Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
  • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
  • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
  • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
  • A61K47/6817—Toxins
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
  • C07K14/70503—Immunoglobulin superfamily
  • C07K14/70514—CD4
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides

Definitions

• the present invention relates to substances useful for the treatment of animals, including humans, which have been subjected to a foreign agent, which agent exerts an undesired effect only after first binding to an endogenous receptor. More particularly, the present inven tion relates to such substances, and methods of use there ⁇ of, which are directly or indirectly derived from the natural endogenous receptor.
• a receptor is a cellu ⁇ lar component that interacts with a specific ligand.
• Ligands classified as agonists when bound to their recep ⁇ tors, activate an effector system and trigger a bio- response.
• Ligands classified as antagonists depress receptors or inhibit the action of the agonist. When, for example, cobra venom or curare is attached to a cholinergic receptor, the binding of acetylcholine is prevented.
• an analogue of the for ⁇ eign material is used to preoccupy the host receptor bind ⁇ ing site, and thus viruses or bacteria are prevented from associating with the tissue they normally would infect.
• Immunological inactivation is "ligand- specific”.
• many bacteria and viruses have the capability of periodically modifying their immunogenic epitopes by random mutations and recombination processes, thereby rendering the immunoglobulin ineffective.
• the use of ligand analogues is "receptor-specific". However, by definition, such analogues occupy the receptor preventing its functionability.
• the present invention employs a novel approach to the problem of prevention of formation of such ligand- receptor complexes which approach is "receptor-specific" yet does not prevent the functionability of the native receptor.
• the novel solution to the problem of prevention of formation of ligand-receptor complexes involves the identification of the molecular structure of the ligand binding site in the native receptor and the production of mimic ligand binding sites. These sites can be used .in vivo to bind toxins or viruses or any other foreign agent in a "target-specific manner".
• the mimic ligand binding sites of the present invention compete in the animal's body with natural binding sites, thus acting as decoys.
• Such substances have been denominated "molecular decoyants" by the present inventor.
• natural receptors are rather large structures, comprising some hundreds of amino acids, and can be as large as a molecular weight of about 250,000.
• the specific binding site is much smaller and this opens up the possibility of preparing artificial, synthetic binding sites, which are effective in binding specific viruses, bacteria, toxins, etc., yet which com ⁇ prise a much smaller number of amino acids, preferably less than 100, and which have therefore a considerably lower molecular weight and thus a correspondingly lower im uno- genicity. It has been found possible to prepare such binding-site-mimicking molecular decoyants which are adap ⁇ ted to bind specific ligands with a size on the order of about 20 amino acids.
• Suc rather small peptide structures can be prepared by physically dividing the endogenous receptor or they can be prepared synthetically by the preparative procedures of peptide chemistry, such as Merri- field synthesis, or by genetic engineering. This opens up the possibility of large scale production of such specific polypeptide structures and their use as active materials in the treatment of animals subjected to pathogenic or toxic agents.
• the present invention is of a very wide applica ⁇ bility as molecular decoyants specific to a wide variety of ligands can be produced.
• the present invention includes prophylactic as well as therapeutic compositions which contain the active molecular decoyant structures in an adequate concentration and quantity.
• Figure 1 shows the process steps for obtaining the 17 amino acid sequence WKHWVYYTCCPDTPYLD by recombinant DNA technology.
• Figure 2 shows the results of the separation on polyacrylamide gels of various samples of an R4137 clone cultured for induction of the trpE fusion protein.
• the cells were either solubilized in sample buffer (T) or sonicated in high salt buffer (500 mM) and centrifuged.
• the supernatant (S-, ) contained 40-60% of the fusion protein as did the pellet (Pi ) .
• the pellet was further extracted with water to generate a supernatant (S 2 ) which contained some 15% of the original fusion protein content and a pellet (P 2 ) .
• Figure 3 is a graph showing the concentration of bound toxin at specific times (C t ) divided by that reached at equilibrium (C eq ) after incubation of R4137 with 12S _ labeled BTX for different periods of time as indicated. The concentrations were measured after applying aliquots to positively charged membrane filter discs. The time was measured in minutes in panel A or seconds in panel B.
• Figure 4 is a graph showing the Scatchard analy ⁇ sis of toxin binding to R4137.
• net bound BTX was determined by adding a 1,000 fold excess of nonradioactive BTX and the bound versus the free toxin for each point was calculated.
• Figure 5 is a graph showing competition of BTX binding.
• the percent of 125 I-labeled BTX (2'10" 8 M) is plotted after mixing with ever increasing concentrations of: non-labeled BTX (•) , cobratoxin ( ⁇ ) , decamethonium (0) d-tubo ⁇ urarine (° ) , NaCl (O) , carbamylcholine (x) or glycine ( ) .
• the mixtures were incubated with equal amounts of R4137 for 30 min at 25°C and the net amount of bound radioactive toxin was determined.
• Figure 6A is a graph plotting the amount of bound 125 I-labeled BTX as a function of the total amount of 1 5 1- labeled BTX applied to a concanavalin-A column having AcChoR immobilized thereon.
• Figure 6B is a graph plotting the amount of bound 125 I-labeled BTX on a concanavalin-A column having AcChoR immobilized thereon as a function of the amount of R4137 applied to the column after different amounts of R4137 and constant amounts of 125 I-labeled BTX were applied thereto.
• Figure 7 is a graph showing the effect of R4137 on the survival rate of d-tubocurarine injected mice.
• Two groups of Balb/C mice 35 in each) were inj cted with either pATH2 or R4137 (approx. 3 nmole BTX binding sites/ mouse) intraperitoneally.
• Five minutes later the mice were given d-tubocurarine (approx. 15 nmole, 9 ⁇ g/mouse, subcu- taneously) .
• the number of survivors as a function of time after the injection of toxin is shown (the data are derived from experiments 2 and 3 of Table 1) .
• BTX ⁇ -bungarotoxin
• AcChoR nicotinic acetylcholine receptor
• the neuro-muscular junction is the site where nerves meet with muscle fibers.
• the point of contact is the synapse and is characterized by the fact that the nerve and muscle are not actually physically connected, but rather form a chemical junction.
• acetylcholine the neuro- transmitter
• the acetylcholine is bound by its receptor which is situated on the extra ⁇ cellular membrane of the muscle, the post-synaptic side of the junction.
• the binding of two molecules of acetylcho- line to their receptor causes an ion-channel to open, the membrane to depolarize and eventually leads to muscle contraction.
• BTX is an antagonist which binds to AcChoR, thereby preventing acetylcholine from reaching its receptor and preventing muscle contraction.
• To make a molecular decoyant for the treatment of animals subjected to BTX one must first identify the particular BTX binding site. The preferred method for doing this is by means of ligand overlay of protein blots. Once the binding site is identi- fied, the minimal sequence may be produced. Upon the administration of such a sequence, the decoy will mimic the binding site and bind with BTX, thereby blocking the unde ⁇ sired activity of the toxin.
• the specific binding site for BTX on the AcChoR is known to be situated on the ⁇ -subunit thereof.
• the minimal essential elements of the binding site which will still permit selective and specific binding of reasonable affinity to BTX may be further identified by means of protein blotting.
• the techniques of protein blotting are discussed in detail in Gershoni, "Protein Blotting: A
• BTX is a polypeptide toxin (74 amino acid resi ⁇ dues) which can be iodinated and binds the receptor with an affinity of Q ⁇ IO' ⁇ M.
• Purified AcChoR is subjected to polyacrylamide gel electrophoresis (PAGE) under mild denat- uration without boiling of the sample and use of lithium dodecyl sulfate, instead of sodium dodecyl sulfate (SDS) . Blots are then prepared and probed with 125 1-labelled BTX.
• the ⁇ -subunit is then proteolysed and then protein blots there ⁇ of probed with alkaline-phosphatase hydrazide, concana- valin-A, BTX and sequence specific antibodies which together have allowed the mapping of the toxic binding site to the region ⁇ -160-330 and more particularly ⁇ -160-210 and even more specifically to the region ⁇ -180-200 (see Neumann et al, "Mapping of the ⁇ -Bungarotoxin Binding Site with the ⁇ -Subunit of the Acetylcholine Receptor", Proc. Natl. Acad. Sci. (USA) . 83:3008-3011 (1986), the entire contents of which are hereby incorporated by reference) .
• BTX-binding sequences can also be produced by recombinant DNA techniques, sub-clones of cDNA of ⁇ -sub- units of mouse or Torpedo californica were prepared using expression vectors.
• the trpE fusion vector pATH2 was used. Restriction fragments of the plasmid p42, a cDNA clone of the ⁇ -subunit of Torpedo californica AcChoR, were purified on 1% agarose gels. Preparative quantities of plasmids were obtained, and ligations in transformations of E_i_ coli strain HB101 were performed by the methods of Maniatis et al.
• fusion proteins were prepared in E. coli trans- formants (Gershoni, "Expression of the ⁇ -Bungarotoxin Binding Site of the Ni ⁇ otinic Acetylcholine Receptor by Escherichia coli Transformants", Proc. Natl. Acad. Sci. (USA) . 84, 4318-4321 (1987), the entire contents of which are hereby incorporated by reference) .
• These fusion pro ⁇ teins were shown to specifically bind BTX (affinity: 10" 7 M) .
• bacterially expressed proteins containing ⁇ -166-200 bind toxin whereas those expressing ⁇ - 201-315 do not.
• Two oligonucleotides were prepared as described in Figure 1(1). They were designed using bacterially preferred codons to code for the amino acid sequence: Gly- Ile-Glu-Gly-Arg-Trp-Lys-His-Trp-Val-Tyr-Tyr-Thr-Cys-Cys- Pro-Asp-Thr-Pro-Tyr-Leu-Asp, which includes ⁇ l84-200 of Torpedo californica AcChoR as well as a pentapeptide intro- Jerusalem N-terminal to residue W184.
• the first glycine is the result of the trinucleotide dGGG which is necessary for the maintenance of a functional S al site.
• the following sequence IEGR is the specific cleavage site for the coagu ⁇ lation factor Xa (CFX) .
• CFX coagu ⁇ lation factor Xa
• the two oligo ⁇ nucleotides were mixed at a ratio of 1:1 heated together and allowed to anneal forming a 9-base pair duplex.
• the complementary strands were then enzymatically "filled in” using Klenow polymerase (1 ⁇ l ; 5 units), as shown in Fig.
• the transformed bacterial clones which contained the insert in proper orientation were selected by 125 1- labeled BTX overlay of colony-blots. These transformants were found to produce an efficient toxin-binding fusion- protein (36kDa designated R4137, Figure 2).
• R4137 could be highly enriched by sonicating the transformed cells in phosphate buffer + 500mM salt. Centrifugation resulted in a pellet which contained 40-60% of the total R4137 and little more ( Figure 2, P, ) . This pellet could be extracted with water to produce a soluble fraction which was predomi- nantly R4137 ( Figure 2, S 2 ) .
• the R4137 in the S 2 fraction was biochemically characterized by measurement of toxin binding thereto in accordance with the techniques described in Gershoni et al, "Molecular Decoys: Ligand-Binding Recombinant Proteins Protect Mice from Curarimimetic Neurotoxins", Proc. Natl. Acad. Sci (USA) . 85, 4087-4089 (1988) , the entire contents of which are hereby incorporated by reference. In essence, aliquots of S 2 were incubated with 125 I-labelled BTX. Then the mixture was filtered through a charge modified membrane filter to separate the bound versus free toxin. The fil ⁇ ters were then counted for radioactivity.
• R4137 demonstrates that the 17 amino acid sequence: ⁇ -184-Trp-Lys-His-Trp-Val-Tyr-Tyr-Thr-Cys- Cys-Pro-Asp-Thr-Pro-Tyr-Leu-Asp-200 is sufficient for BTX binding. Although this binding is appreciably less than that of the intact receptor, it does resemble the binding characteristics of the complete ⁇ -subunit (437 amino acids) of AcChoR.
• R4137 was tested for competition with AcChoR in. vivo.
• Male and female mice (approximately 5 weeks, 20-25g) , both inbred (Balb/C) and outbred (CD1) strains, were first injected intraperitoneally with R4137 or a placebo - a similar fraction derived from bacteria transformed with the unmodified vector pATH2 (these cells have no toxin-binding capacity) .
• R4137 or a placebo - a similar fraction derived from bacteria transformed with the unmodified vector pATH2 (these cells have no toxin-binding capacity) Five minutes later all the mice were challenged with various amount of d- tubocurarine or ⁇ -cobratoxin (CTX) . The dose was gauged to cause 80% death of untreated mice.
• CTX ⁇ -cobratoxin
• mice Bacterial Exp. protein Strain Sex Toxin Dose No. of Survivors (i.p.) (s.c.) g/kg mice
• mice were first injected with a lethal dose of cobra toxin and one hour later given either a placebo or the cholinergic decoyant.
• the animals which received the placebo all died, whereas the decoy-treated animals were dramatically pro ⁇ tected (90% survival).
• the results are shown in Table 2. It should be understood that the same receptor site is involved with all of BTX, CTX and d-tubocurarine as well as decamethonium and rabies-virus.
• R4137 has been proven to be a decoyant against toxin is only a case in point for the general claim of molecular decoyants as therapeutic agents.
• R4137 or improved versions of this molecular decoyant, can serve as an anti ⁇ dote against cobra-like snake bites by specifically inter ⁇ cepting the ⁇ -toxin constituent of these venoms.
• d-tubocurarine is routinely used in surgery as a neuro-muscular blocking agent and a decoyant based on R4137 could be extremely useful as its antidote.
• R4137 is but an intermediate tool which, by its genetic manipulation or chemical processing, would allow those of ordinary skill in the art to design even more efficient cholinergic decoy- ants.
• the present invention is intended to include not only the specific 17 amino acid sequence of R4137, but variations and derivatives thereof which maintain, and preferably improve, its functional or pharmacological characteristics.
• modified peptide sequences can be readily prepared and tested by routine techniques for preferred toxin-binding characteristics so as to more effectively compete against the native receptor. Such modification may involve substitution, deletion or inser ⁇ tion of amino acids or their chemical modification. For example, longer lived decoyants may be obtained in this manner.
• organic mole- cules i.e., not proteinaceous, can be designed so as to satisfy the physico-chemical requirements of a decoyant which must form a functional interface with the toxin.
• the decoy ⁇ ants of the present invention can be modified by extending the polypeptide or by adding specific chemical moieties intended to aid in drug design or to permit the decoyants to be used for additional utilities.
• One such modification would be to extend the polypeptide by moieties intended to affect solubility, e.g. , by the addition of a hydrophilic residue, such as serine, or a charged residue, such as glutamic acid.
• the decoyant could be extended for the purpose of stabilization and preservation of a desired conformation, such as by adding cysteine residues for the formation of disulfide bridges. Another reason to modify the decoyants would be to make the decoyant detectable, even after administration.
• detectable decoyants could be used to detect the presence and/or location of specified pathogenic agents or toxins. For example, detection of an accumulation of R4137 in the area of a dog bite would indicate the presence of rabies-virus. Thus, such detect ⁇ able decoyants could be used for the selective detection and mapping of given foreign agents or for diagnosis of the invasion of such an agent. A further reason for modifying decoyants would be for accelerated clearance of the conjugated foreign agent from the body.
• a decoyant linked to an asialoglyco-moiety would be expected to be cleared by the liver.
• a decoyant mimicking the recep ⁇ tor site of an anti-cancer chemotherapeutic agent and containing such an asialoglyco-moiety, or any other moiety which would aid in its clearance could be used to inacti ⁇ vate and quickly remove excess chemotherapeutic agent after the therapy is completed in order to reduce side effects.
• the present invention comprehends not only decoyants based on the cholinergic binding site but decoyants based on any endogenous receptor for a for ⁇ eign agent which exerts an undesired effect only after binding to that endogenous receptor.
• the first requirement of a decoyant in accordance with the present invention is that it be a mimic of the endogenous receptor, i.e., it must functionally resemble the binding site, although it may differ physically.
• a receptor can be any ligand-binding molecule as, for exam ⁇ ple, the ligand-binding site of a traditional cell-surface receptor, the substrate binding site of an enzyme, the ligand-binding site of gangliosides, etc. It must be understood, however, that a decoyant in accordance with the present invention cannot be an immunoglobulin nor can it be derived from immunoglobulins.
• a decoyant in accordance with the present inven ⁇ tion should not be substantially immunogenic. Reduction of size is a means of diminishing the immunogenicity of a substance, but not all large molecules are as immunogenic as some small molecules. To be classified as a decoyant in accordance with the present invention, the substance must be substantially non-immunogenic in the system of the host, regardless of the size of the substance, although the smallest possible size is preferred.
• a decoyant in accordance with the present inven ⁇ tion must comprise the essential elements of the binding site of a receptor and not substantially more.
• the "essential elements" of a binding site are defined as those elements essential for the decoyant activity, i.e., ligand recognition and bind ⁇ ing.
• a receptor consists of many residues, only a few of which are involved in ligand recognition and binding.
• the decoyants of the present invention may be further modified for purposes of drug design.
• the entire ⁇ -subunit of AcChoR would not qualify as a decoyant, being both immunogenic and also considerably longer than necessary.
• the ⁇ -subunit does, however, contain the potential information needed for the design and construction of a decoyant, i.e., sequence ⁇ -184-200.
• sequence ⁇ -184-200 the potential information needed for the design and construction of a decoyant, i.e., sequence ⁇ -184-200.
• the fact that some additional peptide units may also be present, for example to improve the solubility of the essential required sequence, would not remove the structure from the category of decoyant as long as it is still substantially non-immunogenic and it is still selec- tive, specific and of reasonable affinity.
• Addition of sugar molecules could be a modification with the same effect.
• additions to the molecule for the purpose of drug design are not considered when determining whether the substance contains substantially more than the elements of the endogenous receptor which are required for binding to the foreign agent in question.
• a decoyant must be selective, specific and of reasonable affinity with respect to the agent for which it is designed.
• mannose a simple sugar, may interfere with infection by bacteria that have type-I mannose specific pili; however, the selectivity of mannose is not sufficient and neither is its affinity.
• a decoyant is a drug designed to intercept an invading foreign agent having an undesired effect.
• Such foreign agents may include toxins, poisons, bacteria, viruses, including retroviruses, etc.
• a decoy ⁇ ant can be designed in accordance with the present inven- tion to prevent such binding and thereby eliminate such undesired effect.
• T4 T-cell surface glycoprotein CD4
• HIV-1 human immuno ⁇ deficiency virus
• AIDS acquired immunodeficiency syndrome
• CD4 soluble, secreted forms of CD4 can be used to competitively bind HIV-1 and thus neutralize the infectivity of HIV-1 (Smith et al, "Blocking of HIV-1 Infectivity by a Soluble, Secreted Form of the CD4 Anti- gen". Science. 238, 1704-1707 (1987)).
• Intact CD4 would not be a decoyant in accordance with the present invention in view of its size. It does, however, contain the essence for a decoyant.
• the minimal binding domain of CD4 can be identified using no more than routine experimentation by the means described herein for arriving at the minimal binding domain for the cholinergic receptor, e.g., by means of proteolysis and protein blotting followed by recombinant DNA procedures.
• Another ligand-receptor pair particularly suited for the preparation of decoyants in accordance with the present invention is organophosphate-acetylcholine ester- ase. Such a decoy would relieve some of the effects of nerve gas.
• Other examples are LSD and the serotonin recep ⁇ tor and strychnine and the gly ⁇ ine receptor.
• Table 3 shows additional ligand-receptor pairs for which decoyants in accordance with the present inven ⁇ tion can be designed using no more than routine experimentation:
• Retrovirus type 3 67 kDa glycoprotein of rodent lymphoid and neuronal cells
• the decoyants of the present invention may be administered to an animal, including a human patient, in order to ameliorate the undesired effects of the foreign agent for which it was designed.
• Such decoyants can be used not only for the treatment of humans, but also for the treatment of other animals, including mammals, poultry, fish, etc.
• decoyants in accordance with the present invention could be designed for the protection or treatment of plants.
• the specific effective dosages for the treatment of any given foreign agent can readily be empirically determined by those of ordinary skill in the art without undue experimentation. However, those skilled in the art will understand that the dosage of decoyant will depend to some extent on the amount of foreign agent in the system of the host.
• the ratio of decoyant to foreign agent molecules is preferably in the range of 1:1 to 1:10.
• compositions within the scope of the present invention include compositions wherein the decoyant is present in an effective amount to achieve its intended purpose. Determination of the effective amounts is within the skill in the art.
• the pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
• suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
• the preparations particu ⁇ larly those which can be administered by injection, con ⁇ tain from about 0.1 to 99 percent, and preferably from about 25 to 85 percent by weight, of the active ingredient, together with the excipient.
• any conventional route of administration may be used for the decoyants of the present invention.
• the preferred mode of administration is by injection, e.g., intravenously, intradermally, mtraperitoneally, etc, they may also be administered orally, by suppository or by any other route.
• Suitable formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form.
• suspensions of the active compounds as appropriate oily injection suspensions may be administered.
• Suitable lipo- philic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides.
• Aqueous injection suspensions may contain substances which increase the viscosity of the suspension such as sodium carboxymethyl cellulose, sorbi- tol, and/or dextran.
• the suspension may also contain stabilizers.
• the decoyants of the present inven ⁇ tion may also be administered in the form of liposomes, pharmaceutical compositions in which the active ingredient is contained either dispersed or variously present in corpuscles consisting of aqueous concentric layers adherent to lipidic layers.
• the active ingredient may be present both in the aqueous layer and in the lipidic layer, or, in any event, in the non-homogeneous system generally known as a liposomic suspension.

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