Dm
COMMENT
Intranasal Administration of Peptide Hormones: Factors Affecting Transmucosal Absorption A. E. Pontiroli, G . Pozza lstituto 5an Raffaele,Cattedra di Clinica Medica, Universita di Milano, Milano, ltaly
KEY WORDS
lntranasal administration
Peptides
Insulin
Clucagon
Introduction
The Nose, its Function, and Peptides
The advent of DNA recombinant technology will probably yield more and more peptides of high purity for human research or for treatment of human diseases. Table 1 gives an incomplete list of what is now available. Unfortunately, peptides can not be administered orally and require injection. Contrary to what is commonly believed, injection therapy is not the ideal form of administration. The physician who prescribes injections for a long period (growth hormone to short children, insulin to diabetic patients, calcitonin to patients with osteoporosis or with Paget’s disease of bones) often does not appreciate all the major drawbacks:
The main functions of the nose are heating and humidifying inhaled air, removal of inhaled particles, and the sense of smell. The inner nose has a 150 cm2 surface area, and a total volume of about 15 ml. The threelayered mucosa, 2 to 4 mm thick, 80 % respiratory, 20 % olfactory, is covered by mucus and has a rich lymphatic and capillary network, thus allowing rapid exchange between blood and the inspired air. The epithelium i s made of different kinds of cells, mainly mucous cells and ciliated cells. Ciliated cells generate a unidirectional movement of mucus towards the pharynx, and remove whai is not absorbed through the m u ~ o s a . ~ The awareness that the nose allows administration not only of locally acting drugs, but also of systemically active peptides i s not new, but was limited to small peptides, ten amino acids or less, for which direct absorption is rapid. Harris has listed some of the features that make naturally occurring peptide hormones appealing candidates for intranasal administration: broad pharmacological activity, short half-life, good biological tolerability, poor stability in gastrointestinal fluids, and extensive first pass metabolism in the liver. In addition, these peptides are usually those that are prescribed for chronic and life-long diseases, for substitution therapy, and administered par enter all^.^ Table 2 lists peptides that are currently available for administration by the nasal route. Salmon calcitonin is unusual in view of its large size. Figure 1 shows how the dimensions of the peptides influence intranasal absorption, such that beyond a length of 30 amino acids practically no absorption occurs. Promoters are required to allow absorption of larger peptides, so that it may be that benzyl-alcohol-chloride, a preservative present in the pharmaceutical intranasal formulations of salmon calcitonin, has to be considered a promoter. Human calcitonin i s known to have only 3.4 % absorption, increased six to seven fold by a variety of promoter^.^ Various types of promoters, of entirely different chemical natures, have been used in the past. They belong to four main groups: chelating agent (such as EDTA and citric acid), detergents or surfactants (such as 9-lauryl-
1 . Patients accept injections poorly, especially over long periods, and often default from treatments that are not life saving, or continue with the treatment erratically, with the consequence that many ’treatment failures’ may really be ’patient failures’. 2 . Many patients are unable to carry out injection therapy by themselves, and have to rely on friends or relatives, who must in turn become familiar with aseptic procedures and with injection techniques. 3. Subcutaneous absorption of insulin has an inter- and intra-patient variability of up to 60 Yo, and high variability also occurs with intramuscular growth hormone.’f2 4. Injection therapy does not mimic physiology, since injections are made in traditional sites (for example intramuscularly in the glutei for growth hormone and for calcitonin, subcutaneously in the arms for insulin) with no relationship to the physiological route or rhythm of secretion of the endogenous peptide to be substituted. These are just some of the reasons why alternative routes of peptide administration have been looked for. One such route of interest i s the nasal mucosa.
Correspondence to: Antonio E. Pontiroli, lstituto San Raffaele, Via Olgettina 60, 201 32 Milano, Italy.
770
0 ~ ~ 2 - ~ ~ ~ ~ / 9 0 / 0 9 ~ ~ ~ ~ - 0 ~ $ ~ ~ . ~ ~ & Sons, Ltd.
0 1990 by John Wiley
DIABETIC MEDICINE, 1990; 7: 770-774
DTT7
COMMENT Table 1. Peptide hormones available for clinical use Extractive
Synthetic
DNA-recombinant technology
HCG HMG
Oxytoci n ACTH LHRH and analogues dDAVP TRH GHRH Ceruletide Somatostatin and analogues Calcitonin (human, salmon, eel) a-Natriuretic factor
Insulin Growth hormone (?I Calcrtonin
~
FSH LH Vasopressin Glucagon
HCG, human chorionic gonadotropin; HMG, human menopausal gonadotropin; dDAVP, desmopressin
Table 2. Peptides currently available for intranasal administration Peptide
Indication
LHRH analogues (n = 9, buserelin, LHRH-t, leuprolide, nafarelin)
Prostate carcinoma, (mammary carcinoma, endornetriosis, uterine leiomyoma, precocious puberty, contraception)
Oxytocin ( n = 9)
Lactation, labour induction
~~
~~~
~~~~~
Vasopressin, desmopressin (n = 9)
Diabetes insipidus
LHRH (n = 10) Salmon calcitonin (n = 32)
Cryptorchidisrn Osteoporosis, Paget's disease of bones
n = number of amino acids; ( ) applications under clinical evaluation
ether), fatty acids (oleic acid), and bile Salk6 It i s not clear how the promoters work. They might: (1) alter the mucous layer covering the nasal mucosa; (2) open the tight junctions of the epithelial cells; (3) form reverse micelles within nasal cell membrane^.',^ In the case of bile salts, their capacity to enhance transmembrane transport has been related to their ability to induce haemolysis of isolated erythrocytes and to release proteins from cu Itured epi the1ia . However sod ium g Iycoc holate and sodium taurodihydrofusidate have equal enhancing effects on insulin absorption in spite of greatly differing lytic proper tie^;^ it has also been suggested that bile salts might inhibit proteases of the nasal mucosa, thus enhancing spontaneous absorption of peptides.'O Therefore it is possible that different promoters act at different levels, and, alternatively, that different promoters, of entirely different chemical nature, act by as yet unknown mechanisms or by a combination of different mechanisms.1°
'
Experience with Individual Peptides
Insulin From the early 1920s attempts have been made to administer insulin by the nasal route.','' Today we know INTRANASAL ABSORPTION OF PEPTIDES
that insulin is not absorbed as such and that it requires the presence of promoters such as bile salts, 9-laurylether (a detergent), saponin, or derivatives of fusidic acid. Alternatively, insulin can be diluted in an acid medium (pH 3.1).12,13 The efficacy in humans (fall of blood glucose levels and increase of serum insulin levels) is similar for human and porcine insulin,14 and can be enhanced by increasing the amount of insulin or of the p r ~ m o t e r , ' ~ while sprays are more effective than drop^.'^-'' Plasma insulin levels peak after 10 to 20 min, and a decrease of blood glucose levels takes place between 12 and 45 min.14-18 Monomers of insulin are not absorbed in the absence of a promoter (Pontiroli et a/., unpublished data).
Glucagon Glucagon, albeit highly effective in counteracting hypoglycaemia in insulin-treated diabetic patients, i s infrequently employed in that role. Glucagon is unstable in solution which must therefore be freshly prepared, and its use requires familiarity with aseptic procedures and with injection techniques. lntranasal administration of freshly prepared glucagon solutions raises blood
771
Dm
COMMENT
Growth Hormone Releasing Hormone (GHRH)
100.0
GHRH, available as a 1-29 or a 1-40 amino acids peptide, currently employed for the evaluation of pituitary function, i s of value in the treatment of some children with growth disorders. It requires intermittent or continuous subcutaneous injection or continuous intravenous infusion. Its systemic availability after intranasal administration is very low (0.2 to 0.6 %), and can be increased to about 7.1 % by the addition of bile salt^.^^-^"
50.0
20.0
10.0
Corticotrophin Releasing Hormone (CRH) 5 .O
CRH, 41 amino acids, stimulates ACTH and hence cortisol release; its use in the diagnosis of disorders of the pituitary-adrenal axis has been proposed. CRH also has a low systemic availability (0.1 %) after intranasal administration, significantly enhanced (to 3.0 up to 100 %) by increasing amounts of bile
h
3.0 C
.-0 c
!2
2
(5)
a
a
I
1.0
14
Is; GHRH1-290 (24)
0.5
Comments and Perspectives
1
0.2
. .
0.1
A0 I
0
.
d
.
5 10
20
30
40
50
60
Length of the peptide (amino acids) Figure 1. lntranasal administration of peptide hormones; systemic availability (% absorption, logarithmic scale) as a function of the length of the peptide (number of amino acids); systemic availability of each peptide i s 100 % after intravenous
lntranasal administration of some peptides is now of established clinical value. For others, experimental administration is improving rapidly, and insulin and glucagon are amongst these. Appealing features of this route of administration are the ease of self-treatment, patient compliance, and the pharmacokinetic properties, namely the rapid appearance in plasma after intranasal administration.’,’ The main factors affecting transmucosal absorption of peptides are:
1. 2. 3. 4.
length of the molecule; presence of a promoter for long molecules; nature of the delivery (drops vs sprays);28 sensitivity to endogenous peptidases.26
administration; 0 = without promoters; 0 = with different promoters. Numbers in brackets indicate published papers as they appear in the list of references; a, animal studies; hCT, human calcitonin; VP, vasopressin; LHRHan9, LHRH analogue with 9 amino acids. Other abbreviations as for Table 1
Technical problems that have to be solved however include the development of devices acceptable to patients. It also needs to be shown that the effects are reproducible under different conditions. A common concern i s that local diseases, such as the common cold or chronic rhinitis, might alter the systemic availability of intranasally administered drugs. Two papers have shown that this i s not the case for buserelin or for dDAVP, but data about other, larger peptides are not glucose levels when promoters like sodium glycocholate, sodium deoxycholate or 9-lauryl-ether are p r e ~ e n t . ~ , ” - ~ ~ a ~ a i l a b l e . ~ ~ ~ ~ ” Local toxicity i s a possible side-effect of promoters, as Simply increasing the solubility of glucagon by means of shown by animal s t ~ d i e s , ~ , ” and - ~ ~ some nasal irritation 2 hydroxy-propyl-P-cyclodextrin i s not effective (Pontirol i has been reported in clinical studies (burning, et a/., unpublished data). lntranasal glucagon i s as lachrymation).’,” The concern for local toxicity is of effective but more rapidly acting than oral glucose in course not so great for glucagon, given its likely sporadic raising blood glucose levels in normal subjects, and its use, as compared with insulin, which can be expected effect has a good reproducibility when tested on different to be used every day for years. Newer promoters are days in the same subjects.21 lntranasal glucagon i s therefore required for peptides for which a prolonged also effective in diabetic patients under conditions of administration i s foreseen, and currently promising proeuglycaemia and of hypoglycaemia.21,22As with insulin, moters include phospholipids and natural lung surfactant spray solutions are more effective than drops.20
772
A.E. PONTIROLI. C. POZZA
Dm which are likely to be as active but far less toxic than current promoters.34 lntranasal absorption of other drugs, currently administered by the oral route, i s also appealing for different reasons. For example progesterone in a polysorbate 80 saline solution has a 100 % systemic availability w h e n administered intranasally, and an identical pharmacokinetic profile to intravenous progesterone, w h i l e intraduodenal progesterone has o n l y a 1.2 % systemic a ~ a i l a b i l i t y . ~Propranolol ~ hydrochloride in 2 % methylcellulose, placed i n the nasal cavity, has a 100 % systemic availability, while orally administered propranolol has only a 25 % systemic a ~ a i l a b i l i t y . ~ ~
References 1 . Moses AC, Flier JS. Unconventional routes of insulin administration. In: Alberti KGMM, Krall LP, eds. The Diabetes Annual/3. Amsterdam: Elsevier, 1987: 107-1 20. 2. Albertson-Wikland K, Westphal 0,Westgren U. Daily subcutaneous administration of growth hormone in growth hormone deficient children. Acta Paediatr Scand 1987; 75: 89-97. 3 . Mygind N. Nasal Allergy. Oxford: Blackwell Scientific Publications, 1981. 4. Harris AS. Biopharmaceutical aspects of intranasal administration of peptides. In: Davis SS, lllum L, Tomlinson E, eds. Delivery Systems for Peptide Drugs. New York: Plenum Press, 1986: 191-204. 5. Pontiroli AE, Alberetto M, Calderara A, Pajetta E, Pozza G. Nasal administration of glucagon and human calcitonin to healthy subjects: a comparison of powders and spray solutions and of different enhancing agents. Eur / Clin Pharrnacol 1989; 37: 427-430. 6. Lee VHL. Enzymatic barriers to peptide and protein absorption and the use of penetration enhancers to modify absorption. In: Davis SS, lllum L, Tomlinson E, eds. Delivery Systems for Peptide Drugs. New York: Plenum Press, 1986: 87-1 04. 7. Gordon GS, Moses AC, Silver RD, Flier JS, Carey MC. Nasal absorption of insulin: enhancement by hydrophobic bile salts. Proc Natl Acad Sci USA 1985; 82: 741 9-7423. 8 . Hersey SJ, Jackson RT. Effect of bile salts on nasal permeability in vitro. / Pharm Sci 1987; 76: 876-879. 9. Longenecker JP. Nazlin, transnasal systemic delivery of insulin. In: Davis SS, lllum L, Tomlinson E, eds. Delivery Systems for Peptide Drugs. New York: Plenum Press, 1986: 21 1-220. 10. Muranishi S. Absorption enhancers: mechanisms and applications. In: Prescott LF, Nimmo WS, eds. Novel Drug Delivery. Chichester: Wiley, 1989: 69-77. 11. Pontiroli AE, Secchi A, Alberetto M. Alternative routes of peptide hormone administration. Spec Top Endocrinol Metab 1985; 7: 77-99. 12. Hirai S, lkenaga T, Matsuzawa T. Nasal absorption of insulin in dogs. Diabetes 1977; 27: 296-299. 13. Aungst BJ, Rogers NG, Shefter E. Comparison of nasal, rectal, buccal, sublingual, and intramuscular insulin efficacy and the effects of bile salt promotion enhancers. / Pharmacol Exp Ther 1988; 244: 23-27. 14. Pontiroli AE, Alberetto M, Pajetta E, Calderara A, Pozza G . Human insulin plus sodium glycocholate in a nasal spray formulation: improved bioavailability and effectiveness in normal subjects. Diabete Metabol 1987; 13: 44 1-443. INTRANASAL ABSORPTION OF PEPTIDES
COMMENT Moses AC, Gordon GS, Carey MC, Flier JS. Insulin administered intranasally as an insulin-bile salt aerosol. Effectiveness and r-producibility in normal and diabetic subjects. Diabetes 1983; 32: 1040-1 047. 16. Paquot N, Scheen AJ, Franchimont P, Lefebvre PJ. The intranasal administration of insulin induces significant hypoglycaemia and classical counterregulatory hormonal responses in normal man. Diabete Metabol 1988; 14: 31-36. 17. Salzman R, Manson JE, Friffing GT, et a/. lntranasal aerosolized insulin. Mixed-meal studies and long-term use in type 1 diabetes. New Engl / Med 1985; 312: 1078-1 084. 18. Pontiroli AE, Alberetto M, Secchi A, Dossi G, Bosi I, Pozza G. Insulin given intranasally induces hypoglycaemia in normal and diabetic subjects. Br Med ) 1982; 284: 303-306. 19. Pontiroli AE, Alberetto M, Pozza G. lntranasal glucagon raises blood glucose concentrations in healthy volunteers. Br Med / 1983; 287: 462-463. 20. Pontiroli AE, Alberetto M, Pozza G. Metabolic effects of intranasally administered glucagon: comparison with intramuscular and intravenous injection. Acta Diabetol Lat 1985; 22: 103-1 10. 21. Pontiroli AE, Calderara A, Pajetta E, Alberetto M, Pozza G. lntranasal glucagon as remedy for hypoglycemia. Studies in healthy subjects and type 1 diabetic patients. Diabetes Care 1989; 12: 604-608. 22. Freychet L, Desplanque N, Zirinis P, et a/. Effect of intranasal glucagon on blood glucose levels in healthy subjects and hypoglycaemic patients with insulin dependent diabetes. Lancet 1988; i: 1364-1 366. 23. Evans WS, Vance ML, Kaiser DL, Sellers RP, Borges ILC. Effects of intravenous, subcutaneous and intranasal administration of growth hormone (GH) releasing hormone-40 on serum G H concentrations in normal men. / Clin Endocrinol Metab 1985; 61 : 846-850. 24. Vance ML, Evans WS, Kaiser DL, Burke RL, Rivier J. The effect of intravenous, subcutaneous, and intranasal GHRH analog (Nle27)(1-29)-NH2 on growth hormone secretion in normal men: dose response relationship. Clin Pharmacol Ther 1986; 40: 627-633. 25. Borkenstein M. The effects of intranasal insufflation of growth hormone releasing factor analog GRF 1-29NH2 on growth hormone secretion in children with short stature. Acta Endocrinol (suppl) 1986; 279: 135-1 38. 26. Pontiroli AE, Perfetti MG, Fattor B, Pozza G. Effect of intranasal growth hormone and corticotropin releasing hormone administration on growth hormone and cortisol release: improved bioavailability by means of sodium glycocholate. / Clin Endocrinol Metab 1989; 68: 821-824. 27. De Bold CR, Sheldon WR, DeCherney GS, Jackson RV, Nicholson WE. Effect of subcutaneous and intranasal ovine corticotropin releasing hormone in man: comparison with intravenous administration. ) Clin Endocrinol Metab 1985; 60: 836-840. 28. Pontiroli AE, Calderara A, Pozza G. lntranasal drug delivery. Potential advantages and limitations from a clinical pharmacokinetic perspective. Clin Pharmacokinet 1989; 17: 299-307. 29. Larsen C, Niebuhr Jorgensen M, et a/. Influence of experimental rhinitis on the gonadotropin response to intranasal administration of buserelin. Eur) Clin Pharmacol 1987; 33: 155-1 59. 30. Olanoff LS, Titus CR, Shea MS, Gibson RE, Brooks CD. Effect of intranasal histamine on nasal mucosal blood flow and the antidiuretic activity of desmopressin. / Clin Invest 1987; 80: 890-895. 31. Duchateau GSMJE, Zuidema J, Merkus FWHM. Bile salts and intranasal drug absorption. Int ) Pharm 1986; 31: 15.
773
Dm
COMMENT 32. 33.
34.
774
193-1 99. Hermens AJJ, Merkus WHM. The influence of drugs on nasal ciliary movement. f h a r m Res 1987; 4: 445-449. Hirai 5, Yashiki T, Mima H. Mechanisms for the enhancement of the nasal absorption of insulin by surfactants. Int / Pharm 1981; 9: 173-184. lkegami M, Agata Y, Elkady T, Hallman M, Berry D, lobe A. Comparison of four surfactants: in vitro surface
properties and responses of preterm lambs to treatment at birth. Pediatrics 1987; 79: 38-46.
35.
36.
Hussain AA, Hirai 5, Bawarshi R. Nasal absorption of natural contraceptive steroids in rats. Progesterone absorption. fharm Sci 1981; 70: 466-467. Hussain AA, Foster T, Hirai S, Hashihara T, Batenhorst R. Nasal absorption of propranolol in humans. / fharm ScI 1980; 69: 1240.
A.E. PONTIROLI, C. POZZA
COMMENT
Intranasal Administration of Peptide Hormones: Factors Affecting Transmucosal Absorption A. E. Pontiroli, G . Pozza lstituto 5an Raffaele,Cattedra di Clinica Medica, Universita di Milano, Milano, ltaly
KEY WORDS
lntranasal administration
Peptides
Insulin
Clucagon
Introduction
The Nose, its Function, and Peptides
The advent of DNA recombinant technology will probably yield more and more peptides of high purity for human research or for treatment of human diseases. Table 1 gives an incomplete list of what is now available. Unfortunately, peptides can not be administered orally and require injection. Contrary to what is commonly believed, injection therapy is not the ideal form of administration. The physician who prescribes injections for a long period (growth hormone to short children, insulin to diabetic patients, calcitonin to patients with osteoporosis or with Paget’s disease of bones) often does not appreciate all the major drawbacks:
The main functions of the nose are heating and humidifying inhaled air, removal of inhaled particles, and the sense of smell. The inner nose has a 150 cm2 surface area, and a total volume of about 15 ml. The threelayered mucosa, 2 to 4 mm thick, 80 % respiratory, 20 % olfactory, is covered by mucus and has a rich lymphatic and capillary network, thus allowing rapid exchange between blood and the inspired air. The epithelium i s made of different kinds of cells, mainly mucous cells and ciliated cells. Ciliated cells generate a unidirectional movement of mucus towards the pharynx, and remove whai is not absorbed through the m u ~ o s a . ~ The awareness that the nose allows administration not only of locally acting drugs, but also of systemically active peptides i s not new, but was limited to small peptides, ten amino acids or less, for which direct absorption is rapid. Harris has listed some of the features that make naturally occurring peptide hormones appealing candidates for intranasal administration: broad pharmacological activity, short half-life, good biological tolerability, poor stability in gastrointestinal fluids, and extensive first pass metabolism in the liver. In addition, these peptides are usually those that are prescribed for chronic and life-long diseases, for substitution therapy, and administered par enter all^.^ Table 2 lists peptides that are currently available for administration by the nasal route. Salmon calcitonin is unusual in view of its large size. Figure 1 shows how the dimensions of the peptides influence intranasal absorption, such that beyond a length of 30 amino acids practically no absorption occurs. Promoters are required to allow absorption of larger peptides, so that it may be that benzyl-alcohol-chloride, a preservative present in the pharmaceutical intranasal formulations of salmon calcitonin, has to be considered a promoter. Human calcitonin i s known to have only 3.4 % absorption, increased six to seven fold by a variety of promoter^.^ Various types of promoters, of entirely different chemical natures, have been used in the past. They belong to four main groups: chelating agent (such as EDTA and citric acid), detergents or surfactants (such as 9-lauryl-
1 . Patients accept injections poorly, especially over long periods, and often default from treatments that are not life saving, or continue with the treatment erratically, with the consequence that many ’treatment failures’ may really be ’patient failures’. 2 . Many patients are unable to carry out injection therapy by themselves, and have to rely on friends or relatives, who must in turn become familiar with aseptic procedures and with injection techniques. 3. Subcutaneous absorption of insulin has an inter- and intra-patient variability of up to 60 Yo, and high variability also occurs with intramuscular growth hormone.’f2 4. Injection therapy does not mimic physiology, since injections are made in traditional sites (for example intramuscularly in the glutei for growth hormone and for calcitonin, subcutaneously in the arms for insulin) with no relationship to the physiological route or rhythm of secretion of the endogenous peptide to be substituted. These are just some of the reasons why alternative routes of peptide administration have been looked for. One such route of interest i s the nasal mucosa.
Correspondence to: Antonio E. Pontiroli, lstituto San Raffaele, Via Olgettina 60, 201 32 Milano, Italy.
770
0 ~ ~ 2 - ~ ~ ~ ~ / 9 0 / 0 9 ~ ~ ~ ~ - 0 ~ $ ~ ~ . ~ ~ & Sons, Ltd.
0 1990 by John Wiley
DIABETIC MEDICINE, 1990; 7: 770-774
DTT7
COMMENT Table 1. Peptide hormones available for clinical use Extractive
Synthetic
DNA-recombinant technology
HCG HMG
Oxytoci n ACTH LHRH and analogues dDAVP TRH GHRH Ceruletide Somatostatin and analogues Calcitonin (human, salmon, eel) a-Natriuretic factor
Insulin Growth hormone (?I Calcrtonin
~
FSH LH Vasopressin Glucagon
HCG, human chorionic gonadotropin; HMG, human menopausal gonadotropin; dDAVP, desmopressin
Table 2. Peptides currently available for intranasal administration Peptide
Indication
LHRH analogues (n = 9, buserelin, LHRH-t, leuprolide, nafarelin)
Prostate carcinoma, (mammary carcinoma, endornetriosis, uterine leiomyoma, precocious puberty, contraception)
Oxytocin ( n = 9)
Lactation, labour induction
~~
~~~
~~~~~
Vasopressin, desmopressin (n = 9)
Diabetes insipidus
LHRH (n = 10) Salmon calcitonin (n = 32)
Cryptorchidisrn Osteoporosis, Paget's disease of bones
n = number of amino acids; ( ) applications under clinical evaluation
ether), fatty acids (oleic acid), and bile Salk6 It i s not clear how the promoters work. They might: (1) alter the mucous layer covering the nasal mucosa; (2) open the tight junctions of the epithelial cells; (3) form reverse micelles within nasal cell membrane^.',^ In the case of bile salts, their capacity to enhance transmembrane transport has been related to their ability to induce haemolysis of isolated erythrocytes and to release proteins from cu Itured epi the1ia . However sod ium g Iycoc holate and sodium taurodihydrofusidate have equal enhancing effects on insulin absorption in spite of greatly differing lytic proper tie^;^ it has also been suggested that bile salts might inhibit proteases of the nasal mucosa, thus enhancing spontaneous absorption of peptides.'O Therefore it is possible that different promoters act at different levels, and, alternatively, that different promoters, of entirely different chemical nature, act by as yet unknown mechanisms or by a combination of different mechanisms.1°
'
Experience with Individual Peptides
Insulin From the early 1920s attempts have been made to administer insulin by the nasal route.','' Today we know INTRANASAL ABSORPTION OF PEPTIDES
that insulin is not absorbed as such and that it requires the presence of promoters such as bile salts, 9-laurylether (a detergent), saponin, or derivatives of fusidic acid. Alternatively, insulin can be diluted in an acid medium (pH 3.1).12,13 The efficacy in humans (fall of blood glucose levels and increase of serum insulin levels) is similar for human and porcine insulin,14 and can be enhanced by increasing the amount of insulin or of the p r ~ m o t e r , ' ~ while sprays are more effective than drop^.'^-'' Plasma insulin levels peak after 10 to 20 min, and a decrease of blood glucose levels takes place between 12 and 45 min.14-18 Monomers of insulin are not absorbed in the absence of a promoter (Pontiroli et a/., unpublished data).
Glucagon Glucagon, albeit highly effective in counteracting hypoglycaemia in insulin-treated diabetic patients, i s infrequently employed in that role. Glucagon is unstable in solution which must therefore be freshly prepared, and its use requires familiarity with aseptic procedures and with injection techniques. lntranasal administration of freshly prepared glucagon solutions raises blood
771
Dm
COMMENT
Growth Hormone Releasing Hormone (GHRH)
100.0
GHRH, available as a 1-29 or a 1-40 amino acids peptide, currently employed for the evaluation of pituitary function, i s of value in the treatment of some children with growth disorders. It requires intermittent or continuous subcutaneous injection or continuous intravenous infusion. Its systemic availability after intranasal administration is very low (0.2 to 0.6 %), and can be increased to about 7.1 % by the addition of bile salt^.^^-^"
50.0
20.0
10.0
Corticotrophin Releasing Hormone (CRH) 5 .O
CRH, 41 amino acids, stimulates ACTH and hence cortisol release; its use in the diagnosis of disorders of the pituitary-adrenal axis has been proposed. CRH also has a low systemic availability (0.1 %) after intranasal administration, significantly enhanced (to 3.0 up to 100 %) by increasing amounts of bile
h
3.0 C
.-0 c
!2
2
(5)
a
a
I
1.0
14
Is; GHRH1-290 (24)
0.5
Comments and Perspectives
1
0.2
. .
0.1
A0 I
0
.
d
.
5 10
20
30
40
50
60
Length of the peptide (amino acids) Figure 1. lntranasal administration of peptide hormones; systemic availability (% absorption, logarithmic scale) as a function of the length of the peptide (number of amino acids); systemic availability of each peptide i s 100 % after intravenous
lntranasal administration of some peptides is now of established clinical value. For others, experimental administration is improving rapidly, and insulin and glucagon are amongst these. Appealing features of this route of administration are the ease of self-treatment, patient compliance, and the pharmacokinetic properties, namely the rapid appearance in plasma after intranasal administration.’,’ The main factors affecting transmucosal absorption of peptides are:
1. 2. 3. 4.
length of the molecule; presence of a promoter for long molecules; nature of the delivery (drops vs sprays);28 sensitivity to endogenous peptidases.26
administration; 0 = without promoters; 0 = with different promoters. Numbers in brackets indicate published papers as they appear in the list of references; a, animal studies; hCT, human calcitonin; VP, vasopressin; LHRHan9, LHRH analogue with 9 amino acids. Other abbreviations as for Table 1
Technical problems that have to be solved however include the development of devices acceptable to patients. It also needs to be shown that the effects are reproducible under different conditions. A common concern i s that local diseases, such as the common cold or chronic rhinitis, might alter the systemic availability of intranasally administered drugs. Two papers have shown that this i s not the case for buserelin or for dDAVP, but data about other, larger peptides are not glucose levels when promoters like sodium glycocholate, sodium deoxycholate or 9-lauryl-ether are p r e ~ e n t . ~ , ” - ~ ~ a ~ a i l a b l e . ~ ~ ~ ~ ” Local toxicity i s a possible side-effect of promoters, as Simply increasing the solubility of glucagon by means of shown by animal s t ~ d i e s , ~ , ” and - ~ ~ some nasal irritation 2 hydroxy-propyl-P-cyclodextrin i s not effective (Pontirol i has been reported in clinical studies (burning, et a/., unpublished data). lntranasal glucagon i s as lachrymation).’,” The concern for local toxicity is of effective but more rapidly acting than oral glucose in course not so great for glucagon, given its likely sporadic raising blood glucose levels in normal subjects, and its use, as compared with insulin, which can be expected effect has a good reproducibility when tested on different to be used every day for years. Newer promoters are days in the same subjects.21 lntranasal glucagon i s therefore required for peptides for which a prolonged also effective in diabetic patients under conditions of administration i s foreseen, and currently promising proeuglycaemia and of hypoglycaemia.21,22As with insulin, moters include phospholipids and natural lung surfactant spray solutions are more effective than drops.20
772
A.E. PONTIROLI. C. POZZA
Dm which are likely to be as active but far less toxic than current promoters.34 lntranasal absorption of other drugs, currently administered by the oral route, i s also appealing for different reasons. For example progesterone in a polysorbate 80 saline solution has a 100 % systemic availability w h e n administered intranasally, and an identical pharmacokinetic profile to intravenous progesterone, w h i l e intraduodenal progesterone has o n l y a 1.2 % systemic a ~ a i l a b i l i t y . ~Propranolol ~ hydrochloride in 2 % methylcellulose, placed i n the nasal cavity, has a 100 % systemic availability, while orally administered propranolol has only a 25 % systemic a ~ a i l a b i l i t y . ~ ~
References 1 . Moses AC, Flier JS. Unconventional routes of insulin administration. In: Alberti KGMM, Krall LP, eds. The Diabetes Annual/3. Amsterdam: Elsevier, 1987: 107-1 20. 2. Albertson-Wikland K, Westphal 0,Westgren U. Daily subcutaneous administration of growth hormone in growth hormone deficient children. Acta Paediatr Scand 1987; 75: 89-97. 3 . Mygind N. Nasal Allergy. Oxford: Blackwell Scientific Publications, 1981. 4. Harris AS. Biopharmaceutical aspects of intranasal administration of peptides. In: Davis SS, lllum L, Tomlinson E, eds. Delivery Systems for Peptide Drugs. New York: Plenum Press, 1986: 191-204. 5. Pontiroli AE, Alberetto M, Calderara A, Pajetta E, Pozza G. Nasal administration of glucagon and human calcitonin to healthy subjects: a comparison of powders and spray solutions and of different enhancing agents. Eur / Clin Pharrnacol 1989; 37: 427-430. 6. Lee VHL. Enzymatic barriers to peptide and protein absorption and the use of penetration enhancers to modify absorption. In: Davis SS, lllum L, Tomlinson E, eds. Delivery Systems for Peptide Drugs. New York: Plenum Press, 1986: 87-1 04. 7. Gordon GS, Moses AC, Silver RD, Flier JS, Carey MC. Nasal absorption of insulin: enhancement by hydrophobic bile salts. Proc Natl Acad Sci USA 1985; 82: 741 9-7423. 8 . Hersey SJ, Jackson RT. Effect of bile salts on nasal permeability in vitro. / Pharm Sci 1987; 76: 876-879. 9. Longenecker JP. Nazlin, transnasal systemic delivery of insulin. In: Davis SS, lllum L, Tomlinson E, eds. Delivery Systems for Peptide Drugs. New York: Plenum Press, 1986: 21 1-220. 10. Muranishi S. Absorption enhancers: mechanisms and applications. In: Prescott LF, Nimmo WS, eds. Novel Drug Delivery. Chichester: Wiley, 1989: 69-77. 11. Pontiroli AE, Secchi A, Alberetto M. Alternative routes of peptide hormone administration. Spec Top Endocrinol Metab 1985; 7: 77-99. 12. Hirai S, lkenaga T, Matsuzawa T. Nasal absorption of insulin in dogs. Diabetes 1977; 27: 296-299. 13. Aungst BJ, Rogers NG, Shefter E. Comparison of nasal, rectal, buccal, sublingual, and intramuscular insulin efficacy and the effects of bile salt promotion enhancers. / Pharmacol Exp Ther 1988; 244: 23-27. 14. Pontiroli AE, Alberetto M, Pajetta E, Calderara A, Pozza G . Human insulin plus sodium glycocholate in a nasal spray formulation: improved bioavailability and effectiveness in normal subjects. Diabete Metabol 1987; 13: 44 1-443. INTRANASAL ABSORPTION OF PEPTIDES
COMMENT Moses AC, Gordon GS, Carey MC, Flier JS. Insulin administered intranasally as an insulin-bile salt aerosol. Effectiveness and r-producibility in normal and diabetic subjects. Diabetes 1983; 32: 1040-1 047. 16. Paquot N, Scheen AJ, Franchimont P, Lefebvre PJ. The intranasal administration of insulin induces significant hypoglycaemia and classical counterregulatory hormonal responses in normal man. Diabete Metabol 1988; 14: 31-36. 17. Salzman R, Manson JE, Friffing GT, et a/. lntranasal aerosolized insulin. Mixed-meal studies and long-term use in type 1 diabetes. New Engl / Med 1985; 312: 1078-1 084. 18. Pontiroli AE, Alberetto M, Secchi A, Dossi G, Bosi I, Pozza G. Insulin given intranasally induces hypoglycaemia in normal and diabetic subjects. Br Med ) 1982; 284: 303-306. 19. Pontiroli AE, Alberetto M, Pozza G. lntranasal glucagon raises blood glucose concentrations in healthy volunteers. Br Med / 1983; 287: 462-463. 20. Pontiroli AE, Alberetto M, Pozza G. Metabolic effects of intranasally administered glucagon: comparison with intramuscular and intravenous injection. Acta Diabetol Lat 1985; 22: 103-1 10. 21. Pontiroli AE, Calderara A, Pajetta E, Alberetto M, Pozza G. lntranasal glucagon as remedy for hypoglycemia. Studies in healthy subjects and type 1 diabetic patients. Diabetes Care 1989; 12: 604-608. 22. Freychet L, Desplanque N, Zirinis P, et a/. Effect of intranasal glucagon on blood glucose levels in healthy subjects and hypoglycaemic patients with insulin dependent diabetes. Lancet 1988; i: 1364-1 366. 23. Evans WS, Vance ML, Kaiser DL, Sellers RP, Borges ILC. Effects of intravenous, subcutaneous and intranasal administration of growth hormone (GH) releasing hormone-40 on serum G H concentrations in normal men. / Clin Endocrinol Metab 1985; 61 : 846-850. 24. Vance ML, Evans WS, Kaiser DL, Burke RL, Rivier J. The effect of intravenous, subcutaneous, and intranasal GHRH analog (Nle27)(1-29)-NH2 on growth hormone secretion in normal men: dose response relationship. Clin Pharmacol Ther 1986; 40: 627-633. 25. Borkenstein M. The effects of intranasal insufflation of growth hormone releasing factor analog GRF 1-29NH2 on growth hormone secretion in children with short stature. Acta Endocrinol (suppl) 1986; 279: 135-1 38. 26. Pontiroli AE, Perfetti MG, Fattor B, Pozza G. Effect of intranasal growth hormone and corticotropin releasing hormone administration on growth hormone and cortisol release: improved bioavailability by means of sodium glycocholate. / Clin Endocrinol Metab 1989; 68: 821-824. 27. De Bold CR, Sheldon WR, DeCherney GS, Jackson RV, Nicholson WE. Effect of subcutaneous and intranasal ovine corticotropin releasing hormone in man: comparison with intravenous administration. ) Clin Endocrinol Metab 1985; 60: 836-840. 28. Pontiroli AE, Calderara A, Pozza G. lntranasal drug delivery. Potential advantages and limitations from a clinical pharmacokinetic perspective. Clin Pharmacokinet 1989; 17: 299-307. 29. Larsen C, Niebuhr Jorgensen M, et a/. Influence of experimental rhinitis on the gonadotropin response to intranasal administration of buserelin. Eur) Clin Pharmacol 1987; 33: 155-1 59. 30. Olanoff LS, Titus CR, Shea MS, Gibson RE, Brooks CD. Effect of intranasal histamine on nasal mucosal blood flow and the antidiuretic activity of desmopressin. / Clin Invest 1987; 80: 890-895. 31. Duchateau GSMJE, Zuidema J, Merkus FWHM. Bile salts and intranasal drug absorption. Int ) Pharm 1986; 31: 15.
773
Dm
COMMENT 32. 33.
34.
774
193-1 99. Hermens AJJ, Merkus WHM. The influence of drugs on nasal ciliary movement. f h a r m Res 1987; 4: 445-449. Hirai 5, Yashiki T, Mima H. Mechanisms for the enhancement of the nasal absorption of insulin by surfactants. Int / Pharm 1981; 9: 173-184. lkegami M, Agata Y, Elkady T, Hallman M, Berry D, lobe A. Comparison of four surfactants: in vitro surface
properties and responses of preterm lambs to treatment at birth. Pediatrics 1987; 79: 38-46.
35.
36.
Hussain AA, Hirai 5, Bawarshi R. Nasal absorption of natural contraceptive steroids in rats. Progesterone absorption. fharm Sci 1981; 70: 466-467. Hussain AA, Foster T, Hirai S, Hashihara T, Batenhorst R. Nasal absorption of propranolol in humans. / fharm ScI 1980; 69: 1240.
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