This invention relates the use of glucagon-like peptides such as GLP-1, a GLP-1 analog, or a GLP-1 derivative in methods and compositions for reducing body weight.

This invention relates to the use of glucagon-like peptide-1 (GLP-1), analogs and derivatives of GLP-1, in methods and compositions, particular pharmaceutical formulations, that promote weight-loss.
Obesity, and especially upper body obesity, is the most common nutritional disorder in the over-nourished populations of the world. Numerous studies indicate that lowering body weight dramatically reduces risk for chronic diseases, such as diabetes, hypertension, hyperlipidemia, coronary heart disease, and musculoskeletal diseases. For example, various measures of obesity, including, simple body weight, waist-to-hip ratios, and mesenteric fat depot, are strongly correlated with risk for non-insulin dependent diabetes (NIDDM), also known as type II diabetes. According to the American Diabetes Association (1995) about 80% of NIDDM patients are overweight. Weight-reduction is a specific goal of medical treatment of many chronic diseases, including NIDDM.
Current methods for promoting weight loss are not completely satisfactory. Some obese patients may lose weight through deliberate modification of behavior, such as changing diet and increased exercise. Failure to achieve weight loss by these methods may be due to genetic factors that cause increased appetite, a preference for high-fat foods, or a tendency for lipogenic metabolism. Unfortunately, an estimated 33 billion dollars a year are spent on weight-loss measures that are largely futile. Thus, new methods and compositions such as pharmaceutical agents that promote weight-loss are urgently needed to complement old approaches.
Glucagon-like peptide 1 (GLP-1) is known to play a critical role in the regulation of the physiological response to feeding. GLP-1 is processed from proglucagon and is released into the blood from the endocrine L-cells mainly located in the distal small intestine and colon in response to ingestion of a meal (Nilsson et al., 1991; Krcymann et al., 1987; Mojsov et al. 1986). GLP-1 acts through a G protein-coupled cell surface receptor (GLP-1R) and enhances nutrient-induced insulin synthesis (Fehmann et al, 1992) and release (Fehmann et al., 1995). GLP-1 stimulates insulin secretion (insulinotropic action) and cAMP formation (Mojsov et al., 1992). GLP-1(7-36) amide stimulates insulin release, lowers glucagon secretion, and inhibits gastric secretion and emptying (Nauck, 1993; Gutniak et al, 1992). These gastrointestinal effects of GLP-1 are not found in vagotomized subjects, pointing to a centrally-mediated effect (Orskov et al., 1995). GLP-1 binds with high affinity to isolated rat adipocytes, activating cAMP production (Valverde et al., 1993) and stimulating lipogenesis (Oben, et al., 1991) or lipolysis (Ruiz-Grande et al., 1992). GLP-1 stimulates glycogen synthesis, glucose oxidation, and lactate formation in rat skeletal muscle (Villanueva et al., 1994).
m-RNA encoding the pancreatic-type GLP-1 receptor is found in relatively high quantities in rat pancreatic islets, lung, hypothalamus, and stomach (Billock et al., 1996). Interestingly, despite the knowledge that both GLP-2 and GLP-1 receptors are found in the hypothalamus (Krcymann et al., 1989; Kanse et al., 1988), no central role for GLP-1 was determined until a recent report that GLP-1 administered by the intracerebroventricular route (ICV) markedly inhibits feeding in fasted rats (Turton et al., 1996). The same report indicates that after ICV administration of GLP-1, c-fos, a marker of neuronal activation, appears exclusively in the paraventricular nucleus of the hypothalamus and in the central nucleus of the amygdala, two regions of the brain of primary importance in the regulation of feeding (Morley, 1987). ICV GLP-1 also significantly reduces food intake following injection of the powerful feeding stimulant, neuropeptide Y, in animals fed ad libitum (Turton et al., 1996). A subsequent report demonstrates that GLP-1 administered centrally or peripherally is involved in control of body temperature regulation, but does not affect food intake after acute intraperitoneal administration in rats (O""Shea et al., 1996). A recent article reports that lateral ventricular injections of GLP-1 in sated rats induce extensive stimulation of Fos-ir in the paraventricular nucleus and parvocellular central nucleus of the amygdala, substantiating Turton, et al. (Rowland et al., 1996). Additionally, these investigators described strong activation of other centers involved in the regulation of feeding, including the immediate early gene protein product in the nucleus of the tractus solitarius, the pontine lateral parabrachial nucleus, the basal nucleus of the stria terminals, and the area postrema. GLP-1 receptors accessible to peripheral GLP-1 are found in the rat subfornical organ and area postrema (Orskov et al., 1996).
Turton et al. (1996) specifically state that the effects of GLP-1 on body weight and food intake are caused only by administration of GLP-1 directly in the cerebroventriculum, that intraperitoneal administration of GLP-1, even at relatively high does, does not affect early dark-phase feeding, and that GLP-1 fragments are inactive when administered peripherally, citing (Suzuki et al., 1989). Such statements discourage the use of GLP-1 as a composition (pharmaceutical agent) for reducing body weight, because central routes of administration, such as the ICV route, are not feasible for treating obesity in humans. The physiological effects of GLP-1 documented above have led to the suggestion of its beneficial use for treating diabetes and obesity by transplanting recombinant cell lines encoding GLP-1 or GLP or GLP-1 receptors, for example (WO 96/25487).
Another publication discouraged the use of GLP-1 by interpreting the art to show that xe2x80x9cperipheral administration of GLP-1 had no effect on feeding behavior.xe2x80x9d (WO 97/31943, page 3). This publication also reported an effect of GLP-2 on food intake when administered peripherally.)
Methods and compositions, in particular pharmaceutical formulations, medicaments, using glucagon-like peptide-1 analogs, derivatives, and active peptides thereof, are effective in reducing body weight and in treating obesity. The definition of obesity varies with geographical location, clinical focus, and social preferences. The methods and compositions of the present invention, however, are suitable for any subject in which weight reduction is desired. The invention is not limited for use in, e.g. diabetic patients.
Peripheral administration of GLP-1 (7-36) amide to obese patients quite unexpectedly, and contrary to the implications of Turton et al. (1996), causes a significant reduction in body weight. Thus, an aspect of the present invention is a method of reducing body weight which includes preparing a composition having a glucagon-like peptide-1 compound and administering it to a subject. Suitable glucagon-like peptide-1 compounds include GLP-1, GLP-1 analogs, GLP-1 derivatives, agonists of the GLP-1 receptor, agonists of the GLP-1 signal transduction cascade, compounds that stimulate synthesis of endogenous GLP-1, compounds that stimulate release of endogenous GLP-1, and pharmaceutically-acceptable salts thereof. A pharmaceutically effective dose, that is, a dose sufficient to cause reduction in body weight, is administered.
Methods and compositions, in particular medicaments (pharmaceutical compositions or formulations) using glucagon-like peptide-1, analogs or derivatives thereof, are effective in reducing body weight and in treating obesity. Analogs and derivatives of GLP-1 that are useful for the practice of the invention are those with an increased half life compared to GLP-1 and the ability to effect weight loss when administered to a subject over a period of time. The definition of obesity varies with geographical location, clinical focus, and social preferences. The methods and compositions of the present invention, however, are suitable for any subject in which weight reduction is desired. The invention is not limited for use in, e.g. diabetic patients.
Compounds
GLP-1 analogs, derivatives, variants, precursors and homologues are all suitable for the practice of the invention as long as the active fragment that effects weight loss is included.
xe2x80x9cGLP-1xe2x80x9d means GLP-1(7-37). By custom in the art, the amino-terminus of GLP-1(7-37) has been assigned number 7 and the carboxy-terminus, number 37. The amino acid sequence of GLP-1(7-37) is well-known in the art, but is presented below for the reader""s convenience:
NH2-His7-Ala-Glu-Gly10-Thr-Phe-Thr-Ser-Asp15-Val-Ser-Ser-Tyr-Leu20-Glu-Gly-Gln-Ala-Ala25-Lys-Glu-Phe-Ile-Ala30-Trp-Leu-Val-Lys-Gly35-Arg-Gly37-COOHxe2x80x83xe2x80x83(SEQ ID NO:1)
A xe2x80x9cGLP-1 analogxe2x80x9d is defined as a molecule having a modification including one or more amino acid substitutions, deletions, inversions, or additions when compared with GLP-1. GLP-1 analogs known in the art include, for example, GLP-1(7-34) and GLP-1(7-35), GLP-1(7-36), Val8-GLP-1(7-37), Gln9-GLP-1(7-37), D-Gln9-GLP-1(7-37), Thr16-Lys18-GLP-1(7-37), and Lys18-GLP-1(7-37). Preferred GLP-1 analogs are GLP-1(7-34) and GLP-1(7-35), which are disclosed in U.S. Pat. No. 5,118,666, and also GLP-1(7-36). These compounds are the biologically processed forms of GLP-1 having insulinotropic properties. Other GLP-1 analogs are disclosed in U.S. Pat. No. 5,545,618.
A xe2x80x9cGLP-1 derivativexe2x80x9d is defined as a molecule having the amino acid sequence of GLP-1 or of a GLP-1 analog, but additionally having at least one chemical modification of one or more of its amino acid side groups, a-carbon atoms, terminal amino group, or terminal carboxylic acid group. A chemical modification includes adding chemical moieties, creating new bonds, and removing chemical moieties. Modifications at amino acid side groups include acylation of lysine e-amino groups, N-alkylation of arginine, histidine, or lysine, alkylation of glutamic or aspartic carboxylic acid groups, and deamidation of glutamine or asparagine. Modifications of the terminal amino include the des-amino, N-lower alkyl, N-di-lower alkyl, and N-acyl modifications. Modifications of the terminal carboxy group include the amide, lower alkyl amide, dialkyl amide, and lower alkyl ester modifications. A lower alkyl is a C1-C4 alkyl. Furthermore, one or more side groups, or terminal groups, may be protected by protective groups known to the ordinarily-skilled protein chemist. The xcex1-carbon of an amino acid may be mono- or di-methylated.
In the present invention a preferred group of GLP-1 analogs and derivatives for use in the present invention is composed of the various GLP-1 molecules claimed in U.S. Pat. No. 5,545,618 (""618). Effective analogs of the active GLP-1 peptides, 7-34, 7-35, 7-36 and 7-37 have amino acid substitutions as positions 7-10 and/or are truncated at the C-terminus and/or contain various other amino acid substitutions in the basic peptide. Analogs having D-amino acid substitutions in the 7 and 8 positions and/or N-alkylated or N-acylated amino acids in the 7 position are particularly resistant to degradation in vivo.
The analogs of the invention in ""618 which show enhanced insulin stimulating properties have the sequence, of native GLP-1, 7-34, 7-35, 7-36, or 7-37, or the C-terminal amide thereof, with at least one modification selected from the group consisting of:
(a) substitution of a neutral amino acid, arginine, or a D form of lysine for lysine at position 26 and/or 34 and/or a neutral amino acid, lysine, or a D form of arginine for arginine at position 36;
(b) substitution of an oxidation-resistant amino acid for tryptophan at position 31;
(c) substitution according to at least one of:
Y for V at position 16;
K for S at position 18;
D for E at position 21;
S for G at position 22;
R for Q at position 23;
R for A at position 24; and
Q for K at position 26; (Using the single letter codes for amino acids)
(d) a substitution comprising at least one of:
an alternative small neutral amino acid for A at position 8;
an alternative acidic amino acid or neutral amino acid for E at position 9;
an alternative neutral amino acid for G at position 10; and
an alternative acidic amino acid for D at position 15; and
(e) substitution of an alternative neutral amino acid or the D or N-acylated or alkylated form of histidine for histidine at position 7.
With respect to modifications (a), (b), (d) and (e), the substituted amino acids may be in the D form. The amion acids substituted at position 7 can also be in the N-acylated or N-alkylated forms.
In another aspect, the invention of ""618 is directed to peptides which show enhanced degradation resistance in plasma as compared to GLP-1 (7-37) wherein this enhanced resistance to degradation. In these analogs, any of the above-mentioned truncated forms of GLP-1(7-34) to GLP-1(7-37) or their C-terminal amidated forms is modified by
(a) substitution of a D-neutral or D-acidic amino acid for H at position 7, or
(b) substitution of a D-amino acid for A at position 8, or
(c) both, or
(d) substitution of an N-acylated or N-alkylated form of any naturally occurring amino acid for H at position 7.
Thus analogs which are resistant to degradation include (N-acyl (1-6C) AA)7 GLP-1(7-37) and (N-alkyl (1-6C AA)7 GLP-1(7-37) wherein when AA is a lysyl residue, one or both nitrogens may be alkylated or acylated, AA symbolizes any amino acid consistent with retention of insulin stimulating activity.
For substitutions of D-amino acids in the 7 and 8 positions, the D residue of any acidic or neutral amino acid can be used at position 7 and of any amino acid at position 8, again consistent with insulin stimulating activity. Either or both of position 7 and 8 can be substituted by a D-amino acid; the D-amino acid at position 7 can also be acylated or alkylated. These modified forms are applicable not only to GLP-1(7-37) but also to shorter truncated analogs.
Thus, among the preferred analogs of the ""618 invention are those wherein the (7-34), (7-35), or (7-37) form of GLP-1 has been modified only by substitution of a neutral amino acid, arginine, or a D form of lysine for lysine at position 26 and/or 34 and/or a neutral amino acid, lysine, or a D form of arginine for arginine at position 36 (section (a)). Particularly preferred are those wherein the amino acid substituted for lysine at position 26 and 34 is selected from the group consisting of K+,G, S, A, L, I, Q, R, R+ and M, and for arginine at position 36 is selected from the group of K, K+, G, S, A, L, I, Q, M, and R+. (where + indicates a D form).
Also preferred are analogs wherein the sole modification is the substitution of an oxidation-resistant amino acid for tryptophan at position 31 (section (b)). Particularly favored substitutions are selected from the group consisting of F, V, L, I, A, and Y.
Also preferred are those analogs wherein the only modification is at least one of those specific substitutions set forth in section (c). Particularly preferred are those analogs wherein combined substitutions of S for G at-position 22, R at positions 23 and 24 for Q and A respectively, and Q for K at position 26 have been made, or substitutions of Y for V at position 16 and K for S at position 18 have been made, or these substitutions plus D for E at positions 21 have been made.
Also preferred are analogs wherein the sole modifications are those set forth in section (d). Particularly preferred among these are those wherein the small neutral amino acid substituted for alanine at position 8 is selected from the group consisting of S, S+, GC, C+, Sar, A+, beta-ala and Aib; and/or the acidic or neutral amino acid substituted for glutamic acid at position 9 is selected from the group consisting of E+, D, D+, Cya T, T+, N, N+, Q, Q+, Cit, MSO, and acetyl-K; and/or the alternative neutral amino acid substituted for glycine at position 10 is selected from the group consisting of S, S+, Y, Y+, T, T+, N, N+, Q, Q+, Cit, MSO, acetyl-K, F, and F+; and/or wherein D is substituted for E at position 15.
Also preferred are analogs wherein position 7 alone has been altered (section (e)). Preferred substitutions are those wherein the amino acid substituted for histidine at position 7 is selected from the group consisting of H+, Y, Y+, F, F+, R, R+, Orn, Orn+, M, M+, N-formyl-H, N-formyl-H+, N-acetyl-H, N-acetyl-H+, N-isopropyl-H, N-isopropyl-H+, N-acetyl-K; N-acetyl-K+, P and P+.
Also preferred are embodiments with a combination of only two of the above-referenced classes of modified forms, in addition to the following specific embodiments.
The following specific analogs are preferred:
(H+)7-GLP-1(7-37);
(Y)7-GLP-1(7-37);
(N-acetyl-H)7-GLP-1(7-37);
(N-isopropyl-H)7-GLP-1(7-37);
(A+)8-GLP-1(7-37);
(E+)9-GLP-1(7-37);
(D)9-GLP-1(7-37);
(D+)9-GLP-1(7-37);
(F+)10-GLP-1(7-37);
(S)22(R)23(R)24(Q)26-GLP-1(7-37);
(S)8(Q)9(Y)16(K)18(D)21-GLP-1(7-37).
Preferred forms of analogs with enhanced stability also have only one, or at most two, amino acid modifications.
Preferred substitutions for the histidine at position 7 include the D-forms of acidic or neutral amino acids or the D-forms of histidines. Preferred are P+, D+, E+, N+, Q+, L+, V+, I+ and H+.
The histidine at position 7, or a replacement (D or L), can also be N-alkylated (1-6C) or N-acylated (1-6C). Alkyl groups are straight or branched chain (including cyclic) hydrocarbyl residues of the indicated member of C. Acyl groups are of the formula RCO-wherein R is alkyl. Preferred alkyl groups are t-propyl, xcex1-propyl and ethyl; preferred acyl are acetyl and propionyl. Preferred residues which may be alkylated or acylated include P, D, E, N, Q, V, L, I, K and H in either the D or L form.
Preferred substitutions for alanine at position 8 are the D-forms of P, V, L, I and A; also preferred are the D-forms of D, E, N, Q, K, T, S and H.
Some specific analogs show both enhanced insulin release stimulating activity and enhanced stability.
A preferred group of GLP-1 analogs and derivatives for use in the present invention is composed of molecules of the formula:
R1-X-Glu-Gly10-Thr-Phe-Thr-Ser-Asp15-Val-Ser-Ser-Tyr-Leu20-Y-Gly-Gln-Ala-Ala25-Lys-Z-Phe-Ile-Ala30-Trp-Leu-Val-Lys-Gly35-Arg-R2xe2x80x83xe2x80x83(SEQ ID NO:2)
and the pharmaceutically-acceptable salts thereof, wherein: R1 is selected from the group consisting of L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, b-hydroxy-histidine, homohistidine, alpha-fluoromethyl-histidine, and alpha-methyl-histidine; X is selected from the group consisting of Ala, Gly, Val, Thr, Ile, and alpha-methyl-Ala; Y is selected from the group consisting of Glu, Gln, Ala, Thr, Ser, and Gly; Z is selected from the group consisting of Glu, Gln, Ala, Thr, Ser, and Gly; and R2 is selected from the group consisting of NH2, and Gly-OH; provided that the compound has an isoelectric point in the range from about 6.0 to about 9.0 and further providing that when R1 is His, X is Ala, Y is Glu, and Z is Glu, R2 must be NH2.
Numerous GLP-1 analogs and derivatives having an isoelectric point in the range from about 6.0 to about 9.0 have been disclosed and include, for example:
GLP-1 (7-36)NH2
Gly8-GLP-1 (7-36)NH2
Gln9-GLP-1 (7-37)
D-Gln9-GLP-1 (7-37)
acetyl-Lys9-GLP-1 (7-37)
Thr9-GLP-1 (7-37)
D-Thr9-GLP-1 (7-37)
Asn9-GLP-1 (7-37)
D-Asn9-GLP-1 (7-37)
Ser22-Arg23-Arg24-Gln26-GLP-1 (7-37)
Thr16-Lys18-GLP-1 (7-37)
Lys18-GLP-1 (7-37)
Arg23-GLP-1 (7-37)
Arg24-GLP-1 (7-37)
Another preferred group of active compounds for use in the present invention is disclosed in WO 91/11457, (related to U.S. Pat. No. 5,545,618) and includes GLP-1(7-34), GLP-1(7-35), GLP-1(7-36), or GLP-1(7-37), or the amide form thereof, and pharmaceutically-acceptable salts thereof, having at least one modification including those shown below:
(a) substitution of glycine, serine, cysteine, threonine, asparagine, glutamine, tyrosine, alanine, valine, isoleucine, leucine, methionine, phenylalanine, arginine, or D-lysine for lysine at position 26 and/or position 34; or substitution of glycine, serine, cysteine, threonine, asparagine, glutamine, tyrosine, alanine, valine, isoleucine, leucine, methionine, phenylalanine, lysine, or a D-arginine for arginine at position 36;
(b) substitution of an oxidation-resistant amino acid for tryptophan at position 31;
(c) substitution of at least one of: tyrosine for valine at position 16; lysine for serine at position 18; aspartic acid for glutamic acid at position 21; serine for glycine at position 22; arginine for glutamine at position 23; arginine for alanine at position 24; and glutamine for lysine at position 26; and
(d) substitution of at least one of: glycine, serine, or cysteine for alanine at position 8; aspartic acid, glycine, serine, cysteine, threonine, asparagine, glutamine, tyrosine, alanine, valine, isoleucine, leucine, methionine, or phenylalanine for glutamic acid at position 9; serine, cysteine, threonine, asparagine, glutamine, tyrosine, alanine, valine, isoleucine, leucine, methionine, or phenylalanine for glycine at position 10; and glutamic acid for aspartic acid at position 15; and
(e) substitution of glycine, serine, cysteine, threonine, asparagine, glutamine, tyrosine, alanine, valine, isoleucine, leucine, methionine, or phenylalanine, or the D- or N-acylated or alkylated form of histidine for histidine at position 7; wherein, in the substitutions is (a), (b), (d), and (e), the substituted amino acids can optionally be in the D-form and the amino acids substituted at position 7 can optionally be in the N-acylated or N-alkylated form.
Because the enzyme, dipeptidyl-peptidase IV (DPP IV), may be responsible for the observed rapid in vivo inactivation of administered GLP-1, (Mentlein et al., 1993), administration of GLP-1 analogs and derivatives that are protected from the activity of DPP IV is preferred, and the administration of Gly8-GLP-1(7-36)NH2, Val8-GLP-1(7-37)OH, a-methyl-Ala8-GLP-1(7-36)NH2, and Gly8-Gln21-GLP-1(7-37)OH, or pharmaceutically-acceptable salts thereof, is more preferred.
The use in the present invention of a molecule claimed in U.S. Pat. No. 5,188,666 (""666) is also preferred. Such a molecule includes a peptide having one of the following amino acid sequences:
NH2-His7-Ala-Glu-Gly10-Thr-Phe-Thr-Ser-Asp15-Val-Ser-Ser-Tyr-Leu20-Glu-Gly-Gln-Ala-Ala25-Lys-Glu-Phe-Ile-Ala30-Trp-Leu-Val-Xxe2x80x83xe2x80x83(SEQ ID NO:3)
wherein X may be Lys and Lys-Gly; or a derivative of said peptide, and wherein said peptide may be a pharmaceutically-acceptable acid addition salt of said peptide; a pharmaceutically-acceptable carboxylate salt of said peptide; a pharmaceutically-acceptable lower alkylester of said peptide; or a pharmaceutically-acceptable amide of said peptide selected from the group consisting of amide, lower alkyl amide, and lower dialkyl amide.
The invention in ""666 pertains to a peptide fragment which is insulinotropic and is derivable from a naturally occurring amino acid sequence.
The invention comprises a compound selected from the group consisting of:
(A) a peptide comprising the sequence:
xe2x80x83His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-X
wherein X is selected form the group consisting of:
(a) Lys,
(b) Lys-Gly,
(c) Lys-Gly-Arg;
and (B) a derivative of the peptide; wherein the compound is substantially free of natural contaminants, and has an insulinotropic activity which exceeds the insulinotropic activity of GLP-1 (1-36) or GLP-1 (1-37).
The invention also includes a compound selected from the group consisting of:
(A) a peptide comprising the sequence:
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-X
wherein X is selected form the group consisting of:
(a) Lys,
(b) Lys-Gly,
(c) Lys-Gly-Arg;
and (B) a derivative of the peptide; wherein the compound is substantially free of natural contaminants, and has an insulinotropic activity at a concentration of at least 10xe2x88x9210M.
Of particular interest are peptides of the following formula:
H2Nxe2x80x94Xxe2x80x94COxe2x80x94R1xe2x80x83xe2x80x83(1)
wherein R1 is OH, OM, or xe2x80x94NR2R3;
M is a pharmaceutically acceptable cation or a lower branched or unbranched alkyl group;
R2 and R3 are the same or different and selected from the group consisting of hydrogen and a lower branched or unbranched alkyl group;
X is a peptide comprising the sequence:
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg
NH2 is the amine group of the amino terminus of X; and CO is the carbonyl group of the carboxy terminus of X;
(2) the acid addition salts thereof; and
(3) the protected or partially protected derivatives thereof;
wherein said compound has an insulinotropic activity which exceeds the insulinotropic activity of GLP-1 (1-36) or GLP-1 (1-37).
Another preferred group of molecules for use in the present invention consists of compounds claimed in U.S. Pat. No. 5,512,549 having the general formula:
and pharmaceutically-acceptable salts thereof, wherein R1 may be 4-imidazopropionyl, 4-imidazoacetyl, or 4-imidazo-a, a dimethyl-acetyl; R2 may be C6-C10 unbranched acyl, or absent; R3 may be Gly-OH or NH2; and, Xaa is Lys or Arg.
More preferred compounds of SEQ ID NO:4 for use in the present invention are those in which Xaa is Arg and R2 is a C6-C10 unbranched acyl.
Highly preferred compounds of SEQ ID NO:4 for use in the present invention are those in which Xaa is Arg, R2 is C6-C10 unbranched acyl, and R3 is Gly-OH.
More highly preferred compounds of SEQ ID NO:4 for use in the present invention are those in which Xaa is Arg, R2 is a C6-C10 unbranched acyl, R3 is Gly-OH, and R1 is 4-imidazopropionyl.
The most preferred compound of SEQ ID NO:4 for use in the present invention is that in which Xaa is Arg, R2 is C8 unbranched acyl, R3 is Gly-OH, and R1 is 4-imidazopropionyl.
The use in the present invention of a molecule claimed in U.S. Pat. No. 5,120,712 is highly preferred. Such a molecule includes a peptide having the amino acid sequence:
NH2-His7-Ala-Glu-Gly10-Thr-Phe-Thr-Ser-Asp15-Val-Ser-Ser-Tyr-Leu20-Glu-Gly-Gln-Ala-Ala25-Lys-Glu-Phe-Ile-Ala30-Trp-Leu-Val-Lys-Gly35-Arg-Gly37-OHxe2x80x83xe2x80x83(SEQ ID NO:1)
and a derivative of said peptide, wherein said peptide may be a pharmaceutically-acceptable acid addition salt of said peptide; a pharmaceutically-acceptable carboxylate salt of said peptide; a pharmaceutically-acceptable lower alkylester of said peptide; or a pharmaceutically-acceptable amide of said peptide wherein the amide may be an amide, lower alkyl amide, or lower dialkyl amide.
The use of GLP-1(7-36) amide, or a pharmaceutically-acceptable salt thereof, in the present invention is most highly preferred. The amino acid sequence of GLP-1(7-36) amide is:
NH2-His7-Ala-Glu-Gly10-Thr-Phe-Thr-Ser-Asp15-Val-Ser-Ser-Tyr-Leu20-Glu-Gly-Gln-Ala-Ala25-Lys-Glu-Phe-Ile-Ala30-Trp-Leu-Val-Lys-Gly35-Arg-NH2xe2x80x83xe2x80x83(SEQ ID NO:5)
The use of Val8-GLP-1(7-37)OH, or a pharmaceutically-acceptable salt thereof, in the present invention is most highly preferred. The amino acid sequence of Val8-GLP-1(7-37)OH is:
NH2-His7-Val-Glu-Gly10-Thr-Phe-Thr-Ser-Asp15-Val-Ser-Ser-Tyr-Leu20-Glu-Gly-Gln-Ala-Ala25-Lys-Glu-Phe-Ile-Ala30-Trp-Leu-Val-Lys-Gly35-Arg-Gly37-OHxe2x80x83xe2x80x83(SEQ ID NO:6)
Preparation of the Compounds
Methods for preparing the active compounds used in the present invention, namely, GLP-1, an GLP-1 analog, or a GLP-1 derivative, or any related compound including an active fragment effecting weight loss when administered peripherally, are well-known, and are described in U.S. Pat. Nos. 5,118,666, 5,120,712, and 5,523,549.
The amino acid portion of the active compound used in the present invention, or a precursor thereto, is made by 1) solid-phase synthetic chemistry; 2) purification of GLP molecules from natural sources; 3) recombinant DNA technology; or 4) a combination of these methods.
Solid phase chemical synthesis of polypeptides is well known in the art and may be found in general texts in the area such as Dugas and Penney 1981; Merrifield 1962; Stewart and Young 1969.
For example, the amino acid portion may be synthesized by solid-phase methodology utilizing a 430A peptide synthesizer (PE-Applied Biosystems, Inc., 850 Lincoln Center Drive, Foster City, Calif. 94404) and synthesis cycles supplied by PE-Applied Biosystems. BOC-amino acids and other reagents are commercially available from PE-Applied Biosystems and other chemical supply houses. Sequential BOC chemistry using double couple protocols are applied to the starting p-methyl benzhydryl amine resins for the production of C-terminal carboxamides. For the production of C-terminal acids, the corresponding PAM resin is used. Asn, Gln, and Arg are coupled using preformed hydroxy benzotriazole esters. The following side chain protecting groups may be used:
Arg, Tosyl
Asp, cyclohexyl
Glu, cyclohexyl
Ser, Benzyl
Thr, Benzyl
Tyr, 4-bromo carbobenzoxy
BOC deprotection may be accomplished with trifluoroacetic acid in methylene chloride. Following completion of the synthesis the peptides may be deprotected and cleaved from the resin with anhydrous hydrogen fluoride (HF) containing 10% meta-cresol. Cleavage of the side chain protecting group(s) and of the peptide from the resin is carried out at xe2x88x925xc2x0 C. to 5xc2x0 C., preferably on ice for 60 minutes. After removal of the HF, the peptide/resin is washed with ether, and the peptide extracted with glacial acetic acid and lyophilized.
Techniques well-known to the ordinarily-skilled artisan in recombinant DNA technology may be used to prepare the active compound used in present invention. In fact, recombinant DNA methods may be preferable because of higher yield. The basic steps in recombinant production are:
a) isolating a natural DNA sequence encoding a GLP-1 molecule of the present invention or constructing a synthetic or semi-synthetic DNA coding sequence for a GLP-1 molecule,
b) placing the coding sequence into an expression vector in a manner suitable for expressing proteins either alone or as a fusion proteins,
c) transforming an appropriate eukaryotic or prokaryotic host cell with the expression vector,
d) culturing the transformed host cell under conditions that will permit expression of a GLP-1 molecule, and
e) recovering and purifying the recombinantly produced GLP-1 molecule.
As previously stated, the coding sequences may be wholly synthetic or the result of modifications to the larger, native glucagon-encoding DNA. A DNA sequence that encodes preproglucagon is presented in Lund et al. 1982 and may be used as starting material in the semisynthetic production of the compounds of the present invention by altering the native sequence to achieve the desired results.
Synthetic genes, the in vitro or in vivo transcription and translation of which results in the production of a GLP-1 molecule, may be constructed by techniques well known in the art. Owing to the natural degeneracy of the genetic code, the skilled artisan will recognize that a sizable yet definite number of DNA sequences may be constructed, all of which encode GLP-1 molecules of the present invention.
The methodology of synthetic gene construction is well-known in the art (Brown et al. 1979.) The DNA sequence is designed from the desired amino acid sequence using the genetic code, which is easily ascertained by the ordinarily-skilled biologist. Once designed, the sequence itself may be generated using conventional DNA synthesizing apparatus such as the Model 380A or 380B DNA synthesizers (PE-Applied Biosystems, Inc., 850 Lincoln Center Drive, Foster City, Calif. 94404).
To express the amino acid portion of a compound used in the present invention, an engineered synthetic DNA sequence is inserted in any one of many appropriate recombinant DNA expression vectors through the use of appropriate restriction endonucleases (Maniatis et al., 1989). Restriction endonuclease cleavage sites are engineered into either end of the GLP-1 molecule-encoding DNA to facilitate isolation from, and integration into, amplification and expression vectors well-known in the art. The particular endonucleases employed will be dictated by the restriction endonuclease cleavage pattern of the parent expression vector employed. Restriction sites are chosen to properly orient the coding sequence with control sequences, thereby achieving proper in-frame reading and expression of the protein of interest. The coding sequence must be positioned to be in proper reading frame with the promoter and ribosome binding site of the expression vector, both of which are functional in the host cell in which the protein is to be expressed.
To achieve efficient transcription of the synthetic gene, it must be operably associated with a promoter-operator region. Therefore, the promoter-operator region of the synthetic gene is placed in the same sequential orientation with respect to the ATG start codon of the synthetic gene.
A variety of expression vectors useful for transforming prokaryotic and eukaryotic cells are well known in the art (Promega Catalogue, 1992; Stratagene Catalogue, 1992). Also, U.S. Pat. No. 4,710,473 describes circular DNA plasmid transformation vectors useful for expression of exogenous genes in E. coli at high levels. These plasmids are useful as transformation vectors in recombinant DNA procedures and
(a) confer on the plasmid the capacity for autonomous replication in a host cell;
(b) control autonomous plasmid replication in relation to the temperature at which host cell cultures are maintained;
(c) stabilize maintenance of the plasmid in host cell populations;
(d) direct synthesis of a protein product indicative of plasmid maintenance in a host cell population;
(e) provide in-series restriction endonuclease recognition sites unique to the plasmid; and
(f) terminate mRNA transcription. These circular DNA plasmids are useful as vectors in recombinant DNA procedures for securing high levels of expression of exogenous genes.
Having constructed an expression vector for the amino acid portion of a compound used in the present invention, the next step is to place the vector into a suitable cell and thereby construct a recombinant host cell useful for expressing the polypeptide. Techniques for transforming cells with recombinant DNA vectors are well known in the art and may be found in such general references as Maniatis, et al. supra. Host cells made be constructed from either eukaryotic or prokaryotic cells.
Prokaryotic host cells generally produce the protein at higher rates and are easier to culture. Proteins expressed in high-level bacterial expression systems characteristically aggregate in granules or inclusion bodies, which contain high levels of the overexpressed protein. Such protein aggregates typically must be recovered, solubilized, denatured and refolded using techniques well known in the art (Kreuger et al., 1990; U.S. Pat. No. 4,923,967).
Preparation of GLP-1 Analogs and Derivatives
Alterations to a precursor GLP-1 or GLP-1 amino acid sequence to produce a desired GLP-1 analog or GLP-1 derivative, or active fragment thereof, are made by well-known methods: chemical modification, enzymatic modification, or a combination of chemical and enzymatic modifications. The techniques of classical solution phase methods and semi-synthetic methods may also be useful for preparing the GLP-1 molecules used in the present invention. Methods for preparing the GLP-1 molecules of the present invention are well known to an ordinarily skilled peptide chemist.
Addition of an acyl group to the epsilon amino group of Lys34 may be accomplished using any one of a variety of methods known in the art (Bioconjugate Chem. 1990; Hashimoto et al., 1989).
For example, an N-hydroxy-succinimide ester of octanoic acid can be added to the lysyl-epsilon amine using 50% acetonitrile in borate buffer. The peptide can be acylated either before or after the imidazolic group is added. Moreover, if the peptide is prepared recombinantly, acylation prior to enzymatic cleavage is possible. Also, the lysine in the GLP-1 derivative can be acylated as taught in WO 96/29342.
The existence and preparation of a multitude of protected, unprotected and partially-protected, natural and unnatural, functional analogs and derivatives of GLP-1 (7-36)amide and GLP-1(7-37) molecules have been described (U.S. Pat. Nos. 5,120,712; 5,545,618 and 5,118,666; Orskov et al., 1989; WO 91/11457).
Optionally, the amino and carboxy terminal amino acid residues of GLP-1 derivatives may be protected, or, optionally, only one of the termini is protected. Reactions for the formation and removal of such protecting groups are described in works known to those of skill in the art including, for example, Protective Groups in Organic Chemistry 1973; Green, 1981; Schrxc3x6der and Lxc3xcbke, 1965. Representative amino-protecting groups include, for example, formyl, acetyl, isopropyl, butoxycarbonyl, fluorenylmethoxycarbonyl, carbobenzyloxy, and the like. Representative carboxy-protecting groups include, for example, benzyl ester, methyl ester, ethyl ester, t-butyl ester, p-nitro phenyl ester, and the like.
Carboxy-terminal, lower-alkyl-ester, GLP-1 derivatives used in the present invention are prepared by reacting the desired (C1-C4) alkanol with the desired polypeptide in the presence of a catalytic acid such as hydrochloric acid. Appropriate conditions for such alkyl ester formation include a reaction temperature of about 50xc2x0 C. and reaction time of about 1 hour to about 3 hours. Similarly, alkyl ester derivatives of the Asp and/or Glu residues can be formed.
Preparation of a carboxamide derivative of a compound used in the present invention is formed, for example, as described in Stewart et al., 1984.
A pharmaceutically-acceptable salt form of GLP-1, of a GLP-1 analog, or of a GLP-1 derivative may be used in the present invention. Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such salts include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Preferred acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and, especially, hydrochloric acid.
Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and the like. The salt forms are particularly preferred.
A GLP-1, GLP-1 analog, or GLP-1 derivative used in the present invention may be formulated with one or more excipients before use in the present invention. For example, the active compound used in the present invention may be complexed with a divalent metal cation by well-known methods. Such metal cations include, for example, Zn++, Mn++, Fe++, Co++, Cd++, Ni++, and the like.
Compositions of the Invention
Optionally, the active compound used in the present invention may be combined with a pharmaceutically-acceptable buffer, and the pH adjusted to provide acceptable stability, and a pH acceptable for parenteral administration.
Optionally, one or more pharmaceutically-acceptable anti-microbial agents may be added. Meta-cresol and phenol are preferred pharmaceutically-acceptable anti-microbial agents. One or more pharmaceutically-acceptable salts may be added to adjust the ionic strength or tonicity. One or more excipients may be added to further adjust the isotonicity of the formulation. Glycerin is an example of an isotonicity-adjusting excipient.
GLP-1 receptors and the signal transduction cascade initiated by ligand binding to the GLP-1 receptor are described in WO 96/25487; Thorens, 1992; Thorens et al., 1993; Widmann et al., 1994. The GLP-1 receptor is a membrane protein with seven transmembrane domains, coupled to heterotrimeric G-proteins that link activation of the receptor by ligand binding to production of intracellular secondary messengers, especially, cyclic adenosine monophosphate (cAMP). cAMP, in turn, activates a specific protein kinase, cAMP-dependent protein kinase (protein kinase A, PKA). This enzyme phosphorylates a number of key response elements present in the promoter region of certain genes. In pancreatic b-cells and other neuroendocrine cells, phosphorylation of some specific proteins of the regulated secretory pathway stimulates peptide secretion by stimulating exocytosis of secretory granules.
Various compounds are known to stimulate secretion of endogenous GLP-1. For example, exposure of STC-1 cells to certain secretagogues, such as, the adenylate cyclase activator, forskolin, or the protein kinase-C-stimulating agent, 12-O-tetradecanoylphobol-13-acetate (TPA), caused significant increases in release of GLP-1 (Abello et al., 1994). The STC-1 cell line originated from an intestinal tumor in transgenic mice carrying insulin-promoting oncogenes, and STC-1 cells are known to contain m-RNA transcripts of pro-glucagon, from which GLP-1 is generated. Other compounds, such as, somatostatin, gastric inhibitory polypeptide, glucose-dependent insulinotropic peptide, bombesin, calcitonin gene-related peptide, gastrin-releasing peptide, cholinergic agonists, the b-adrenergic agonist, isoproterenol, and the muscarinic cholinergic agonist, bethanechol, are similarly known to cause release of endogenous GLP-1 (Plaisancie et al., 1994; Orskov et al., 1986; Brubaker, 1991; Buchan, et al., 1987).
Administration of Compositions
Administration may be via any route known to be effective by the physician of ordinary skill, except that parenteral administration directly into the central nervous system is not a route taught or claimed in this invention. Peripheral, parenteral administration is preferred. Parenteral administration is commonly understood in the medical literature as the injection of a dosage form into the body by a sterile syringe or some other mechanical device such as an infusion pump. For the purpose of this invention, peripheral parenteral routes include intravenous, intramuscular, subcutaneous, and intraperitoneal routes of administration. Intravenous, intramuscular, and subcutaneous routes of administration of the compounds used in the present invention are more preferred. Intravenous and subcutaneous routes of administration of the compounds used in the present invention are yet more highly preferred. For parenteral administration, an active compound used in the present invention preferably is combined with distilled water at an appropriate pH.
Certain compounds used in the present invention to effect weight-loss may also be amenable to administration by the oral, rectal, nasal, or lower respiratory routes, which are non-parenteral routes. Of the said non-parenteral routes, the lower respiratory route is preferred for administration of peptides used in the instant invention. Various formulations of peptide compounds for administration by the lower respiratory tract are disclosed in U.S. Pat. Nos. 5,284,656 and 5,364,838. Publication WO 96/19197 discloses aerosol formulations of various peptides suitable for enhancing lower respiratory tract absorption of the compounds used in the instant invention. The oral route of administration is preferred for compounds used in the instant invention.
Additional pharmaceutical methods may be employed to control the duration of action. Controlled release preparations may be achieved by the use of polymers to complex or absorb the active compound used in the present invention. Extended duration may be obtained by selecting appropriate macromolecules, for example, polyesters, polyamino acids, polyvinylpyrrolidone, ethylenevinyl acetate, methylcellulose, carboxymethylcellulose, or protamine sulfate, and by selecting the concentration of macromolecules, as well as the methods of incorporation, in order to prolong release. Another possible method to extend the duration of action by controlled release preparations is to incorporate an active compound used in the present invention into particles of a polymeric material such as polyesters, polyamino acids, hydrogels, poly (lactic acid) or ethylene vinylacetate copolymers. Alternatively, instead of incorporating a compound into these polymeric particles, it is possible to entrap a compound used in the present invention in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules, respectively, or in colloidal drug delivery systems, for example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules, or in macroemulsions. Such teachings are known to those of skill in the art and disclosed, e.g. in Remington""s Pharmaceutical Sciences, 1980.
Dose
The dose of GLP-1, GLP-1 analog, or GLP-1 derivatives, or active fragments effective in a particular subject to cause weight-loss will depend on a number of factors, among which are included the subject""s sex, weight and age, the underlying causes of obesity, the route of administration and bioavailability, the persistence of the administered compound in the body, the formulation, and the potency. Where administration is intermittent, the dose per administration should also take into account the interval between doses, and the bioavailability of the administered compound. Where administration is continuous, a suitable dosage rate is between 0.25 and 6 pmol/kg body weight/min, preferably from about 0.5 to about 1.2 pmol/kg/min. It is within the skill of the ordinary physician to titrate the dose and rate of administration of compositions containing GLP-1, GLP-1 analogs, or GLP-1 derivatives, or active fragments thereof to achieve the desired clinical result, that is weight loss.
xe2x80x9cPharmaceutically acceptablexe2x80x9d means suitable for administration to a human, that is, does not contain toxic elements, undesirable contaminants or the like, and does not interfere with the activity of the active compounds therein.

Use of GLP-1 analogs and derivative adminstered peripherally in regulation of obesity


An optical sight includes an optical train having an optical path therethrough, an entrance, and an exit. A reticle is visible through the exit of the optical path. An unpowered reticle illumination source has a first light source that illuminates the reticle responsive to the level of ambient light, and a second light source that illuminates the reticle with an unpowered light source. The reticle illumination source preferably has a scintillation material positioned so that ambient light entering the ambient-light receiver is incident upon the scintillation material, whereupon the scintillation material responsively emits secondary light. A light-gathering prism receives the secondary light and has a diffusing surface disposed to illuminate the reticle using the secondary light. An unpowered light source is positioned to emit light through the diffusing surface to be incident upon the reticle. The unpowered light source may be a tritium light source.

Refractive or reflective optical sights are used in a wide variety of applications to obtain increased magnification of a scene. In one common application, an optical sight is affixed to the upper side of the barrel of a rifle-type weapon used by a soldier or a hunter. The user sights through the optical sight to acquire a target and aim the weapon toward the target to increase the likelihood of hitting the target with a projectile fired from the weapon.
A reticle is typically provided in the optical path of the optical sight to aid the user of the weapon in aiming the weapon. The reticle normally has reference markings or other information that aids the user in aiming the optical sight and thence the weapon toward the intended target. The reference markings usually include a cross hair, bulls-eye, center dot, or similar marking to indicate the bore sight of the weapon. The reference markings may also include elevation, windage, and other reference markings that assist the user in aiming the weapon.
The reticle must be visible to the user of the optical sight. In some designs, the reticle is illuminated by an artificial light source within the optical sight. The use of reticle illumination adds cost and weight, but it ensures that the reticle will be visible in a wide range of lighting conditions including normal daylight, low-light ambient conditions, and near-darkness conditions.
There is a need for an improved approach to ensure proper illumination of the reticle of an optical sight, so that the reticle always remains visible to the user peering through the optical sight. The present invention fulfills this need, and further provides related advantages.

Optical sight having an unpowered reticle illumination source


A window glass having shaped metallic brackets with a U-shaped cross section which are force-fittingly connected by clamping to the edge areas of the glass, wherein the window glass is provide on at least one surface on the edge area overlapped by the shaped metallic bracket with a raised layer which securely adheres to the glass surface and which is made of a highly elastic polymer which produces a large-surface force connection to the abutting shaped shank with partial elastic deformation. The window glass avoids the use of adhesives between the shaped brackets and glass surface and is suitable for industrial production.

1. Field of the Invention:
This invention relates to plate glass, particularly window glass for motor vehicles, which has shaped metallic brackets or border moldings, having a U-shaped cross section, attached by clamping to the edge areas of the glass.
2. Description of the Prior Art:
Window glass having one or more pressed-on brackets or border molding are used, for example, as lowerable door windows in motor vehicles. With lowerable door windows of this type, it is known to arrange a baked-on layer of a rough surfaced ceramic paint along the lower edge of the glass plate, and to press a U-shaped metallic bracket, with an intermediate strip or shaped section of an elastically resilient material, onto the edge area. This metallic bracket transfers the mechanical forces to the window glass to open and close the window. The ceramic layer serves to increase the adhesive effect (DE-OS 30 30 948).
It is also known and common to attach metallic brackets having a U-shaped attachment section to window glass with an intermediate cured or hardened adhesive therebetween. The attachment of shaped brackets with an intermediate adhesive does result in a durable connection, but it has the disadvantage that the common adhesives require a lengthy curing period. During this hardening period the glass plates cannot be processed further. For example, the glass plates cannot be built into an automobile body, because the metallic bracket can thereby shift on the window glass. The mounting of the shaped brackets on the window glass with the use of an adhesive, therefore, cannot take place on the conveyor line of a motor vehicle assembly line, but rather the mounting process must take place previously and at a different location. This requires an additional labor and transportation expense with corresponding associated costs.
Therefore, a need continues to exist for a window glass with a shaped metallic bracket attached thereto without the necessity of using an adhesive between the shaped metallic bracket and the window glass.

Window glass for motor vehicles and a method for the manufacture thereof


A waterborne contact adhesive comprises and aqueous emulsion of A) between about 50 and about 80 weight percent (based on A) plus B) solids) of an emulsified acrylic polymer, said acrylic polymer having an acid number of between about 5 and about 50, and an N-methylol acrylamide content of between about 0.5 and about 5 wt % based on monomer solids; B) between about 20 and about 50 weight percent (based on A) plus B) solids) of a latex of an elastomer, particularly natural rubber latex, and C) anionic surfactant in amount sufficient to stabilize the aqueous dispersion of A) and B).

By "contact adhesive" is meant herein an adhesive which is typically applied to two surfaces to be adhered together, dried to form clear film adhesive layers, and brought into contact with pressure so as to form an immediate, durable bond. Such adhesives are used, for example, in laminating plastic, such as Formica.RTM., to particle board for kitchen counter tops (high pressure laminate (HPL)) and for gluing foam to wood in sandwich panels. Once the contact adhesives are pressed together, the adhered pieces are to be ready for further processing, such as cutting; contact adhesives being formulated so as not to require adhesive curing to achieve the requisite bond strength.
Most contact adhesives, heretofore, have been solvent-borne. Low boiling point organic solvents as carriers for contact adhesives provide the advantage of rapid dry times, whereupon the workpieces may be contact-adhered very soon after application of the adhesive composition. Increasingly, however, organic-borne compositions are becoming disfavored for the volatiles they release both to the immediate workplace or the general environment.
Waterborne contact adhesives have been developed, Fastbond.RTM. adhesives produced by 3M being a prime example. While Fastbond.RTM. adhesives have met with considerable success, they are based primarily on neoprene latexes, a relatively expensive substance. Resistivity to high temperature of Fastbond.RTM. is less than desired. High-temperature resistance is important in a contact adhesive as the adhered workpieces may be subject to further processing, such as cutting, which may generate considerable localized heat and may result, for example, in delamination at the edges. Also, Fastbond.RTM., like most other waterborne contact adhesives, still contains some organic solvent.


This invention provides for, inter alia, a transdermal therapeutic system comprising at least one therapeutically active substance, which is oxidizable by hydroperoxides, wherein the amount of oxidative degradation of said active substances(s) and the corresponding formation of oxidative degradation products is reduced, which comprises one or more constituents of said transdermal therapeutic system being in contact with said active substance(s), wherein the sum of the peroxide number(s) (PON) of each of said constituents related to their percentage of the whole amount of said constituents as expressed by the formula       ∑          i      =      1        n          xe2x80x83          (                  N        i            ·              PON        /        100              )

Disregarding a few fairly uncommon special forms, transdermal therapeutic systems (TTS) may be differentiated into two basic groups, those known as matrix systems and those known as reservoir systems. In the case of those known as matrix systems, in the simplest case the active substance is dissolved in a self-adhesive layer or in some cases only suspended in the form of crystals. Reservoir systems represent a type of pouch comprising an inert backing layer and an active substance permeable membrane, the active substance being located in a liquid preparation within this pouch. Usually, the membrane is provided with a layer of adhesive which serves to anchor the system on the skin.
Irrespective of specific embodiments of the transdermal system, the active substance is delivered to the skin by diffusion during use and is therefore required to be present, at least in part, in dissolved form.
In this form, the active substance is particularly sensitive to reactions with constituents of the formulation which may lead to an impairment of the stability. Examples of such reactions include:
a) the bonding of the active substance via an amide or ester bond to carboxyl groups or ester groups of the polymers or permeation enhancers used;
b) the reaction of a carboxyl group or ester group of the active substance with alcoholic groups of tackifying resins or permeation enhancers;
c) the hydrolysis or alcoholysis of ester groups by water or alcohols, respectively.
Such reactions, which may be inferred directly from the functional groups of the active substance and of the auxiliaries, are no surprise to the skilled worker. Corresponding risks to stability are therefore usually discovered very quickly by means of appropriate compatibility studies at elevated temperature and can then be avoided by means of appropriate reformulations of adverse active substance/auxiliary combinations.
Furthermore, the stability of the active substance and of the auxiliaries may be put at risk by reaction with active oxygen. Such active oxygen is, naturally, the oxygen of the air. An effective means of protecting the active substance present in the TTS against this oxygen is to package the TTS under a nitrogen atmosphere and/or to insert antioxidants into the packaging as well.
Despite these precautionary measures, however, it has to date been necessary to accept quite often a greater or lesser decrease in the amount of active substance when a TTS comprising oxidation sensitive active substances is stored for prolonged periods. The causes of this were not previously known.
It has now surprisingly been found that raw materials used to produce TTS may to a considerable extent comprise active oxygen in another form, namely in the form of hydroperoxides.
These hydroperoxides may form by the following mechanism in accordance with the autoxidation reactions described in the literature:
In the first step, known as the induction phase, free radicals are formed by exposure to heat and/or light, promoted by trace amounts of heavy metals and accompanied by the loss of a hydrogen atom. In the second step, known as the propagation phase, these radicals react with oxygen to form peroxy radicals. These peroxy radicals then attack further molecules, forming hydroperoxides and a new free radical. Thus a chain reaction has begun which continues until this chain is terminated by the reaction of two radicals with one another, as shown for example in the equation below.
Owing to its relatively low reactivity, the peroxide radical, functioning as a chain transfer agent, attacks particularly those sites which lead to a low-energy radical on the substrate. Preferred sites of this kind are Cxe2x80x94H bonds in benzyl or allyl position, tertiary Cxe2x80x94H bonds, and Cxe2x80x94H bonds in the vicinity of ether oxygens. As a result, raw materials possessing such groups are especially susceptible to the formation of hydroperoxides.
The antioxidants or stabilizers which are used to protect oxidation sensitive active substances may intervene in this reaction chain. Antioxidants may be differentiated into free-radical scavengers and oxygen scavengers. Free-radical scavengers such as tocopherol and its derivatives, for example, remove or inactivate free radicals and so interrupt the chain mechanism of autoxidation. Oxygen scavengers, such as ascorbyl palmitate, for example, react directly with the oxidative agent and so prevent the chain reaction starting.
The addition of antioxidants/stabilizers only makes sense, however, if the starting materials themselves do not comprise hydroperoxides with an oxidative action and if the drug form is protected against the ingress of oxygen by the packaging.
Surprisingly, it has been found that in all classes of raw material used to produce transdermal therapeutic systems, with the exception of materials in film form, there are representatives which on supply or after brief storage are already loaded with considerable amounts of hydroperoxides. Specifically, this means that polymers, tackifying resins, permeation enhancers and solvents or solubilizers may have a hydroperoxide content which can to a considerable extent impair the stability of an oxidation sensitive active substance.
The peroxide content is commonly expressed by means of the so-called peroxide number PON, which indicates the amount of milliequivalents of active oxygen per kg of substance. There are various methods of determining the peroxide number. The most customary is to react a defined amount of substance in a chloroform/glacial acetic acid solution with an excess of iodide ions and then to back-titrate the resultant iodine using sodium thiosulfate. A less common method, which is restricted to aqueous solutions, is to react the substance with titanium(IV) ions and to measure the resultant peroxo complex by photometry. A semiquantitative test for peroxides which is particularly easy to implement is carried out using commercial test electrodes.
The table below lists the measured peroxide numbers of some exemplary substances used to produce reservoir and matrix systems, following approximately 6 months"" storage at room temperature. The peroxide numbers were measured by the two first-mentioned methods.
The peroxide number of the finished patches may be determined by the same method. However, it is rather difficult to dissolve a sufficient amount of patch in a reasonable amount of chloroform. An easier method is to measure the peroxide loading of the individual substances and to calculate the peroxide number of the active substance component of the patches in accordance with the following formula:       ∑          i      =      1        n          xe2x80x83          (                  N        i            ·              PON        /        100              )
n: number of formulation constituents of the active substance component of the system
N: percentage content of the formulation constituents in the active substance constituents of the system (numerical value)
PON: peroxide number of the individual constituents of the active substance component of the system
It has been found experimentally that the hydroperoxides present in the raw materials may react in diverse ways with the active substance with which they come in contact. Active substances which have been found to be particularly sensitive are those possessing one of the following substructures:
secondary or tertiary amino groups
Cxe2x80x94C double bonds
Cxe2x80x94H groups in allyl position
benzylic Cxe2x80x94H groups
tertiary Cxe2x80x94H groups
sulfide or sulfoxide groups
The corresponding reaction products are as follows:
In many cases, these reactions at the corresponding functional groups of the active substances are accompanied by follow-on reactions.
For example, it has been found that, in the case of 17-xcex2-estradiol, initial hydroxylation in the benzyl position (C 9) is followed by elimination of the hydroxyl group in the form of water, accompanied by the formation of xcex949(11) 17-xcex2-estradiol. This reaction is favored since a conjugated double bond is formed as a result.
In the case of an active substance having an amine-substituted tetrahydronaphthol fragment (N-0923) it has been found that first of all a N-oxide is formed which then reacts further in an elimination reaction (Cope elimination) in accordance with the reaction scheme below to form a dihydronaphthol and hydroxylamine.
In the case of calcium antagonists of the dihydropyridine type, the following degradation mechanism was found.
It is unclear whether the first attack takes place on the nitrogen or on the tertiary Cxe2x80x94H bond of the dihydropyridine ring. In any case, what follows here again is elimination of water, which is energetically favored owing to the formation of an aromatic state. The subsequent reaction to the N-oxide following oxidation of the dihydropyridine ring is observed only in the reaction with t-butyl hydroperoxide in accordance with equation 5b. In patch systems, the amount formed is too small to be observed at low conversions.
The examples depicted above show that from the reaction products it is often not possible to perceive that hydroperoxides have participated directly in the degradation reaction. To determine the sensitivity of the active substance to oxidation reactions with hydroperoxides, an easily implemented test reaction has been developed. For this purpose, the active substance in chloroform or another appropriate solvent is reacted with t-butyl hydroperoxide under reflux. If oxidative degradation products of the active substance are found in this reaction mixture, they can be attributed to the reaction with hydroperoxide. Often, degradation of the active substance is also evident very simply from a discoloration of the test solution. The practical conclusion to be drawn from a positive outcome of the test reaction is that when formulating a transdermal system using this active substance the auxiliaries used should include only those which are substantially free from hydroperoxides.
The object on which the present invention is based is to provide a transdermal therapeutic system (TTS) in which the formation of oxidative degradation products of the oxidation sensitive active substances present in said TTS is reduced during the storage of said TTS. As already set out above, this object is achieved by using only those formulation constituents which are substantially free of hydroperoxides when producing a TTS comprising one or more oxidation sensitive active substances. In accordance with the invention, these formulation constituents are those which, together, in the proportions provided by the recipe for the TTS, have a peroxide number (PON) of not more than 20, preferably not more than 10, with particular preference not more than 5.
The term formulation constituents embraces all substances of the TTSxe2x80x94with the exception of the pharmaceutical active substance or substancesxe2x80x94in which the active substance(s) are present.
They include: as building blocks of the single-layer or multilayer matrix or of the reservoir system: e.g., polymers of hydrocarbons such as polyethylenes, polypropylenes, polyacrylates, polymethacrylates, polyurethanes, polyisobutylenes, polyvinylpyrrolidone; hydrocarbon resins; silicones; rubber; copolymers of vinylpyrrolidone with acrylic acids, acrylic acid derivatives, ethylene and/or vinyl acetate; resins based on rosin derivatives and/or polyterpenes. As functional additives or auxiliaries: e.g., plasticizers and tackifiers such as rosin esters, examples being hydrogenated or partially hydrogenated glycerol esters of rosin, polyterpenes; permeation enhancers such as terpenes or terpene derivatives, unsaturated fatty acids or their derivatives, esters of long-chain fatty acids, diethylene glycol or its derivatives, for example; alkylmethyl sulfoxides, azones and limonenes; crystallization inhibitors such as polyvinylpyrrolidone, for example; polyacrylic acid or cellulose derivatives; solvents such as polyethylene glycol, diethylene glycol and/or its derivatives, propanediol or oleyl alcohol, for example.
If formulation constituents intended for the production of transdermal therapeutic systems comprising oxidation sensitive active substances are already loaded with considerable amounts of hydroperoxides when supplied, these substances need to be substantially freed from hydroperoxides prior to use. This can be done by destroying hydroperoxides by means of strongly reducing substances. A highly suitable reducing agent and pharmaceutically permitted auxiliary is, for example, sodium bisulfite or sodium hydrogen sulfite. In aqueous or predominantly aqueous solution, this substance can be used to destroy peroxides without problems in a quick reaction. Unfortunately, however, the majority of auxiliaries and polymers used for transdermal systems either are insoluble in water or else water is not compatible with the other auxiliaries used. Surprisingly, it has now also been found that the destruction of hydroperoxides is also possible if the solid substance is dissolved in a water-miscible solvent, preferably ethanol or methanol, and an aqueous solution of an inorganic sulfite, e.g., sodium hydrogen sulfite, is slowly added with stirring to the first solution. Although instances of precipitation occur very quickly when the sulfite solution is added to the solution of the auxiliary, the sulfites still have sufficient time to destroy the hydroperoxides by reduction.
If the solution of the hydrogen sulfite has a sufficient concentration, the small amount of water introduced can usually be tolerated without problems. This is especially the case when the water is removed together with other solvents during coating and drying. Liquid auxiliaries may be reacted with an aqueous solution of sodium hydrogen sulfite even without additional solvent.
Following this treatment, the materials are virtually free from peroxides and may be used without concern even if loaded considerably beforehand. An additional improvement in stability may be achieved by the addition of antioxidants, which retard or suppress the formation of new peroxides during the storage of the systems.
Regarding the tolerable upper limit of the peroxide content of the constituents in contact with the active substance, an upper peroxide number limit of 20, better still 10, preferably 5, should not be exceeded.
The limit of 10 is a result of the following exemplary calculation on a typical transdermal therapeutic matrix system having a size of 20 cm2 and a coating weight of 100 g/m2 and an active substance concentration of 10% g/g. For an assumed molecular weight of the active substance of 200 daltons, accordingly, the system contains 20 mg or 0.1 mmol of active substance, and, with a peroxide number of 10, a total of 0.2xc2x710xe2x88x922 mmol of active oxygen. This means that not more than 2% of the active substance present in the system may be oxidized. In view of the fact that this reaction needs time and is retarded by the consumption of active oxygen, there is a good chancexe2x80x94with a peroxide number of 10, and under certain circumstances an upper limit of 20xe2x80x94that the system will be sufficiently stable for 2 years.
Improved stability is of course achieved by reducing the peroxide loading further (preferably to a PON of 5 or less); by treating the peroxide-loaded auxiliaries with sulfites in accordance with the method described and/or choosing auxiliaries which do not tend to form peroxides.

Transdermal therapeutic systems having improved stability and their production

Abstract: where

Abstract: N is the percentage content of the whole amount of said constituents in the TTS,

Abstract: n is the number of said constituents in the TTS,

Abstract: i is the running number

Abstract: PON is the peroxide number of each of the constituents,

Abstract: is not greater than 20.


An electromagnetic generator without moving parts includes a permanent magnet and a magnetic core including first and second magnetic paths. A first input coil and a first output coil extend around portions of the first magnetic path, while a second input coil and a second output coil extend around portions of the second magnetic path. The input coils are alternatively pulsed to provide induced current pulses in the output coils. Driving electrical current through each of the input coils reduces a level of flux from the permanent magnet within the magnet path around which the input coil extends. In an alternative embodiment of an electromagnetic generator, the magnetic core includes annular spaced-apart plates, with posts and permanent magnets extending in an alternating fashion between the plates. An output coil extends around each of these posts. Input coils extending around portions of the plates are pulsed to cause the induction of current within the output coils.

1. Field of Invention
This invention relates to a magnetic generator used to produce electrical power without moving parts, and, more particularly, to such a device having a capability, when operating, of producing electrical power without an external application of input power through input coils.
2. Description of the Related Art
The patent literature describes a number of magnetic generators, each of which includes a permanent magnet, two magnetic paths external to the permanent magnet, each of which extends between the opposite poles of the permanent magnet, switching means for causing magnetic flux to flow alternately along each of the two magnetic paths, and one or more output coils in which current is induced to flow by means of changes in the magnetic field within the device. These devices operate in accordance with an extension of Faraday""s Law, indicating that an electrical current is induced within a conductor within a changing magnetic field, even if the source of the magnetic field is stationary.
A method for switching magnetic flux to flow predominantly along either of two magnetic paths between opposite poles of a permanent magnet is described as a xe2x80x9cflux transferxe2x80x9d principle by R. J. Radus in Engineer""s Digest, Jul. 23, 1963. This principle is used to exert a powerful magnetic force at one end of both the north and south poles and a very low force at the other end, without being used in the construction of a magnetic generator. This effect can be caused mechanically, by keeper movement, or electrically, by driving electrical current through one or more control windings extending around elongated versions of the pole pieces 14. Several devices using this effect are described in U.S. Pat. Nos. 3,165,723, 3,228,013, and 3,316,514, which are incorporated herein by reference.
Another step toward the development of a magnetic generator is described in U.S. Pat. No. 3,368,141, which is incorporated herein by reference, as a device including a permanent magnet in combination with a transformer having first and second windings about a core, with two paths for magnetic flux leading from each pole of the permanent magnet to either end of the core, so that, when an alternating current induces magnetic flux direction changes in the core, the magnetic flux from the permanent magnet is automatically directed through the path which corresponds with the direction taken by the magnetic flux through the core due to the current. In this way, the magnetic flux is intensified. This device can be used to improve the power factor of a typically inductively loaded alternating current circuit.
Other patents describe magnetic generators in which electrical current from one or more output coils is described as being made available to drive a load, in the more conventional manner of a generator. For example, U.S. Pat. No. 4,006,401, which is incorporated herein by reference, describes an electromagnetic generator including permanent magnet and a core member, in which the magnetic flux flowing from the magnet in the core member is rapidly alternated by switching to generate an alternating current in a winding on the core member. The device includes a permanent magnet and two separate magnetic flux circuit paths between the north and south poles of the magnet. Each of the circuit paths includes two switching means for alternately opening and closing the circuit paths, generating an alternating current in a winding on the core member. Each of the switching means includes a switching magnetic circuit intersecting the circuit path, with the switching magnetic circuit having a coil through which current is driven to induce magnetic flux to saturate the circuit path extending to the permanent magnet. Power to drive these coils is derived directly from the output of a continuously applied alternating current source. What is needed is an electromagnetic generator not requiring the application of such a current source.
U.S. Pat. No. 4,077,001, which is incorporated herein by reference, describes a magnetic generator, or dc/dc converter, comprising a permanent magnet having spaced-apart poles and a permanent magnetic field extending between the poles of the magnet. A variable-reluctance core is disposed in the field in fixed relation to the magnet and the reluctance of the core is varied to cause the pattern of lines of force of the magnetic field to shift. An output conductor is disposed in the field in fixed relation to the magnet and is positioned to be cut by the shifting lines of permanent magnetic force so that a voltage is induced in the conductor. The magnetic flux is switched between alternate paths by means of switching coils extending around portions of the core, with the flow of current being alternated between these switching coils by means of a pair of transistors driven by the outputs of a flip-flop. The input to the flip flop is driven by an adjustable frequency oscillator. Power for this drive circuit is supplied through an additional, separate power source. What is needed is a magnetic generator not requiring the application of such a power source.
U.S. Pat. No. 4,904,926, which is incorporated herein by reference, describes another magnetic generator using the motion of a magnetic field. The device includes an electrical winding defining a magnetically conductive zone having bases at each end, the winding including elements for the removing of an induced current therefrom. The generator further includes two pole magnets, each having a first and a second pole, each first pole in magnetic communication with one base of the magnetically conductive zone. The generator further includes a third pole magnet, the third pole magnet oriented intermediately of the first poles of the two pole electromagnets, the third pole magnet having a magnetic axis substantially transverse to an axis of the magnetically conductive zone, the third magnet having a pole nearest to the conductive zone and in magnetic attractive relationship to the first poles of the two pole electromagnets, in which the first poles thereof are like poles. Also included in the generator are elements, in the form of windings, for cyclically reversing the magnetic polarities of the electromagnets. These reversing means, through a cyclical change in the magnetic polarities of the electromagnets, cause the magnetic flux lines associated with the magnetic attractive relationship between the first poles of the electromagnets and the nearest pole of the third magnet to correspondingly reverse, causing a wiping effect across the magnetically conductive zone, as lines of magnetic flux swing between respective first poles of the two electromagnets, thereby inducing electron movement within the output windings and thus generating a flow of current within the output windings.
U.S. Pat. No. 5,221,892, which is incorporated herein by reference, describes a magnetic generator in the form of a direct current flux compression transformer including a magnetic envelope having poles defining a magnetic axis and characterized by a pattern of magnetic flux lines in polar symmetry about the axis. The magnetic flux lines are spatially displaced relative to the magnetic envelope using control elements which are mechanically stationary relative to the core. Further provided are inductive elements which are also mechanically stationary relative to the magnetic envelope. Spatial displacement of the flux relative to the inductive elements causes a flow of electrical current. Further provided are magnetic flux valves which provide for the varying of the magnetic reluctance to create a time domain pattern of respectively enhanced and decreased magnetic reluctance across the magnetic valves, and, thereby, across the inductive elements.
Other patents describe devices using superconductive elements to cause movement of the magnetic flux. These devices operate in accordance with the Meissner effect, which describes the expulsion of magnetic flux from the interior of a superconducting structure as the structure undergoes the transition to a superconducting phase. For example, U.S. Pat. No. 5,011,821, which is incorporated herein by reference, describes an electric power generating device including a bundle of conductors which are placed in a magnetic field generated by north and south pole pieces of a permanent magnet. The magnetic field is shifted back and forth through the bundle of conductors by a pair of thin films of superconductive material. One of the thin films is placed in the superconducting state while the other thin film is in a non-superconducting state. As the states are cyclically reversed between the two films, the magnetic field is deflected back and forth through the bundle of conductors.
U.S. Pat. No. 5,327,015, which is incorporated herein by reference, describes an apparatus for producing an electrical impulse comprising a tube made of superconducting material, a source of magnetic flux mounted about one end of the tube, a means, such as a coil, for intercepting the flux mounted along the tube, and a means for changing the temperature of the superconductor mounted about the tube. As the tube is progressively made superconducting, the magnetic field is trapped within the tube, creating an electrical impulse in the means for intercepting. A reversal of the superconducting state produces a second pulse.
None of the patented devices described above use a portion of the electrical power generated within the device to power the reversing means used to change the path of magnetic flux. Thus, like conventional rotary generators, these devices require a steady input of power, which may be in the form of electrical power driving the reversing means of one of these magnetic generators or the torque driving the rotor of a conventional rotary generator. Yet, the essential function of the magnetic portion of an electrical generator is simply to switch magnetic fields in accordance with precise timing. In most conventional applications of magnetic generators, the voltage is switched across coils, creating magnetic fields in the coils which are used to override the fields of permanent magnets, so that a substantial amount of power must be furnished to the generator to power the switching means, reducing the efficiency of the generator.
Recent advances in magnetic material, which have particularly been described by Robert C. O""Handley in Modern Magnetic Materials, Principles and Applications, John Wiley and Sons, New York, pp. 456-468, provide nanocrystalline magnetic alloys, which are particularly well suited forth rapid switching of magnetic flux. These alloys are primarily composed of crystalline grains, or crystallites, each of which has at least one dimension of a few nanometers. Nanocrystalline materials may be made by heat-treating amorphous alloys which form precursors for the nanocrystalline materials, to which insoluble elements, such as copper, are added to promote massive nucleation, and to which stable, refractory alloying materials, such as niobium or tantalum carbide are added to inhibit grain growth. Most of the volume of nanocrystalline alloys is composed of randomly distributed crystallites having dimensions of about 2-40 nm. These crystallites are nucleated and grown from an amorphous phase, with insoluble elements being rejected during the process of crystallite growth. In magnetic terms, each crystallite is a single-domain particle. The remaining volume of nanocrystalline alloys is made up of an amorphous phase in the form of grain boundaries having a thickness of about 1 nm.
Magnetic materials having particularly useful properties are formed from an amorphous Coxe2x80x94Nbxe2x80x94B (cobalt-niobium-boron) alloy having near-zero magnetostriction and relatively strong magnetization, as well as good mechanical strength and corrosion resistance. A process of annealing this material can be varied to change the size of crystallites formed in the material, with a resulting strong effect on DC coercivity. The precipitation of nanocrystallites also enhances AC performance of the otherwise amorphous alloys.
Other magnetic materials are formed using iron-rich amorphous and nanocrystalline alloys, which generally show larger magnetization that the alloys based on cobalt. Such materials are, for example, Fexe2x80x94Bxe2x80x94Sixe2x80x94Nbxe2x80x94Cu (iron-boron-silicon-niobium-copper) alloys. While the permeability of iron-rich amorphous alloys is limited by their relatively large levels of magnetostriction, the formation of a nanocrystalline material from such an amorphous alloy dramatically reduces this level of magnetostriction, favoring easy magnetization.
Advances have also been made in the development of materials for permanent magnets, particularly in the development of materials including rare earth elements. Such materials include samarium cobalt, SmCo5, which is used to form a permanent magnet material having the highest resistance to demagnetization of any known material. Other magnetic materials are made, for example, using combinations of iron, neodymium, and boron.
It is a first objective of the present invention to provide a magnetic generator which a need for an external power source during operation of the generator is eliminated.
It is a second objective of the present invention to provide a magnetic generator in which a magnetic flux path is changed without a need to overpower a magnetic field to change its direction.
It is a third objective of the present invention to provide a magnetic generator in which the generation of electricity is accomplished without moving parts.
In the apparatus of the present invention, the path of the magnetic flux from a permanent magnet is switched in a manner not requiring the overpowering of the magnetic fields. Furthermore, a process of self-initiated iterative switching is used to switch the magnetic flux from the permanent magnet between alternate magnetic paths within the apparatus, with the power to operate the iterative switching being provided through a control circuit consisting of components known to use low levels of power. With self-switching, a need for an external power source during operation of the generator is eliminated, with a separate power source, such as a battery, being used only for a very short time during start-up of the generator.
According to a first aspect of the present invention, an electromagnetic generator is provided, including a permanent magnet, a magnetic core, first and second input coils, first and second output coils, and a switching circuit. The permanent magnet has magnetic poles at opposite ends. The magnetic core includes a first magnetic path, around which the first input and output coils extend, and a second magnetic path, around which the second input and output coils extend, between opposite ends of the permanent magnet. The switching circuit drives electrical current alternately through the first and second input coils. The electrical current driven through the first input oil causes the first input coil to produce a magnetic field opposing a concentration of magnetic flux from the permanent magnet within the first magnetic path. The electrical current driven through the second input coil causes the second input coil to produce a magnetic field opposing a concentration of magnetic flux from the permanent magnet within the second magnetic path.
According to another aspect of the present invention, an electromagnetic generator is provided, including a magnetic core, a plurality of permanent magnets, first and second pluralities of input coils, a plurality of output coils, and a switching circuit. The magnetic core includes a pair of spaced-apart plates, each of which has a central aperture, and first and second pluralities of posts extending between the spaced-apart plates. The permanent magnets each extend between the pair of spaced apart plates. Each permanent magnet has magnetic poles at opposite ends, with the magnetic fields of all the permanent magnets being aligned to extend in a common direction. Each input coil extends around a portion of a plate within the spaced-apart plates, between a post and a permanent magnet. An output coil extends around each post. The switching circuit drives electrical current alternately through the first and second pluralities of input coils. Electrical current driven through each input coil in the first plurality of input coils causes an increase in magnetic flux within each post within the first plurality of posts from permanent magnets on each side of the post and a decrease in magnetic flux within each post within the second plurality of posts from permanent magnets on each side of the post. Electrical current driven through each input coil in the second plurality of input coils causes a decrease in magnetic flux within each post within the first plurality of posts from permanent magnets on each side of the post and an increase in magnetic flux within each post within the second plurality of posts from permanent magnets on each side of the post.