Pain management with liposome-encapsulated analgesic drugs

Abstract

liposome-encapsulated opioid analgesic agents delivered by the pulmonary route provide local, or systemic analgesia superior to that produced by the solution form of these agents administered by parentral (intravenous, intramuscular, or subcutaneous injection) or oral routes.

Description

DESCRIPTION OF THE INVENTION

The present invention broadly relates to the use of liposome encapsulation to improve the analgesic effects of opioid analgesic agents administered to an individual via the pulmonary system. A major advantage of this invention is the obtainment of a sustained analgesic effect using a noninvasive method of drug delivery. Because of the noninvasive nature of this drug delivery system, it is particularly suitable for certain patient populations, such as small children where other delivery systems are problematic. The present invention may be used to provide systemic analgesic treatment both for human and veterinary purposes. Analgesic agents, such as opioids, are good candidates for liposome encapsulation.

The amount of the opioid analgesic agent or drug to be included in the liposomal preparation is not, per se, critical and can vary within wide limits depending inter alia on the particular agent, the intended application and the lipid used. Generally, the opioid analgesic agent may be included in an amount of between about 0.005 to 10% by wt. of the liposomal preparation and more usually may be included in an amount of between 0.01 and 0.1% by wt.

Inhaled liposome-encapsulated opioid analgesic agents are expected to have less variability than other routes of drug delivery (e.g. transdermal administered fentanyl), will not require a functioning bowel, can provide rapid onset of analgesic action suitable for acute pain management, and will be inexpensive to manufacture. In other words, inhalation of liposome-encapsulated opioid analgesic agents offers the following benefits as a method of analgesic drug administration: (1) a simple and noninvasive route of administration; (2) a rapid onset of analgesia from absorption of free opioid (in the range of 10-20% of the opioid dose); (3) a sustained analgesia from continued release of liposome-encapsulated opioid (approximately 80-90% of the opioid dose) and (4) a low cost. Thus, inhaled liposome-encapsulated fentanyl may provide a significant advance in our therapeutic armamentarium against acute and chronic pain, at lower cost than currently available therapies.

The sustained release property of the liposomal product can be regulated by the nature of the lipid membrane and by the inclusion of other excipients in the composition of the liposomal products. Decades of research in liposome technology permits a reasonable prediction on the rate of drug release based on the composition of the liposome formulation. The rate of drag release is primarily dependent on the nature of the phospholipids, e.g. hydrogenated (--H) or unhydrogenated (--G), or the phospholipid/cholesterol ratio (the higher this ratio, the faster the rate of release), the hydrophilic/lipophilic properties of the active ingredients and by the method of liposome manufacturing.

Materials and procedures for forming liposomes are well-known to those skilled in the art and need not be described herein in detail. Reference is made to U.S. Pat. Nos. 4,485,054, 4,761,288 and 4,937,078, the disclosures of which are hereby incorporated by reference, for the disclosure of suitable liposome preparation techniques. As described therein, the liposomes can be prepared as multilamellar lipid vesicles (MLV), unilamellar lipid vesicles, including small unilamellar vesicles (SUV) and large unilamellar vesicles (LUC) and as multivesicular liposomes. Many other liposome manufacturing techniques also can be used to make the final liposomal product containing the appropriate active ingredient, lipids, and other excipients as will be understood by those skilled in the art. For example, suitable liposomes also can be prepared using the known ethanol or ether injection methods. Suitable active ingredients are opioid analgesic agents including such opioid agents as alfentanil, anileridine, codiene, diamorphine, fentanyl, hydrocodone, hydromorphone, meperidine (pethidine), morphine, oxycodone, oxymorphone, propoxyphene and sufentanil and the opioid agonists and antagonists pentazocine and nalbuphine. Lipid components are usually phospholipids and cholesterol; excipients are tocopherol, antioxidants, viscosity inducing agents, and/or preservatives.

Phospholipids are particularly useful, such as those selected from the group consisting of phosphatidylchloines, lysophosphatidylchloines, phosphatidylserines, phosphatidylethanolamines, and phosphatidylinositols. As noted, such phospholipids often are modified using for example, a modifying agent selected from the group consisting of cholesterols, stearylamines, stearic acid, and tocopherols. The lipid typically is dissolved in a solvent and the solvent then is evaporated, typically under a reduced pressure, to yield a thin lipid film containing any lipophilic analgesic agent. Afterwards, the film is hydrated, with agitation, using an aqueous phase containing any desired electrolytes and any hydrophilic analgesic agent, and lipid vesicles entrapping the analgesic agent are produced. As recognized by those skilled in the art, while certain materials and procedures may give better results with certain drugs, the use of particular materials and procedures are not narrowly critical and optimum conditions can be determined using routine testing. Additionally, as also noted, a preservative or antioxidant often will be added to the preparation.

In summary, the pharmacokinetic profiles of this new noninvasive method of opioid delivery indicate that pulmonary administration of the liposome-encapsulated opioid analgesic agents offers significant advantages over the conventional parenteral opioid administration as a method of analgesic drug administration with rapid onset and sustained analgesic effect.

The liposome-encapsulated opioid analgesic agents normally are administered to a human patient in an amount to provide an accepted and necessary level of therapeutic postoperative analgesic plasma concentration, commonly agreed to be in the range of 0.2 to 1.2 ng/ml. As will be recognized by those skilled in the art, the required amount of encapsulated opioid in a single dose will depend on a variety of factors including inter alia body weight, lung capacity, lung function and the like. Inhalation of between about 1000 μg to 4000 μg per dose will be suitable in many cases. Of course, within the broad practice of the present invention the dose amount can be varied as needed to obtain any desired effect.

In accordance with the present invention, the liposome-encapsulated opioid analgesic agents can be delivered by direct inhalation of an aerosol using any of the variety of known methods for delivering drugs through the pulmonary system.

The bioavailability or the amount of drug delivered to the lungs can be improved with the use of a large initial volume of solution placed in the nebulizer, a higher compressed gas flow rate (12 I.min^-1) to produce a higher percentage of small droplets (1-5μ), deep inhalation with breath holding, and the use of positive expiratory pressure (Resistex ™, D. C. Lung Co. Inc., Sebastopol, Calif., U.S.A.) during the aerosol therapy (Newman S. P.: Chest 88(2):152s-160s, 1985 and Anderson J. B., et al: Eur J Resp Dis 63(suppl) 119:97-100, 1982).

The following examples are illustrated of the present invention, and are not to be regarded as limiting. In the following examples, representative active ingredients: fentanyl, alfentanil, sufentanil and morphine were encapsulated into uni- and multi-lamellar liposomes using a procedure described by Mesei M., et al: U.S. Pat. No. 4,485,054. Briefly, the phospholipids, cholesterol and lipophilic opioid analgesic agents (and other lipid soluble agents, if present in the formula) were dissolved in chloroform/methanol mixture in a pear shape flask containing glass beads. The solvent was then evaporated to dryness in a rotary evaporator under reduced pressure at 30°C C. until a smooth, thin lipid film was obtained on the surface of the flask and glass beads. The film was then hydrated with a sterile aqueous solution containing any water soluble (hydrophilic) opioid analgesic agents (this would include most salt forms of the analgesic compounds), at the transition temperature of the phospholipid, by shaking 30 minutes in a Lab Line Orbit Environment-Shaker. The sterile water may contain some electrolytes, e.g., sodium chloride, sodium bicarbonate, and/or calcium chloride in an amount that renders the final product isotonic and yields a pH near 7.4. In the following examples, the ethanol was generally added to the aqueous phase before forming the liposomes or to the finished liposomal product. The liposomes were then separated from the glass beads by filtering through a Buchner funnel without filter paper. In some cases, where a low solubility of the active ingredient limited higher drug concentration in the final liposomal product, or where it is desired to increase the level of opioid analgesic agent initially absorbed as free opioid, the multiphase liposomal drug delivery system described and claimed in Mezei in U.S. Pat. No. 4,761,288; can be utilized to advantage. Both the base and salt forms of the active ingredient have been used for preparing the liposomal-encapsulated product.

OPIOID FORMULAS FOR INHALATION

Example 1.
Formula (for each 100 ml):
	Fentanyl citrate	40.0	mg
	Soy lecithin (unhydrogenated)	5000.0	mg
	Cholesterol	500.0	mg
	Ethanol 95%	5.0	ml
	Sterile water for injection	q.s. to 100.0	ml
Example 2.
Formula (for each 100 ml):
	Fentanyl citrate	60.0	mg
	Soy lecithin (unhydrogenated)	5000.0	mg
	Cholesterol	500.0	mg
	Ethanol 95%	5.0	ml
	Sterile water for injection	q.s. to 100.0	ml
Example 3.
Formula (for each 100 ml):
	Fentanyl citrate	40.0	mg
	Soy Lecithin (unhydrogenated)	2000.0	mg
	Cholesterol	200.0	mg
	Ethanol 95%	5.0	ml
	Sterile water for injection	q.s. to 100.0	ml
Example 4.
Formula (for each 100 ml):
	Fentanyl (based)	40.0	mg
	Soy ecithin (hydrogenated)	2,000.0	mg
	Cholesterol	200.0	mg
	Ethanol 95%	10.0	ml
	Sterile water for injection	q.s. to 100.0	ml
Example 5.
Formula (for each 100 ml):
	Fentanyl citrate	60.0	mg
	Soy lecithin (hydrogenated)	5,000.0	mg
	Cholesterol	500.0	mg
	Ethanol 95%	5.0	ml
	Sterile water for injection	q.s. to 100.0	ml
Example 6.
Formula (for each 100 ml):
	Alfentanil HCl	200.0	mg
	Soy lecithin (hydrogenated)	5,000.0	mg
	Cholesterol	1,000.0	mg
	Sterile water for injection	q.s. to 100.0	ml
Example 7.
Formula (for each 100 ml):
	Sufentanil	10.0	mg
	Soy lecithin (hydrogenated)	2,000.0	mg
	Cholesterol	200.0	mg
	Ethanol 95%	10.0	ml
	Sterile water for injection	q.s. to 100.0	ml
Example 8.
Formula (for each 100 ml):
	Morphine	400.0	mg
	Soy lecithin (hydrogenated)	7,000.0	mg
	Cholesterol	1,000.0	mg
	Ethanol 95%	10.0	ml
	Sterile saline solution	q.s. to 100.0	ml

PHARMACOKINETIC EVALUATIONS

Apart from drowsiness, nausea and vomiting which are known side effects of opioids, none of the subjects had any complications during the pharmacokinetic study reported below. The oxygen saturation of the subjects was maintained above 85% during the study while breathing room air. There were no significant hemodynamic changes during the study.

EXAMPLE 9

Liposome-Encapsulated Fentanyl

Ten healthy volunteers were recruited to study the plasma opioid concentration-time profiles of several liposome formulations of entanyl (Examples 1, 3, and 4) administered through the pulmonary system by inhalation. None of the studied subjects had a history of cardiovascular, respiratory, hepatic or renal dysfunction. Subjects with a history of analgesic abuse, opioid addition, or opioid allergies were excluded. Volunteers fasted for 5 hours prior to the study. Studies were conducted in a post-anesthetic care unit with monitoring of blood pressure, heart rate and pulse oximetry. A 16 gauge intravenous catheter was inserted under local anaesthesia to facilitate blood sampling. During Phase I of the study, each volunteer received an intravenous injection of 200 μg of fentanyl, insolution form (Sublimaze ™, Janssen Pharmaceutica, New Jersey), over one minute through a 21 gauge butterfly needle in the contralateral forearm. Venous blood samples (3 mls each) were drawn at 2, 4, 6, 8, 10, 15, 20, 25, 30, 60, 90, and 120 minutes and at 4, 6, 8, 12, 18, and 24 hours. The plasma was separated immediately following the blood collection and stored at -20°C C. under analyzed.

Phase II of the study was conducted under similar conditions following a four-week washout period. The volunteers were divided into 3 groups: Group A (3 subjects) received the composition of Example 1; Group B (4 subjects) received the composition of Example 3; and Group C 93 subjects) received the composition of Example 4. Each volunteer received 2000 μg of liposome-encapsulated fentanyl (either Example 1, 3 or 4) in a 5 ml preparation via a nebulizer (Power Mist ™, Hospitak, Lindenhurst, N.Y., U.S.A.) with 6 l.min^-1 flow of oxygen over 15 minutes. Venous blood (3 mls) was drawn at 5, 10, 15, 20, 25, 30, 60, 90, and 120 minutes, and at 4, 8, 12, 20, 24, 32, 40, and 48 hours. The plasma was separated immediately following the blood collection and stored at -20°C C. until analyzed.

All plasma fentanyl concentrations were determined using a modified radioimmunoassay (RIA) technique as described by Michiels and colleagues (Michiels M., et al: Eur J Clin Pharmacol 12: 153-158, 1977).

The plasma fentanyl concentration-time profiles of intravenous (IV) administration and via the inhalation of liposome-encapsulated fentanyl of one of three subjects in Group A (Example 1) are shown in FIGS. 1A and 1B. The illustrated fentanyl concentration-time profiles demonstrate that there are major advantages of inhaled liposome-encapsulated fentanyl over the intravenous administered fentanyl in providing pain relief. Following a bolus IV injection of 200 μg of fentanyl, there is an initial peak plasma fentanyl concentration of 4.67 ng.ml^-1 (see insert of FIGS. 1A and 1B). This peak fentanyl concentration far exceeds the reported necessary therapeutic postoperative analgesic concentrations range of 0.2 to 1.2 ng.ml^-1 Gourlay G. K., et al: Anesth Analg 67:329-37, 1988) and, has actually reached the limit which may cause respiratory depression (Glass P. S. A., et al: In Anesthesia, 3rd Edition, Miller R. E. (ed): Churchill Livingstone, New York, pp 367-88, 1990). However, due to rapid distribution and elimination, plasma fentanyl concentration (C_fen) fell below the therapeutic range (0.2 ng.ml^-1) in less than 4 hours. In other words, to obtain the benefit of only a short duration of pain relief, patients initially are exposed to a potential risk of respiratory depression following parenteral administration of opioid such as fentanyl. In contrast, following the inhalation of the liposome-encapsulated fentanyl, the peak C_fen (1.2 ng.ml^-1) is rapidly achieved in 15 minutes (see inset of FIG. 1B) and is well below the threshold for possible respiratory depression. The plasma C_fen is maintained within the therapeutic analgesic range for almost 24 hors which is substantially longer than obtained with IV administration (FIG. 1A).

The 24 hour mean (±sem) plasma fentanyl concentrations of Example 1 (3 subjects), Examples 2 (4 subjects) and Example 3 (3 subjects) are shown in FIG. 2. The formulation of Example 1 provided the best plasma fentanyl concentration profile in comparison with the other 2 formulations. The pharmacokinetic parameters following the inhalation of the 3 different formulations of liposome-encapsulated fentanyl are summarized in Table 1. Absorption of fentanyl was modest and reasonably rapid and bioavailability ranged between 8.4 to 17.5%. While Example 1 provides the highest bioavailability compared to the other two formulations, overall, the amount of opioid absorbed in each example is in good agreement with other reports on the bioavailability of drugs administered through the pulmonary system, which ranges between 10 to 20% (Tattersfield A. E.: In Bronchodilator Therapy, Clark T. J. H. (ed): ADIS Press Ltd., Auckland, New Zealand, pp 76-92, 1984).

TABLE 1
Mean (±sd) pharmacokinetic parameters following the inhalation
of encapsulated fentanyl of three different liposome formulations.
Liposome	Time to
Formula-	Peak				Cfen at	Cfen at
tion	Absorption	Bio-	Cmax	TMax	8 hr	24 hr
Example	(min)	availability	(ng · ml-1)	(min)	(ng · ml-1)	(ng · ml-1)
1	8.33 ±	0.175 ±	1.24 ±	15 ±	0.374 ±	0.258 ±
	2.36	0.078	0.398	0.0	0.16	0.208
3	22.5 ±	0.084 ±	1.08 ±	28 ±	0.209 ±	0.120 ±
	4.33	0.008	0.258	4.69	0.08	0.036
4	15 ± 8.165	0.125 ±	1.16 ±	23.33 ±	0.17 ±	0.088 ±
		0.043	0.411	2.36	0.064	0.017
Cmax = Peak plasma fentanyl concentration.
Tmax = Time to peak plasma fentanyl concentration.

EXAMPLE 10

Liposome-Encapsulated Alfentanil

On separate occasions and under similar conditions as described above, a healthy volunteer received an intravenous injection of 500 μg of alfentanil, in solution form (Alfenta ™, Janssen Pharmaceutica, New Jersey), over one minute and 5 ml (4.0 mg) of liposome-encapsulated alfentanil (Example 6) via a nebulizer (Power Mist ™, Hospitak, Lindenhurst, N.Y., U.S.A.) with 6 l.min^-1 flow of oxygen over 15 minutes. Venous blood (3 mls) was collected at regular intervals as described above. The plasma was separated immediately following the blood collection and stored at -20°C C. until analyzed. All plasma alfentanil concentrations were determined using a modified radioimmunoassay (RIA) techniques as described by Michiels and colleagues (Michiels M., et al: J Pharm Pharmacol 35:86-93, 1983).

The plasma alfentanil concentration-time profiles following both IV and aerosol administration are shown in FIGS. 3A and 3B. Following the IV administration, the plasma alfentanil concentration peaks rapidly. This is followed by a characteristic rapid decline of alfentanil concentration secondary to its rapid clearance by the body. The concentration of alfentanil is undetectable beyond 12 hours following the IV administration. In contrast, alfentanil concentration peaks within 25 minutes following the inhalation of liposome-encapsulated alfentanil. The plasma alfentanil is maintained substantially higher within the therapeutic analgesic range for a significantly longer period than the IV administration.

PHARMACODYNAMIC EVALUATIONS

EXAMPLE 11

Following the pharmacokinetic study with healthy volunteers, a clinical study was conducted to determine the effectiveness of inhaled liposome-encapsulated fentanyl for post-operative pain control. Three patients having lumbar discectomy under a standardized anesthetic technique were studied. When pain medication was first requested, each patient received 3000 μg of liposome-encapsulated fentanyl (Example 5) aerosol in the post anesthetic care unit following the operation. The opioid analgesic requirement and frequent visual analogue pain scores for the first 24 hours following the surgery were recorded. The average 24 hour morphine requirement following the liposome-encapsulated fentanyl aerosol was 18 (±10.4) mg which is substantially less than patients who had a similar operation but die not receive the fentanyl aerosol. Most patients required approximately 10 mg of morphine every 4 hours (60 mg for the first 24 hours) following the lumbar spine operation. Following the administration of the liposome-encapsulated fentanyl, the visual analogue pain score was also reduced from an average baseline score of 6.7 (prior to the administration of aerosol fentanyl) to a mean score of less than 5 for 24 hours (FIG. 4). The reduction in the first 24 hour post-operative opioid analgesic requirement as well as the lower visual analogue pain scores following the aerosol suggest that pulmonary route of administering liposome-encapsulated fentanyl provides an effective method of drug delivery of opioid.

On two separate occasions, liposome-encapsulated sufentanil (Example 7 which contains 500 μg of sufentanil in 5 ml) and morphine (Example 8 which contains 200 mg of morphine in 5 ml) were administered to a patient with multiple painful joints secondary to rheumatoid arthritis. Following, the administration of the liposome-encapsulated opioid, there was a significant reduction in the visual analogue pain score as well as the analgesic requirement for up to 48 hours in comparison with the baseline. These results confirmed the data obtained from fentanyl study that inhalation of liposome-encapsulated opioid provides a rapid onset and sustained relief of pain.

In summary, our preliminary pharmacodynamic data show that inhalation of liposome-encapsulated opioid is safe and efficacious in providing pain relief to patients who are suffering from both acute and chronic pain.

The principles, preferred embodiments and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed as limited to the particular forms disclosed, since they are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art without departing from the spirit of the invention.

Claims

1. A method of managing pain in a patient comprising administering to said patient a composition containing a liposome-encapsulated opioid analgesic agent through said patient's pulmonary system.

2. The method of claim 1 in which the liposome-encapsulated opioid analgesic agent comprises multilamellar lipid vesicles.

3. The method of claim 1 wherein the liposome-encapsulated opioid analgesic agent comprises unilamellar lipid vesicles.

4. The method of claim 1 wherein the liposome-encapsulated opioid analgesic agent is multivesicular.

5. The method of claim 1 wherein the liposome-encapsulated opioid analgesic agent comprises a multiphase liposomal system.

6. The method of claim 1 wherein the liposome-encapsulated opioid analgesic agent is prepared using a phospholipid.

7. The method of claim 6 wherein the phospholipid is selected from the groups consisting of phosphatidylcholines, lysophosphatidylcholines, phosphatidylserines, phosphatidylethanolamines, phosphatidylinositols and mixtures thereof.

8. The method of claim 6 wherein said phospholipid is provided in admixtures with a modifying agent selected from the group consisting of cholesterol, stearyl amines, stearic acid, tocopherols, and mixtures thereof.

9. The method of claim 8 wherein said opioid analgesic agent is selected from the group consisting of alfentanil, anileridine, codiene, diamorphine, fentanyl, hydrocodone, hydromorphone, meperidine (pethidine), morphine, oxycodone, oxymorphone, propoxyphene, sufentanil, pentazocine and nalbuphine.

10. The method of claim 1 wherein the composition contains said opioid in an amount of between 0.005% to 10% by weight.

11. A method for providing systemic analgesia in a patient by administering a liposomal both a free and liposome-encapsulated opioid analgesic agent by inhalation through said patient's pulmonary system, said analgesic agent being selected from the group consisting of fentanyl, alfentanil and sufentanil.

12. The method of claim 1 wherein the opioid analgesic agent is fentanyl or a salt form thereof.

13. The method of claim 12 wherein the opioid analgesic is fentanyl base.

14. The method of claim 12 wherein the opioid analgesic is fentanyl citrate.

15. The method of claim 1 wherein the opioid analgesic is alfentanil or a salt form thereof.

16. The method of claim 15 wherein the opioid analgesic is alfentanil base.

17. The method of claim 15 wherein the opioid analgesic is alfentanil HCl.

18. The method of claim 1 wherein the opioid analgesic is sufentanil.

19. The method of claim 2 wherein the free form selected opioid analgesic agent is in the range of 10-20% of opioid dose.

20. The method of claim 2 wherein the selected analgesic agent is fentanyl citrate.

21. The method of claim 1 wherein the opioid analgesic agent is selected from the group consisting of fentanyl, alfentanyl and sufentanil.

22. A method of managing pain in a patient comprising administering to said patient a composition containing both free and liposome-encapsulated fentanyl citrate through said patient's pulmonary system, wherein said liposome-encapsulated fentanyl citrate is prepared using a phosphatidylcholine in admixture with cholesterol, and wherein said liposome-encapsulated fentanyl citrate comprises a mixture of unilamellar vesicles and multilamellar vesicles.

23. The method of claim 22, wherein the composition comprises an amount of fentanyl citrate suitable to afford a plasma concentration in a range of between 0.2 ng/ml to about 1.2 ng/ml.

24. A method for providing systemic analgesia in a patient by administering both free and liposome-encapsulated fentanyl citrate by inhalation through said patient's pulmonary system, wherein said liposome-encapsulated fentanyl citrate is prepared using a phosphatidylcholine in admixture with cholesterol, and wherein said liposome-encapsulated fentanyl citrate comprises a mixture of unilamellar vesicles and multilamellar vesicles.

25. The method of claim 24, wherein the composition comprises an amount of fentanyl citrate suitable to afford a plasma concentration in a range of between about 0.2 ng/ml to about 1.2 ng/ml.