. A second dose can then be given if necessary.

Conveniently, an injectable pharmaceutical composition is prepared by dissolving the panthenol in a suitable solvent, e.g. water, and injecting the solution into, or closely adjacent to, the affected joint. The initial treatment may cause some pain and it may, therefore, be desirable to co-administer a local anaesthetic, such as bupivicaine or lignocaine, either as a separate injection at the same time or shortly before the injection of the panthenol, or as a coformulation with panthenol.

Other physiologically active materials may be co-administered, if desired, e.g. cysteine or glucosamine.

The injectable pharmaceutical compositions of this invention may be used in the treatment of several painful conditions associated with inflammation or reduced movement of joints. Although some relief may be obtained using the present invention to treat rheumatoid arthritic conditions, such treatment is not recommended because it will be only temporary due to the immune reaction cause of the disease. The main aim of the invention is to treat traumatic arthritic conditions, which are normally found to occur in only one joint at a time. Examples include tennis elbow, housemaid's knee, frozen shoulder, inflamed knee joints, ankle joints and hip joints and back pain associated with inflammation or restricted movement in the spinal vertebrae, such as posttraumatic spondylitis.

For large joints, i.e. most joints except vertebrae, the injectable pharmaceutical composition may be injected into the capsule of the joint by intra-articular injection.

The injectable pharmaceutical composition may also be administered closely adjacent to the joint, but outside the capsule so that it can diffuse into the capsule, by peri-articular injection. For small joints, especially the vertebrae, injection outside the capsule is preferred, to avoid the risk of damage to the joint; this also enables the use of large dose (and hence large volume) injections which would be difficult to accommodate in small joints.

Facet joints requiring injection are identified by an area of extreme tenderness in the area of pain and spasm in the patient's back. A needle inserted at right angles into this area will be located in or close to the facet joint. The solution does not have to be injected directly into the joint as it will diffuse into it; injections into and around the joint are equally effective.

An injection into the region of a joint may be within about 5, 4, 3, 2 or 1 cm of the capsule of the joint, or closer.

A dose of about 2 mis of an aqueous solution containing about 500 mg of dexpanthenol can be effective. Preferably the dose contains about 1000 mg of dexpanthenol, for example, as about 4 mis of an aqueous solution containing about 250 mg/ml. A programme of injections is generally desirable in which dosages similar to that indicated above are given at intervals of a few days to a few weeks. When administering an injection of 2 mis containing 500 mg dexpanthenol, if the injection is painful, it may be appropriate to discontinue the injection at delivery of 1 ml, providing 250 mg of dexpanthenol, and repeat the dose at a later time. Similarly, the preferred 1 ,000 mg dose may be given as, for example, two consecutive 500 mg doses.

Reduced inflammation and increased freedom of movement is usually noticeable within 48 hours from the initial injection. Using the 1000 mg dose, patients have reported an estimated 80% reduction of pain after the first injection.

To provide short-term pain relief during the course of the injection, so as to negate any pain due to the effect of the injection itself, a suitable injectable formulation comprises 1000 mg of dexpanthenol and 1-10 mg of bupivicaine, for example, as 4 mis of an aqueous solution containing 250 mg/ml. dexpanthenol and 1 ml of a solution containing 1 mg of bupivicaine or 2 ml of a 0.5% solution of bupivicaine. The dose of bupivicaine can be adjusted dependin on the reaction of indivaula patiens to the injection.

Alternatively the bupivicaine, or other local anaesthetic can be administered as a separate injection immediately before an injection of dexpanthenol.

Test Data

Example 1 62 patients (26 men; 33 women) aged 21 to 85 years were treated for traumatic inflammatory conditions. The patients were administered one or more intra-articular or peri-articular injections, ie into the inflamed joint or nearby area, of dexpanthenol in combination with a long acting local anaesthetic [4 ml of an aqueous solution of dexpanthenol Ph Eur (providing 1000 mg of dexpanthenol); 1 ml of 0.1 % bupivacaine (providing 1 mg of bupivacaine)].

In terms of pain relief following injection, efficacy outcome of the treatment is shown in the table below:

Site of complaint n* Outcome

Improved Temporarily No Worsened Not n (%) improved change n (%) reported n (%) n (%) n (%)

Back (post-traumatic 54 30 (55.6) 6 (11.1 ) 6 (11.1 ) 3 (5.6) 9 (16.7) spondylitis)

Hip 22 9 (40.9) 4 (18.2) 2 (9.1 ) 2 (9.1 ) 5 (22.7)

Knee 8 5 (62.5) 0 (0) 1 (12.5) 0 (0) 2 (25.0)

Other 14 5 (35.7) 3 (21.4) 1 (7.1 ) 1 (7.1 ) 4 (28.6)

Total 98 49 (50.0) 13 (13.2) 10 (10.2) 6 (6.1 ) 20 (20.4)

* Some patients reported more than one site

In this cohort of patients, 87% of patients complained of back pain, which was often accompanied by pain in other joints or sites. Where reported, three-quarters of all patients benefited from pain relief, while less than 10% said that their condition had worsened. Several patients mentioned that they experienced improvement after the initial injection, which continued to improve with time. Although, in most cases, the complaint was reported as 'improved' only, there was indication that several patients had considerable benefit from the treatment.

From case notes of the 62 patients, injections of dexpanthenol in combination with bupivicaine into the joint or nearby area was generally safe and well tolerated. Five (8%) of the 62 patients reported adverse events, including numbness and injection site pain, which resolved with time.

Injection of facet joints has previously almost invariably been done using MRI to ensure exact placing of the needle. However in the above testing it was found that facet joints are easily treated by injection without the use of MRI. By palpating the patient's back in the area of pain and spasm, there is often an area of extreme tenderness about 5 cms from the midline, indicating the site of the inflamed facet joints. If a needle is inserted at right angles into this area, it will be located in or exceedingly close to the facet joint. The dexpanthenol solution does not have to be injected directly into the joint, as it will diffuse into the joint from an injection adjacent to it; both are equally effective.

Example 2

The cohort of patients assessed in Example 1 primarily reported back pain to the test physician. Treatment of some patients who reported specific joint pain is summarised below.

Bepanthene is a aqueous solution containing 250 mg/ml of dexpanthenol Ph Eur, 4 mis bepanthene provides 1000 mg dexpanthenol

An injection of 2 mis of 0.5% bupivicaine provides 10 mg bupivicaine

Hip pain

Injection - 4 ml bepanthene, 2 ml of 0.5% bupivacaine

Patient 1 - hip - 1 injection - "considerable relief" straight away.

Patient 2 - left hip - 1 injection - "immediate improvement" Patient 3 - right hip - 1 injection - "hip improving, no sudden change after injection"

Patient 4 - right hip - 1 injection - " hip better"

Tennis elbow

Injection - 1-2 ml bepanthene, 0.5-1 ml of 0.5% bupivacaine

Patient 1 - both elbows injected - better

Patient 2 - 4 injections - full recovery

Patient 3 - right elbow - 2 injections - better

Patient 4 - right elbow - 2 injections - better

Shoulder pain

Injection into Capsule - 4 ml bepanthene, 2 ml of 0.5% bupivacaine

Injection adjacent Capsule (into Tendon) - 1-2 ml bepanthene, 0.5-1 ml of 0.5% bupivacaine

Patient 1 - left shoulder - 2 injections - improved

Patient 2 - 12 injections over 6 months - 95% improvement

Ankle Pain Injection - 4 ml bepanthene, 2 ml of 0.5% bupivacaine

Patient 1 - 1 injection - better

Patient 2 - 2 injections - better

Patient 3 - 1 injection - better

Patient 4 - 9 injections over 2 - months 90% improvement

Knee Pain

Injection - 4 ml bepanthene, 2 ml of 0.5% bupivacaine

Patient 1 - right knee 3 injections, left knee 2 injections - " knees have been feeling a lot better"

Claims

1. Use of panthenol in the preparation of a pharmaceutical composition for administration by intraarticular or periarticular injection of a joint which is inflamed or painful due to traumatic arthritis.

2. Use according to claim 1 , wherein panthenol is used as dexpanthenol.

3. Use according to claim 1 or 2, wherein the injectable pharmaceutical composition comprises an aqueous solution of panthenol.

4. Use according to any one of the preceding claims, wherein the injectable pharmaceutical composition includes a co-formulated local anaesthetic.

5. Use according to any one of claims 1 to 4, wherein a local anaesthetic is coadministered with panthenol in a separate injection.

6. Use according to any one of claims 1 to 5, wherein the injectable pharmaceutical composition is a formulation comprising at least 250 mg of dexpanthenol.

7. Use according to any one of claims 1 to 6, wherein the injectable pharmaceutical composition is a formulation comprising about 1000 mg of dexpanthenol.

8. Use according to any one of claims 1 to 6, wherein the injectable pharmaceutical composition is a formulation comprising 250 - 1000 mg of dexpanthenol and 1 - 10 mg bupivivaine.

9. Use according to any one of claims 1 to 8 wherein the medicament is for intraarticular or periarticular injection of elbow, shoulder, knee, ankle, hip and facet joints.